1 Introduction

Musculoskeletal (MSK) complaints in children are common. However, not all MSK complaints are due to rheumatic diseases. Etiologies range from benign conditions to serious conditions requiring prompt attention. Therefore, a complete history and physical examination, in addition to essential investigations and imaging, is essential to distinguish rheumatic conditions from other diseases (Fig. 24.1). Most of the differential diagnoses have been covered in other chapters; however, besides trauma and infectious causes including septic arthritis and reactive arthritis, some common causes of non-rheumatic joint pain in children include the following:

Fig. 24.1
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Differential diagnosis of juvenile arthritis

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Toxic synovitis of the hips is a common self-limited form of reactive arthritis usually occurs after an upper respiratory tract infection commonly affecting boys younger than 8 years. The child presents with painless limp or complains of pain in the groin, anterior thigh, or knee (referred pain). Unlike patients with septic arthritis, the child appears well, while the affected limb is held in a position of external rotation and flexion. Investigations are normal or show mild increases in inflammatory markers. Management is supportive with rest and analgesia.

Growing pain is benign short-lived vague pain limited to calf, thigh, and shin commonly affecting children between the ages of 3 to 10 years. Pain is severe in intensity, often occurs late in the day, or awakens the child at night. The child is otherwise well and asymptomatic during the day, having no functional limitations. The pain is intermittent in nature, with symptom-free intervals lasting days to months. There is often a family history of growing pains. Importantly, the physical examination, laboratory data, and radiological investigations are normal. Management consists of reassurance and supportive analgesia.

Childhood malignancies, such as leukemia, lymphoma, and neuroblastoma, may present with daytime and nighttime joint pain. Clinical characteristics include severe pain that is out of proportion to clinical findings, lack of morning stiffness, and the ability to localize the pain to the bone on palpation. Patient may have constitutional symptoms including fever, weight loss, and night sweats. Similarly, the presence of thrombocytopenia and high LDH may indicate the presence of malignancy.

Slipped capital femoral epiphysis (SCFE) is a condition in which the femoral head is displaced from femoral neck. It commonly affects overweight boys between the ages of 10 and 14 years or children with endocrine problems such as hypothyroidism or growth hormone deficiency. The complaint of hip pain may be acute or insidious and can frequently present with knee pain. Examination reveals a flexed and externally rotated hip with painful and limited passive internal rotation. Diagnosis is radiological and patients should be placed on non-weight-bearing crutches until an urgent orthopedic consultation for a surgical intervention is made.

Legg Calve Perthes disease is self-limiting avascular necrosis of the femoral capital epiphysis commonly affecting boys from 4 to 10 years. Children present with painful limp and limited range of motion of the hip joint. Initial radiographs may be normal; therefore, MRI is more sensitive in detecting early disease. Patients should be kept non-weight-bearing until an urgent orthopedic referral. Treatment is aimed at maintaining the femoral head within the acetabulum, which can be achieved conservatively with abduction splints or casts or surgically with an osteotomy of the proximal femur.

2 Learning Objectives

By the end of this chapter, you should be able to:

  • List common causes of non-rheumatic joint pain in children.

  • Recognize some of the similarities and differences between childhood and adult onset rheumatic diseases.

  • Distinguish the characteristic clinical features of juvenile idiopathic arthritis subtypes.

  • Explore the classification criteria of pediatric vasculitis with emphasis on the clinical presentation and management of Kawasaki disease.

  • Discuss the spectrum of autoinflammatory syndromes.

3 Pediatric Rheumatic Diseases

Children are not little adults. By acknowledging the similarities and difference between adult and childhood types of rheumatic diseases, it will be easier to identify those features that are characteristic of or specific to children. Many pediatric rheumatic diseases have different disease phenotypes, outcome measures, investigations, and treatment that are distinct from adult rheumatic diseases. The next sections will highlight the clinical features that are specific to pediatric rheumatic diseases.

4 Childhood Onset SLE

The diagnosis and treatment of childhood onset SLE (cSLE) is similar in many aspects to adult SLE (aSLE). However, differences in disease demographics, clinical presentation, disease course, and outcome exist between cSLE and aSLE.

Onset of SLE during childhood period occurs in 10–20% of all SLE cases. There is less female prediction in cSLE as the female to male ratio with pediatric SLE changes from 4:3 with disease onset during the first decade of life to 4:1 during the second decade to 9:1 in aSLE [1]. cSLE often presents with more acute and severe disease manifestation at the time of diagnosis with a higher frequency of renal, neurological, and hematological involvement, while cutaneous and musculoskeletal features are more common at disease onset in aSLE [2]. SLE Disease Activity Index (SLEDAI), at diagnosis and over disease course, tends to be much higher in cSLE [3]. Comparative studies support that cSLE is more often treated with high doses of corticosteroids and immunosuppressive medications than aSLE [4]. Despite improved survival rates in SLE patients, there remains substantial morbidity due to disease damage. cSLE is associated with more rapid accrual of damage than is SLE in adults, and it involves mostly ocular, renal, and musculoskeletal damages [4].

5 Juvenile Dermatomyositis

Adult and juvenile onset dermatomyositis share the hallmark clinical presentation of pathognomic skin rash and muscle weakness described in Chap. 8; however, each has distinct demographics, clinical features, and associated outcomes [5].

JDM is rare, with incidence of 2–4 per million children [6]. The mean age of onset of JDM is 7 years with 25% of patients presenting younger than 4 years of age [7]. The rash of JDM can be atypical, occurring anywhere in the body, and is more frequently associated with ulcerative change than in adults. Anti-p155/140 autoantibody is the most prevalent myositis specific antibody found in 30% of patients with JDM and is associated with cutaneous rash with skin ulceration, generalized lipodystrophy, low creatinine kinase levels, and a chronic course of disease [8].

The clinical course in JDM is monophasic (40–60%), chronic (40–60%), and polyphasic (>5%).

Predictors of chronic course include delay in treatment, higher skin disease activity at baselines, ongoing Gottron’s papules and periungual nail fold capillary changes beyond 3 months of treatment [9]. In addition, the presence of subcutaneous edema on MRI at diagnosis and extensive myopathic and severe arteropathic changes on the initial muscle biopsy are predictors of a chronic illness course [9]. Approximately 20–47% of patients with JDM develop calcinosis at presentation or after many years of illness [10]. JDM has not been clearly associated with the development of malignancy which is a significant cause of mortality in adults with DM.

Treatment of JDM consists of combination of corticosteroids (2 mg/kg) with slow taper and methotrexate 15 mg/m2 s/c. Other treatment modalities include cyclophosphamide for interstitial lung disease or vasculitis. IVIG, cyclosporine, mycophenolate mofetil, and rituximab are used in refractory cases.

6 Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is comprised of a heterogeneous group of several disease subtypes that are characterized by the onset of arthritis prior to the age of 16 years with symptoms that persist for more than 6 weeks after exclusion of other causes of juvenile arthritis Fig. 24.1. Arthritis is diagnosed in the presence of joint effusion or two or more of the following: limited range of movement, joint line tenderness, or painful range of movement and warmth. The current classification system by the International League of Associations for Rheumatology (ILAR) recognizes seven distinct subtypes of JIA, based on their presentation within the first 6 months [11]. The categories of JIA and their diagnostic criteria are defined in Fig. 24.2. There is evident heterogeneity with respect to demographic, genetic, and clinical features among the JIA subtypes, translating into heterogeneity in the responses to treatment.

Fig. 24.2
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International League of Associations for Rheumatology (ILAR) classification of JIA

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Oligoarticular JIA is the most common subtype with relative frequency of 30–60% in Caucasian population with peak age at 1–3 years [11]. It is divided into two further subsets: persistent, if arthritis remains confined to four or fewer joints during the whole disease course, and extended, if arthritis spreads to more than four joints after the initial 6 months of illness. The arthritis affects medium to large size joints with the knee being most common joint affected followed by ankle and wrist. Both wrist and ankle arthritis in addition to elevated inflammatory markers (ESR) at disease onset have been recognized as predictors of an extended course [12]. The classic disease phenotype includes asymmetric arthritis, early disease onset, female predilection, high frequency of positive ANA, and high risk of uveitis [13]. Positive ANA represents a high-risk factor for development of chronic uveitis which occurs in 20–30% of oligoarticular JIA [14]. Chronic uveitis can be asymptomatic until the point of visual loss, making it crucial to undergo regular ophthalmologic screening (Fig. 24.3) [15].

Fig. 24.3
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Modified recommended guidelines for ophthalmologic screening in JIA

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Polyarticular JIA, subdivided into rheumatoid factor positive and rheumatoid factor negative, accounts for 10–30% of JIA cases occurring most commonly in young girls with an early peak between ages 1–4 years and a later peak of 6–12 years [11]. It is likely that the older group with rheumatoid factor positivity represents disease that is similar to adult rheumatoid arthritis. The arthritis tends to be symmetrical and involves large and small joints [16]. In contrast to oligoarticular JIA, systemic manifestation including low grade fever, anorexia, malaise, and growth failure can be present [16]. Chronic asymptomatic uveitis develops less frequently and is more common in RF negative polyarticular JIA [11]. Children with RF positive polyarthritis can develop similar complication to adult disease including rheumatoid nodules, Felty syndrome, rheumatoid vasculitis, and pulmonary disease in rare cases [17].

Systemic onset JIA accounts for 10% of cases of JIA with a broad peak of onset between 1 and 5 years, and it also occurs in adolescence and adulthood [ 11]. Children of both sexes are equally affected. [18] The systemic symptoms of fever, fatigue, and anemia may overshadow or proceed the arthritis by 6 weeks to 6 months. The arthritis is typically symmetrical and polyarticular and can be extensive and resistant to treatment. The systemic manifestation include fever spikes >38.5 °C occurring once or twice daily, which return to baseline or below temperatures. This inflammation is accompanied by a salmon colored evanescent macular rash accompanying fever spikes. Extra-articular manifestation include serositis, hepatosplenomegaly, and lymphadenopathy. An infectious workup and a bone marrow aspirate are strongly considered before starting treatment. Systemic JIA is associated with macrophage activation syndrome (MAS), a potentially life-threatening complication which can manifest as a change in the fever pattern from intermittent to continuous and improvement in arthritis [19]. A recent classification criteria for MAS has been proposed [20] (Fig. 24.4).

Fig. 24.4
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New Classification Criteria for Diagnosis of Macrophage Activation Syndrome

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Psoriatic JIA (PsA) affects 5% of patients with JIA and has a bimodal age of distribution in preschool years and in late childhood [11]. Psoriasis often begins after the onset of arthritis in children and may not be evident [ 21]. The pattern of joint inflammation is clinically diverse [22, 23]. Disease at younger age of onset tends to have asymmetric involvement of large and small joints of hand and feet, which differentiates it from oligoarticular JIA [14]. Dactylitis, a clinical hallmark of the disease is also a common manifestation of younger children. Children with older age of onset, who are often HLA B27 positive, tend to develop enthesitis, spinal, and sacroiliac disease [22, 23]. Asymptomatic chronic anterior uveitis occurs in 15–20% of children with PsA and is associated with the presence of ANA [ 25]. Acute symptomatic anterior uveitis observed in adult patients, is rare in children [25].

Enthesitis-related arthritis (ERA) affects <5% of patients with JIA, characterized by the presence of arthritis and enthesitis, typically occurs in boys older than 6 years of age with positive HLA B27 [11]. In contrast to adult ankylosing spondylitis at presentation, axial involvement is not common, while sacroiliitis can be silent [26]. However, axial disease with symptomatic sacroiliitis becomes common within 5 years of diagnosis [27, 28]. Peripheral arthritis of the lower limbs and predominantly the hips is commonly seen [29]. The hallmark of ERA is enthesitis, with resultant pain and swelling at entheseal sites. Other distinguishing manifestation is tarsitis. Symptomatic anterior uveitis may develop in children with ERA, and this usually presents with significant eye pain and redness, which may be unilateral [20]. Although cardiopulmonary involvement is uncommon, aortic insufficiency has been reported.

Undifferentiated arthritis does not represent a distinct subset but includes patients who do not meet the criteria for any category or who meet the criteria for more than one subtype of JIA [30].

Laboratory and Imaging Studies: Most children with JIA have no laboratory abnormalities. Preliminary investigations should be aimed at excluding differential diagnosis (Fig. 24.5). Children with systemic JIA and polyarticular JIA commonly show evidence of inflammation with elevated inflammatory markers and anemia of chronic disease. A complete blood count and peripheral should be performed to exclude leukemia which can present as low WBC and platelet count. ANA should be performed to identify patients at higher risk for developing uveitis, while RF should be performed in polyarticular JIA to identify patients with worse prognosis.

Fig. 24.5
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Preliminary investigation to be considered for evaluation of Juvenile Idiopathic Arthritis

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Plain radiographs have limited ability to identify early erosive changes and have poor sensitivity to identify active synovitis. Ultrasound is well suited to assess synovitis, capture erosions, and guide local injections. MRI is able to identify early changes and most sensitive indicator of joint inflammation.

Treatment: The main stay of treatment of JIA aims at controlling inflammation, maintaining function, and preventing joint damage and blindness. This can be achieved through a multidisciplinary team comprising a pediatric rheumatologist, ophthalmologist, orthopedic surgeon, specialist nurse, physical therapist, occupational therapist, and psychologist. ACR treatment recommendations for JIA categories are outlined (Figs. 24.6 and 24.7).

Fig. 24.6
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Adopted from 2011 and 2019 American College of Rheumatology Recommendations for Treatment of Oligoarticular JIA (A) and Polyarticular JIA (B). CRP: C reactive protein; ESR: erytherocyte sedimentation rate; GADA: global assessement of overall disease activity; GAWB: global assessement of overall well-being; IATH: intra-articular trimcinolone hexacetonide

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Fig. 24.7
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Management of systemic juvenile idiopathic arthritis

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First-line therapy in JIA consists of nonsteroidal anti-inflammatory drugs (NSAIDs). Only a few NSAIDs are approved for use in children: the most common are naproxen (15–20 mg/kg), ibuprofen (30–50 mg/kg), and indomethacin (1–4 mg/kg). There is limited data on the safety and efficacy of Cox 2 inhibitors [31]. Intra-articular corticosteroids (IAC) may also be used as first line in the treatment of Oligoarticular JIA [32]. Triamcinolone hexacetonide (TH) is the drug of choice for IAC. Due to its lower solubility, it has longer lasting duration of action than other preparations [33]. The dose of TH administered is1mg/kg (max 40 mg) for the knee joint or half of this dose for ankle and wrist [24]. The role of systemic corticosteroids is limited to the extra-articular manifestations of systemic arthritis and as a bridging therapy in severe polyarthritis awaiting the therapeutic effects of second-line agents or biologics.

Second-line therapy includes conventional disease modifying antirheumatic drugs (DMARDs). Methotrexate remains the most widely used at a dose of 10–15 mg/m2 per week either orally or subcutaneously. There is increased bioavailability of the drug in the subcutaneous route at higher doses, and increased efficacy after switching from oral to subcutaneous administration has been reported [34, 35]. Methotrexate should be continued for at least 6–12 months after achieving disease remission. No difference in the relapse rate was found between patients who were discontinued from methotrexate at 12 months vs. 6 months of disease remission [36]. Experience with leflunomide in JIA is limited but is an alternative option in case of intolerance [37].

Biologic DMARDs are shown to be highly safe and effective in the treatment of JIA as demonstrated in various randomized controlled studies with anti-TNF inhibitors (etanercept, adalimumab, infliximab), anti-CLA4 (abatacept), anti-IL1 (anakinra), and anti-IL-6 (tocilizumab) [38,39,40,41,42]. Stepwise treatment algorithms have been proposed by the ACR for treatment of oligoarticular JIA, polyarticular JIA, and systemic onset JIA. However, there is recent evidence to demonstrate the benefits of early aggressive therapy with both conventional and biologic DMARDs in treatment of JIA such as TREAT, STOP JIA, and BeST for Kids studies [43,44,45].

7 Childhood Vasculitis

Childhood vasculitis is often a challenging and complex as the diagnosis can be primary or secondary to infections, drugs, and other rheumatic diseases. If vasculitis is suspected, then the approach to history, physical examination, workup, and classification is similar to the approach used in adult vasculitis.

The EULAR/Pediatric Rheumatology European Society (PReS) consensus criteria for childhood onset vasculitis are listed in (Table 24.1) [46]. Of the primary vasculitides, Henoch Schönlein purpura (HSP) and Kawasaki disease (KD) are the most common, while the other vasculitides are observed rarely in childhood [46]. As other types of vasculitides have been previously described in Chap. 19, this section will focus on KD which is of particular interest to pediatric age group.

Table 24.1 EULAR/PRES Consensus Criteria for Childhood Vasculitis
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8 Kawasaki Disease

Kawasaki disease is an acute, self-limiting systemic vasculitis predominantly affecting the coronary arteries, causing coronary artery aneurysms (CAA) in 15–25% of untreated patients [47]. The disease has a diverse distribution worldwide with an ethnic bias toward Asians.

KD predominantly affects children younger than 5 years of age with peak age incidence at 2 years. Patients at extreme end of ages, younger than 3 months, or older than 5 years are affected less often but are at increased risk for CAA formation. Pathogenesis of KD is thought to be due to genetic factors and infectious triggers due to disease characteristics which include winter and spring seasonal variation, community outbreaks, increased risk in siblings, and higher risk in Asians even if they migrate to western countries [48, 49].

KD presents in children as unexplained fever for ≥5 days with the additional four out of the five characteristic clinical features described in Fig. 24.8. The diagnosis of incomplete KD can be made in children in presence of two to three of the principal clinical features, commonly occurring in young children. The evaluation algorithm of incomplete KD requires the presence of supportive laboratory evidence and echo cardiac findings (Fig. 24.9) [50]. The supplementary supporting laboratory criteria include three of the following: hypoalbuminemia <30 mg/dl, anemia for age, elevation of alanine aminotransferase, thrombocytosis after 7 days, leukocytosis >15,000/mm3, and sterile pyuria ≥10 WBC/HPF. Diagnostic challenge often arises given the significant overlap in clinical feature with other pediatric illnesses in (Fig. 24.10). Treatment of KD as per the American Heart Association (AHA) treatment guidelines includes intravenous immune globulin (IVIG) 2gm/kg as single infusion and aspirin (30–50 mg/kg) [50]. Aspirin is then continued until resolution of fever by 48–72 hours before switching to low dose ASA (5 mg/kg) for 6 weeks and until inflammatory parameters normalize. However, approximately 20% of patients with KD fail to respond to initial treatment with IVIG. [50,51,52] The RAISE study has demonstrated that treatment of selected high-risk KD patients with IVIG/aspirin was associated with the development of CAA in 23% [53]. The Kobayashi scoring system has been developed in Japan to predict IVIG resistance and to identify children at highest risk of developing CAA (Table 24.2) [54]. Treatment of severe high-risk KD patients with IVIG/aspirin and corticosteroids in the primary therapy has significantly reduced the development of CA [ 53, 55]. The United Kingdom has developed recent guidelines for the treatment of KD including patients with high-risk features (Fig. 24.11) suggesting a role for anti-TNF- α if systemic inflammation persists despite IVIG, aspirin, and corticosteroids. [56] Live vaccines should be delayed for at least 3 months following treatment with IVIG, mainly due potential lack of effectiveness and potential detrimental immune activation [7].

Fig. 24.8
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Diagnostic Criteria for Kawasaki Disease

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Fig. 24.9
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American Heart Association Guidelines for Treatment of KD

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Fig. 24.10
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Differential diagnosis of KD:

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Table 24.2 Kobayashi Scoring System for Predicting IVIG Resistance
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Fig. 24.11
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Recommended clinical guideline for the management of Kawasaki disease in the UK

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9 Autoinflammatory Syndromes

Autoinflammatory syndromes (AIS) are a growing cluster of heterogeneous disorders, characterized by recurrent attacks of unprovoked self-limited fever and systemic inflammation involving different sites such as skin, joints, gastrointestinal, or central nervous system. AA amyloidosis is the most serious long-term complication. AIS is secondary to abnormal activation of the innate immune system leading to overproduction of pro-inflammatory cytokines, such as interleukin (IL)-1𝛽, and tumor necrosis factor (TNF)-𝛼, which leads to pathological delay of inactivation of inflammatory response [57]. The spectrum of monogenic AIS, share overlapping wide range of clinical features as described in (Fig. 24.12) [58].

Fig. 24.12
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Spectrum of autoinflammatory disease syndromes. AD: autosomal dominant, AR: autosomal recessive, BLAUs: Blau syndrome, CANDLEs: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature, CINCAs: chronic infantile neurologic cutenous articular syndrome. CRMO chronic recurrent multifocal osteomyelitis, DIRA: deficiency of interleukin-1-receptor antagonist, DITRA: deficiency of IL-36 receptor antagonist, FCAS: familial cold auto-inflammatory syndrome; FMF: familial Mediterranean fever, MAJEEDs: Majeed syndrome, MKD: mevalonate kinase deficiency syndrome, MWS: Muckle-Wells syndrome, MLRP12-AD: NLRP12 associated auto-inflammatory disease, NNS: Nakojo-Nishimura syndrome, NSAIDs: non-steroidal anti-inflammatory drugs, PAPA: pyogenic arthritis, poderma gangrenosum and acne syndrome, PHID: pigmentary hypertrichosis and non-autoimmune insulin dependent diabetes mellitus syndrome, TRAPS: tumor necrosis factor receptor associated periodic syndrome

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These syndromes should be suspected in patients, especially young children, typically with recurrent fever and/or with episodic multisystem inflammation, in the absence of infection. However, some occasionally AIS manifest as inflammation without fever and the inflammation can be persistent rather than episodic. The interval between attacks is variable, and the child remains completely well between febrile episodes. During attacks, laboratory tests are characterized by leukocytosis and elevation of acute phase reactants that normalize in the periods between fever episodes. A family history of these syndromes is often but not always obtained, including a history of unexplained deafness, renal failure, or amyloidosis. Initial workup for patients with AIS should be focused on ruling out serious conditions such as infection, malignancies, or immunodeficiency disorders. However, repeated attacks typically four to six attacks over an observation period of 9–12 months would require further genetic testing for AIS. Diagnosis of AIS can be challenging due to overlapping clinical features; however, AIS can be differentiated by age of onset, ethnicity, attack triggers, duration of attacks, disease-free intervals between attacks, clinical manifestations, and the response to therapy as described in (Table 24.3) [59, 60].

Table 24.3 Clues that help differentiate auto inflammatory syndromes
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