Systemic onset JIA (SOJIA) is defined by the presence of arthritis in at least one joint with or preceded by quotidian fever of at least 2 weeks duration. The arthritis is often polyarticular affecting both large and small joints [23, 24]. It is accompanied by one or more of the following: evanescent rash, lymphadenopathy , hepatomegaly or splenomegaly , or serositis . SOJIA occurs in 5–15 % of children with JIA. Males and females are equally affected with no predominant age of onset. Laboratory findings include leukocytosis , thrombocytosis , anemia, increased transaminases, and markedly increased ferritin , erythrocyte sedimentation rate (ESR) , and C-reactive protein (CRP) ; however, macrophage activation syndrome is a complication of SOJIA which presents similarly to secondary hemophagocytic lymphohistiocytosis with extremely elevated ferritin, hypoalbuminemia, elevated PT, PTT, low fibrinogen, and cytopenias (especially thrombocytopenia) [23, 25]. ESR may be low or normal due to disseminated intravascular coagulation. This complication must be recognized promptly, and treatment should be initiated as quickly as possible.

The course of systemic onset JIA is variable with a mean duration of activity of 6 years [26]. Up to 40 % of children with this subtype will experience a monophasic course with complete remission; however recent studies have shown over half of these children have chronic disease [23].

Oligoarthritis affects 1–4 joints during the first 6 months of the disease [1, 7, 10]. This is the most common subtype accounting for 50–88 % of children with JIA [23]. It is more common in females with onset usually before the age of 6 years. The ILAR classification divides this group of children into two categories; persistent oligoarthritis and extended oligoarthritis. Children with persistent oligoarthritis have no more than four joints affected during the course of the disease while those with extended oligoarthritis develop arthritis in more than four joints after the first 6 months of the disease.

Oligoarthritis typically affects the lower extremities; especially the knee and ankle [25]. Rheumatoid factor is always negative but antinuclear antibodies (ANA) are present in up to 80 % of children [27]. Overall, the prognosis is good for children with oligoarthritis. However, up to 50 % progress to extended oligoarthritis [27]. Risk factors for development of extended oligoarthritis include upper extremity arthritis, positive ANA, and elevated ESR [23, 28–30].

Rheumatoid factor negative polyarthritis is defined as arthritis that affects five or more joints during the first 6 months of the disease with a negative RF. This subtype affects 20–30 % of children and is more common in females [7, 23]. This category is the most heterogeneous subtype of JIA and may include two subsets of disease. The first subset includes children less than 6 years old, primarily female, with asymmetric arthritis, and positive ANA. These children have an increased risk for development of uveitis [31]. The second subset includes children 7–9 years old with symmetric arthritis affecting large and small joints and a negative ANA [25, 32, 33].

Children with RF negative polyarthritis typically have mild anemia as well as an elevated ESR and CRP. Up to 40 % have positive ANA. These children have a variable clinical course which is likely dependent upon the subset of the disease. Even so, approximately one-third experience a long-term remission [34].

This subtype includes children with arthritis affecting five or more joints during the first 6 months of the disease with two positive tests for RF separated by at least 3 months. This category accounts for 5–10 % of children with JIA [7, 23]. RF positive polyarthritis is more common in adolescent females.

Symmetric polyarthritis of multiple joints especially the small joints of the hands, wrist, and feet are characteristic. Rheumatoid nodules may also occur along the forearm and elbow. Low grade fever is not uncommon at the onset of the disease. Laboratory features include a positive RF, positive anti-cyclic citrullinated peptide (anti-CCP), elevated ESR and CRP, as well as mild anemia.

Rheumatoid factor positive polyarthritis is likely an early form of adult rheumatoid arthritis since the two diseases share several human leukocyte antigen (HLA) associations as well as serologic markers [23]. This group of children has a poor long-term prognosis characterized by severe erosive disease [35–37].

Juvenile psoriatic arthritis (JPA) includes children with arthritis and psoriasis or arthritis with any two of the following: psoriasis in a first-degree relative, dactylitis (inflammation of an entire digit due to synovitis and tenosynovitis ), and nail pitting or onycholysis (separation of the nail from the nail bed). JPA accounts for 2–15 % of children with JIA. The onset has a bimodal distribution with one peak at toddler age, similar to oligoarticular JIA, and another peak during the pre-teen to teenage years [21, 23, 38]. There is a slight female preponderance with onset typically between the ages of 7–10 years old.

The arthritis of JPA is asymmetric involving both the large and small joints. The knee and ankle as well as small joints of the hand and foot are most commonly affected [39]. Up to 20 % of children develop uveitis which may be more resistant to therapy compared to oligoarthritis associated uveitis [27, 31, 40–43]. Laboratory features include mild anemia as well as an elevated ESR and CRP. Up to one-half of children will have a positive ANA test.

The long-term outcome of these children is less clear than the other subtypes of JIA. Previous studies using a different classification system indicated that many children have chronic active disease [44].

Enthesitis-related arthritis (ERA) is defined by the presence of arthritis or enthesitis (inflammation at the insertion of a ligament, tendon, fascia, or joint capsule to bone or cartilage) with at least two of the following: history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain, positive HLA-B27, arthritis onset after 6 years old in a male, acute symptomatic uveitis, history of an HLA-B27 related disease (ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease (IBD), Reiter’s syndrome, or acute anterior uveitis) in a first-degree relative. This subtype occurs in up to 1–7 % of children with JIA and is more common in boys older than 8 years [23, 45]. Genetic factors such as HLA-B27 may predispose to the development of ERA [2].

The arthritis of ERA usually affects the peripheral joints before axial involvement occurs. The peripheral arthritis typically presents with asymmetric lower extremity oligoarthritis [27]. Axial involvement typically follows but may take years to manifest. Axial disease typically begins in the hip joint, progresses to the sacroiliac joint and then up the spine. Most patients will eventually develop sacroiliitis and lumbosacral spine disease [46].

Children with ERA may have mild as well as a variably elevated ESR. Up to 90 % of patients will have positive HLA-B27. Long-term outcomes tend to be worse than those children with polyarticular or oligoarticular JIA [47].

This subtype is defined as children who do not fulfill the inclusion criteria of any category or are excluded because of filling criteria in two or more categories of JIA. This group accounts for 2–23 % of children with JIA [7].

Systemic lupus erythematosus (SLE) is an uncommon disease in childhood. It is a chronic relapsing, remitting multisystem autoimmune disease characterized by wide range of manifestations. End organ damage results from autoantibody binding to tissues as well as immune complex deposition. The most widely used classification criteria for the diagnosis of SLE was established by The American College of Rheumatology in 1982 and revised in 1997 (Table 20.6) [141, 142]. Recently the Systemic Lupus International Collaborating Clinics (SLICC) group proposed revised criteria to include newer immunologic criteria (Table 20.7) [143]. Using this classification, at least four criteria must be satisfied to establish the diagnosis of SLE. Of these four criteria, at least one must be clinical and one immunologic, or the patient must have biopsy proven nephritis, or anti double-stranded DNA antibodies.

Childhood SLE tends to be more aggressive and has poorer outcomes compared to adults with the disease [144–146]. Numerous studies have demonstrated that renal, neurologic, and hematologic manifestations are more common among children at presentation [145–149]. As a consequence, children and adolescents frequently require higher doses of corticosteroids to control the disease manifestations [150, 151].

Although it has been known by various names since the time of Hippocrates, SLE was not described in great detail until the nineteenth and twentieth centuries [144]. With the discovery of the lupus erythematosus (LE) cell phenomenon by Hargraves and coworkers in 1948, it became possible to diagnose SLE more precisely [152]. Retinopathy in SLE was first reported by Bergmeister in 1929 [153]. The incidence of retinopathy in patients with end-stage disease was 50 % prior to the widespread use of corticosteroids, however this has markedly decreased in more recent times [154].

Approximately 10–20 % of patients with SLE develop the disease during childhood and adolescence [146, 155–158]. The incidence ranges from 0.3 to 0.9 per 100,000 children-years while prevalence rates of 3.3–8.8 per 100,000 have been reported [159]. The median age at diagnosis is 11–12 years but most children are diagnosed during adolescence. Onset prior to 8 years old is less common occurring in only about 20 % of children [159–161]. Similar to adults, the disease is more common in females with a female:male ratio of 4–5:1 [160, 162–164]. Childhood SLE is more common among certain ethnic groups including Native Americans, African Americans, Hispanics and Asians [165, 166]. The disease tends to be more severe among African Americans and Hispanics [167].

Systemic lupus erythematosus can affect any organ system in children. Renal and central nervous system involvement are more common in children and can lead to significant morbidity [143]. Children with SLE often present with nonspecific constitutional symptoms including fatigue, weight loss, fever, arthralgias, and alopecia. Common presenting signs among adolescents are rash, mucositis, fever, and arthritis [167]. Cutaneous lesions are present in up to 80 % of children at initial diagnosis. The characteristic malar rash as well as a maculopapular rash, photosensitive lesions, vasculitic lesions, palmar erythema, and Raynaud phenomenon are common [168]. Classic discoid lupus is uncommon in children compared with adults [160]. Mucosal ulcers involving the hard palate, tongue and the nasal septum are painless and therefore may not be detected during examination. Arthritis with minimal pain occurs in up to 80 % of children [168]. Similar to the arthritis of JIA, both small and large joints are affected but does not result in bone destruction or deformity in most children. Arthralgias are also common in children with SLE. Renal involvement is a leading cause of morbidity and mortality affecting up to 75 % of children [160]. Up to 20 % of affected children develop end stage renal disease within 10 years of onset [169, 170]. Neuropsychiatric involvement occurs in up to 65 % of patients [171]. Headache is the most common manifestation in up to 95 % of children [172]. Psychosis and seizures are also relatively common among children with SLE [173, 174]. Cranial and peripheral neuropathies are less common than central nervous system (CNS) manifestations. Gastrointestinal involvement is common with abdominal pain a frequent complaint [168]. Pericarditis and or pleuritis affects up to one-half all children with SLE [156, 160]. Vascular abnormalities have also been reported including cutaneous vasculitis, retinal vasculitis, and small vessel CNS vasculitis [168].

The ophthalmic manifestations of SLE in adults have been documented in numerous reviews [175–182]. There are few reviews or large series describing the ocular findings among children with SLE [144, 183].

Keratoconjunctivitis sicca is the one of the most common ocular manifestations in children with SLE [156, 183, 184]. The frequency of KCS ranges between 2–13 %, however the methods used to diagnose KCS in these studies differs which may influence the incidence among the published reports. Episcleritis has also been reported in children with SLE [185, 186]. Anterior uveitis may occur but is uncommon in childhood SLE [144, 183, 187]. Orbital pseudotumor has also been reported as the presenting sign of SLE in a 9 year-old girl [188].

Neuroophthalmic manifestations have been described in children with SLE. Ocular motility disorders include oculomotor palsy , abducens palsy , internuclear ophthalmoplegia , and nystagmus [189–194]. Visual field defects , optic neuropathy , optic neuritis , amaurosis fugax , papilledema , and idiopathic intracranial hypertension have also been described in these patients [189, 190, 195–197]. Scintillating scotoma has been reported as the initial symptom in a child subsequently diagnosed with SLE [198].

Retinopathy (Fig. 20.3) is the most common vision threatening complication in patients with SLE affecting up to 29 % of adults with the disease [178]. Retinopathy has been considered an indicator of systemic disease activity in adults; especially CNS disease [180, 182]. In most patients, the retinopathy resolves when the underlying disease is controlled [181]. Patients with anti-phospholipid antibodies may have a greater risk of severe retinopathy with vascular occlusions [199–201]. It is unclear if these same risk factors are true for children with lupus retinopathy.

The most common manifestation of classic lupus retinopathy is the cotton-wool spot. With fluorescein angiography , these lesions appear as avascular zones [202–204]. Intraretinal hemorrhages, capillary dilation, venous engorgement or tortuosity, focal arteriolar constriction, or extensive arteriolar narrowing may be present [204]. The pathogenesis of these manifestations involves immune complex deposition in the vessel wall with endothelial swelling, vascular constriction and thrombus formation [205]. This form of retinopathy tends to have a good prognosis and severe visual loss is uncommon [175, 182].

A severe vaso-occlusive retinopathy can develop in patients with SLE. Although rare, this form of retinopathy often results in poor visual outcomes [206–208]. Diffuse capillary nonperfusion , retinal arterial and arteriolar occlusion , retinal neovascularization , and vitreous hemorrhage are characteristic of this occlusive retinopathy [207]. Antiphospholipid antibodies and thrombus formation may contribute to the pathogenesis of this retinopathy since there appears to be a strong association between CNS disease, the presence of antiphospholipid antibodies and severe occlusive retinopathy [209].

In a study of 37 children with SLE, retinopathy was described in only one child. In this child, the retinal lesions regressed and disappeared despite systemic disease progression [210]. In a larger cohort of 108 patients with childhood SLE, 7 % had cotton-wool spots that resolved within several weeks while receiving systemic corticosteroids for other manifestations of the disease [144]. In a more recent publication describing 52 children, 10 % of children developed retinopathy. Most of these children had mild retinopathy although one developed severe occlusive vasculitis [183, 184]. A number of case reports have also described various forms of retinopathy including severe occlusive retinopathy, central retinal vein occlusion, bilateral retinal venous occlusion, macular infarction, and retinal vascular occlusion [186, 189, 211–215].

Choroidal disease has been rarely reported in patients with SLE (Fig. 20.4) [216–219]. Manifestations include multifocal serous retinal detachments, choroidal effusion, secondary angle closure glaucoma, choroidal infarction, and choroidal neovascularization. A single case report describes a child with anterior uveitis, vitreous inflammation, and a large serous retinal detachment [220]. It is uncertain if this case represents true lupus choroidopathy since most other reports do not describe simultaneous intraocular inflammation. Central serous retinopathy (CSR) has been reported in two children with SLE [221, 222]. The cause of CSR in these patients is unclear since many have underlying renal disease with hypertension and often are receiving corticosteroid therapy. Most patients with SLE and CSR have good visual outcomes [219].

Antimalarial agents are often used in patients with SLE [223]. They are considered a mainstay of therapy and have been shown to reduce disease activity and improve survival in these patients [224]. In children, hydroxychloroquine and chloroquine are often used as disease maintenance therapy and to treat rash and arthritis [168]. Ocular toxicity of these drugs can occur and some cases result in severe, permanent visual loss [225–230]. Keratopathy is a well-known complication of chloroquine and hydroxychloroquine treatment. Bilateral golden-brown deposits in a whorl-like pattern (vortex keratopathy) are found in the cornea but are not visually significant in most cases [227, 231].

Retinal toxicity is a rare complication of chloroquine and hydroxychloroquine therapy but can result in irreversible visual loss [229, 232]. Recent studies indicate that patient age, daily dose, or patient weight do not influence the risk of retinal toxicity [233]. The risk of toxicity increases with duration of therapy. Incidence rates greater than 1 % have been reported after 5–7 years and 2 % after 10–15 years of therapy [233]. Renal or liver disease may also increase the risk of toxicity due to reduced clearance of the drug [234]. Clinical manifestations of toxicity include central visual loss, impaired color vision, central visual field defects, retinal pigment epithelial abnormalities, and bull’s eye maculopathy [235]. Retinal toxicity is often classified as premaculopathy or true retinopathy [236]. Patients with premaculopathy typically are asymptomatic and may have mild macular pigmentary abnormalities. Those with true retinopathy are often symptomatic and have persistent paracentral or central scotomata. In addition, a bull’s eye maculopathy with or without a scotoma also suggests true retinopathy. In a series of 117 children with SLE, macular changes were found in eight patients who were treated with chloroquine or hydroxychloroquine for 1–5 years [237]. Despite the low risk of toxicity, all patients treated with chloroquine or hydroxychloroquine should undergo ophthalmologic screening to ensure detection of toxicity at the earliest stage of development. A baseline ophthalmologic examination is recommended during the first year of use of the medication followed by annual screening beginning 5 years after starting therapy [234]. Specific screening procedures are outlined in Table 20.8. Tests not recommend for use in screening include fundus photography, color vision, Amsler grid, fluorescein angiography, time-domain optical coherence tomography, full-field electroretinogram , or electrooculogram [234, 238].

Ocular complications of systemic corticosteroids also occur in childhood SLE. Five percent of children treated with systemic corticosteroids for a mean of 45 months developed posterior subcapsular cataract while glaucoma was reported in 3 % of patients receiving corticosteroids for a mean of 21 months [237]. Both of these complications developed in children receiving higher doses of corticosteroids compared to those without cataract or glaucoma.

The diagnosis of SLE in children is based upon clinical manifestations and presence of characteristic autoantibodies. The SLICC revised criteria were developed to improve research studies but can be used to establish the diagnosis in many patients [143, 168]. The presence of multiple autoantibodies is characteristic in patients with SLE. Testing for ANA, anti-ds DNA, anti-Sm, and antiphospholipid antibody should be performed in all children. Serum complement levels may reveal hypocomplementemia in patients with major organ involvement [239]. The direct Coomb’s test should also be performed since it is also one of the SLICC immunologic criteria. Nonspecific acute phase reactants are often elevated with the exception of CRP which is typically normal or minimally elevated during exacerbations of the disease [168]. Urinalysis is used to monitor for proteinuria and hematuria .

A multidisciplinary team approach is typically required for the treatment of SLE in children and adolescents [168]. Individualized therapy is based upon disease severity, organ involvement, and potential side effects of specific medications [240, 241]. Most children with SLE are treated with systemic corticosteroids and many also receive immunosuppressive therapy to control the disease [242, 243].

Oral and intravenous corticosteroids are a mainstay of therapy in children with SLE. They are highly effective in achieving rapid disease control [168]. Oral prednisone and prednisolone , are used most often in doses up to 2.0 mg/kg. Intravenous methylprednisolone is typically used as intermittent pulse therapy in doses of 30 mg/kg (maximum of 1000 mg/dose). Following control of the disease, the dose is decreased over time to the lowest dose tolerated to reduce the risk of side effects [240, 243, 244]. Steroid-sparing agents may be required in cases resistant to tapering or in children who develop intolerable side effects.

Virtually all children are treated with hydroxychloroquine to reduce disease activity and autoantibody production. It is also useful in the management of cutaneous manifestations and to decrease the risk of thrombotic and premature atherosclerosis [171, 243, 245]. Antimalarial therapy has been shown to reduce disease activity, prolong survival, reduce infections, and possibly protect against osteoporosis [224]. Children treated with hydroxychloroquine should undergo ophthalmologic examinations as previously discussed to screen for potential retinal toxicity.

Several immunosuppressive agents are used in childhood SLE. Methotrexate is used in children with persistent arthritis without other systemic manifestations [168]. Azathioprine is useful for the treatment of arthritis, skin disease, serositis, and renal disease [243]. Mycophenolate mofetil is increasingly used to induce remission in lupus nephritis as well as an overall steroid-sparing therapy [168, 243, 246]. Cyclophosphamide is another treatment option for children with the most severe disease manifestations such as resistant nephritis, neuropsychiatric disease, and other life threatening manifestations [243]. The potential for serious side effects including infertility, future malignancy, bone marrow suppression, infection, and hemorrhagic cystitis should be considered before initiating cyclophosphamide therapy . A number of biologic agents that target B cells, T cells, and several cytokines are currently being investigated for the treatment of SLE. Belimumab is a monoclonal antibody that inhibits the B lymphocyte stimulator and has recently received approval for use in adult SLE [247].

There is little information regarding the optimal treatment of KCS in children with SLE. Therefore, a general treatment approach similar to that used in children with JIA seems reasonable. Artificial tears are first-line therapy in these children. Nonpreserved tears are preferable similar to children with JIA. Topical corticosteroids may be considered as adjunctive therapy but the risk of cataract and glaucoma should be considered. Also, topical cyclosporine emulsion may be useful in resistant cases of KCS. In severe cases or in children who develop toxicity to topical agents, punctal occlusion may be useful.

Patients with mild lupus retinopathy typically require no treatment and have good visual outcomes since the retinopathy improves with treatment of the systemic disease [175, 181, 182]. Severe occlusive retinopathy is treated with systemic corticosteroids and immunosuppressive steroid-sparing agents [175, 176, 178, 201]. Panretinal photocoagulation is recommended for patients with retinal neovascularization. Vitrectomy and anti-vascular endothelial growth factor therapy may be also be useful in patients with neovascularization although their use in children has not been described. Despite treatment, over one-half of affected eyes have a final visual acuity of 20/200 or worse [206, 207].

Lupus choroidopathy may resolve with control of the underlying systemic disease [216, 248]. In most cases, treatment with systemic corticosteroids with or without immunosuppressive agents is effective [178, 216]. In patients who develop CSR while receiving corticosteroids, a reduction in dosage has been suggested by some authors [249, 250]. However, corticosteroid therapy should not be withheld in patients with severe systemic disease especially if CSR develops during a systemic exacerbation [251].

There is no effective treatment for chloroquine or hydroxychloroquine retinal toxicity other than stopping the drug. In some patients, visual loss can progress despite cessation of the drug [234, 252]. Signs of possible toxicity include subtle changes in macular pigmentation, visual field sensitivity, or any of the objective screening tests. Any of these early changes should be confirmed with additional testing. In patients with early signs of toxicity, discontinuation of the drug or close monitoring at 3–6 month intervals may be considered [234]. The decision to continue the drug should be made in conjunction with the treating rheumatologist based upon the risk and benefits of continued therapy. Any sign of probable toxicity including bull’s eye maculopathy or parafoveal abnormalities detected with any objective screening test should prompt cessation of the drug. After the drug is stopped, reevaluation should be performed 3 months later and annually until the abnormalities remain stable [234].

Juvenile-onset spondyloarthropathies (JSpA) are a group of inflammatory disorders characterized by enthesitis , arthritis with involvement of the spinal and sacroiliac joints, strong association with HLA-B27 and onset prior to 16 years old [253–255]. While the majority of patients with juvenile arthritis only develop peripheral arthritis, a subset of these patients is at risk of developing axial joint disease which can potentially progress to spondyloarthropathy (SpA) . These patients who share the common characteristics of lower extremity arthritis and enthesitis were previously classified as oligoarticular juvenile rheumatoid arthritis type II or seronegative enthesopathy and arthropathy syndrome [1]. Rosenberg and Petty first described the syndrome of seronegative enthesopathy and arthropathy as distinct group of juvenile arthritis who had a predisposition to developing spondyloarthropathy [256]. Juvenile ankylosing spondylitis (JAS) and reactive arthritis (ReA) represent two of the well-known differentiated juvenile-onset spondyloarthropathies [256–258].

Classification of children with spondyloarthropathies has been difficult with several different systems in use although none are universally accepted [259–261]. The ILAR JIA classification, categorizes children with JSpA into one of three subtypes: ERA, JPA or undifferentiated arthritis [262, 263]. However, the ILAR classification does not specifically address children with JAS and excludes children with ReA[262].

Juvenile ankylosing spondylitis shares a number of features with adult ankylosing spondylitis (AS) but also differs in several characteristics. Similar to adult AS, these children demonstrate radiographic evidence of sacroiliitis and HLA-B27 is often present [264, 265]. Unlike adult AS, classic inflammatory back pain is not a typical presenting feature in JAS. Children tend to have peripheral arthritis and enthesitis as well as worse hip disease compared to adults. Significant delays in the diagnosis are common among children; especially girls with JAS [264]. In addition, children have a higher risk for uveitis [266].

The most commonly used criteria for ReA are from the Berlin Third International Workshop of ReA (Table 20.9) [267]. Most cases are due to enteric or genital infections although a small number may be associated with an upper respiratory tract infection. The organisms responsible for most infections in children include Shigella flexneri , Salmonella spp. , Yersinia enterocolitica , Campylobacter spp. and Chlamydia spp [253]. Infection with Shigella , Salmonella , Yersinia , and Campylobacter presents as a gastroenteritis while Chlamydia presents as a genital infection or less commonly an upper respiratory infection. The pathophysiology of the arthritis is thought to be a localized inflammatory reaction resulting from nonviable bacterial components [268].

Ankylosing spondylitis is a disease of ancient times. Ruffer and Raymond in 1912 described AS in the mummies of ancient Egypt [269, 270]. In 1974, Short described 18 cases of AS extending over 3000 years from 2900 B.C. to 200 A.D. derived from Egyptian sources [271]. Separate descriptions by von Bechterew, Strumpell, and Marie at the end of the nineteenth century promoted the general recognition of AS, and the eponyms, “Marie-Strumpell disease” and “von Bechterew’s disease” bear their names [272].

A major breakthrough in the understanding of AS came in 1973 when two studies reported the association of HLA-B27 with AS [273, 274]. This genetic disease association accounts for the increased prevalence of AS among relatives of patients, and the rarity of AS in non-Caucasian populations, where the frequency of HLA-B27 is low [272]. It also accounts for the high incidence of uveitis in association with AS, since 50 % of all cases of acute anterior uveitis are HLA-B27 positive [273].

Sir Benjamin Brodie described the triad of urethritis , arthritis, and conjunctivitis in five patients in 1818 [275]. Stoll was probably the first to describe the association of arthritis, conjunctivitis, and urethritis with a diarrhea illness in 1776 [276]. In 1916, Reiter also described the triad of arthritis, urethritis, and conjunctivitis following dysentery [277]. The first description of Reiter syndrome in a 16 year-old was reported 2 years later by Junghanns [278]. In 1947, the initial case of a preadolescent with Reiter syndrome was published [279]. In 1947, Harkness reaffirmed that Reiter syndrome may follow both dysenteric and venereal infections [280]. The association of HLA-B27 with Reiter syndrome was subsequently described in 1973 [281]. Although widely used in the past, the term Reiter syndrome is no longer used. With the discovery of Reiter’s Nazi past and complicity with war atrocities, several rheumatology journal editors in 2003 suggested removal of the eponym from the literature and replacing it with the term reactive arthritis [282, 283].

With no universally accepted classification system, reports describing the epidemiology of JSpA vary widely [14, 284]. The estimated incidence of JSpA in the United States is 2.0 per 100,000 children and 1.4-2.1 per 100,000 children in Canada [38, 285, 286]. Using data extrapolated from adults, the prevalence of JSpA is estimated at 11–86 per 100,000 children [287]. Children of any age can be affected but JSpA is more common between 8 and 12 years of age. Boys are more frequently affected than girls, especially in the prepubescent years. However, the number of girls with JSpA increases with age and eventually equals the prevalence among boys [284, 287].

Juvenile ankylosing spondylitis is a differentiated JSpA with onset by 16 years of age [288]. Initial manifestation of JAS typically are asymmetric peripheral oligoarthritis, enthesopathy affecting the lower extremities, and hip and shoulder arthritis [289–291]. Most children eventually develop polyarthritis ; typically after the first year of the disease [292]. Axial symptoms are uncommon early in the disease occurring in less than 15 % of children [284]. Characteristic axial disease with inflammation involving the vertebral joints tends to occur later [284, 289, 292–295]. Axial disease typically begins at the hip joints and progresses gradually to the sacroiliac joints and up the spine. The unique feature in SpA is the process of abnormal new bone formation in the spine that causes ankylosis (or fusion) [296].

Extra-articular manifestations can also occur in JAS. Nonspecific inflammatory bowel disease may affect up to 80 % of children [297–299]. In addition, recurrent anterior uveitis has been reported in up to 27 % of children with JAS [273, 274, 300–302]. Other extra-articular manifestations such as aortic valve insufficiency, cardiac conduction disturbances, amyloidosis, pulmonary, and renal disease are rare in JAS [291, 301–303].

Reactive arthritis is another differentiated form of JSpA typically occurring after an infection with an arthritogenic bacteria. The clinical course and severity of ReA varies widely. Two disease patterns are common; a short self-limited course or a chronic relapsing course. Symptoms of the inciting infection first develop followed a latent period up to 4 weeks before the onset of a mono- or oligoarthritis usually involving the lower extremities [253, 304]. However, the initial infection may be asymptomatic in some children. The first episode of arthritis typically involves the knees or ankles. Dactylitis , which is caused by inflammation of the joints and tendon sheathes in the finger or toe can also be seen. Due to its appearance, dactylitis is commonly described as a “sausage” digit. Recurrent arthritis is common in children with ReA [305]. Constitutional symptoms such as fever, fatigue, weight loss, and muscle weakness may occur during disease exacerbations. Some children eventually progress to ankylosing spondylitis or ERA [306].

Skin manifestations are relatively common in ReA. Keratoderma blennorrhagica is seen in up to 10 % of patients while circinate balinitis occurs in up to 40 % of males [304]. Rashes, erythema nodosum and nail changes have also been reported. Other extra-articular manifestations include conjunctivitis, uveitis, urethritis, cervicitis, myocarditis, aortic insufficiency and pericarditis [253, 305–309].

Acute non-granulomatous anterior uveitis is the most frequent extra-articular manifestation in JAS affecting up to 27 % of patients [273, 310]. Children are more likely to develop uveitis or have a history of uveitis compared to adults with AS [266, 289, 311]. Most children with JAS-associated uveitis are boys; reflecting the overall male predominance of the underlying disease [312]. In addition, most children with uveitis and JAS are HLA-B27 positive. The uveitis is usually symptomatic and recurrent but most patients do not experience severe sequelae [273]. In some patients, the uveitis can become chronic which may increase the risk for ocular complications and vision loss [312, 313]. Symptoms in most patients are pain, redness or blurred vision of one or both eyes. The disease is unilateral at presentation in 82–100 % of cases [273, 312]. Bilateral involvement develops in approximately 25 % of patients with simultaneous involvement of both eyes seen in less than 20 %. In patients with recurrent disease, uveitis tends to reappear within 3–8 months following the initial episode [273]. Acute attacks are characterized by the presence of anterior chamber cell and flare in most cases, while posterior synechiae , cataracts , and band keratopathy are associated with more chronic disease [273]. Posterior segment inflammation has been described in patients with AS but it is difficult to determine the specific manifestations in children since most series include more adults than children. Nevertheless, vitritis , cystoid macular edema , retinal vasculitis , and papillitis have been reported in several studies [313–316].

Uveitis develops within 1–12 years after the onset of arthritis and/or enthesitis in up to 90 % of patients; however, uveitis can occasionally antedate the onset of arthritis by up to a year [273]. Similar to JIA, there appears to be no association between articular or systemic disease activity and uveitis in JAS.

The most common ophthalmic manifestation of ReA is a mucopurulent papillary or follicular conjunctivitis [317]. In a review of 21 cases of pediatric Reiter’s syndrome by Lockie, conjunctivitis was the most common initial symptom [318]. The conjunctivitis usually occurs early in the disease course and is typically bilateral, painless and resolves spontaneously. In most cases, symptoms are mild, although some patients may experience severe blepharospasm and photophobia [319].

Additional ocular manifestations in children with ReA include episcleritis, scleritis, and anterior uveitis. Vitritis, macular edema, and optic nerve edema occur rarely [320]. Punctate and subepithelial keratitis have also been reported as well as corneal scarring [317, 321–324].

The diagnosis of JSpA is based primarily upon clinical manifestations. Laboratory testing may reveal a mild anemia and an elevated ESR. In a retrospective study of 103 patients with JSpA, HLA-B27 was present in 75.9 % of patients [325]. Imaging may help establish the diagnosis and is often useful to monitor disease progression. Conventional radiographs of involved peripheral joints show changes similar to these seen in children with JIA, but evaluation of the sacroiliac joints by conventional radiography is difficult in children. Plain radiography cannot detect active inflammation and can only detect joint damage that occurs after long-standing disease [284]. Contrast enhanced magnetic resonance imaging (MRI) is often used to detect signs of early inflammation of axial skeleton, especially the sacroiliac joint [326].

Diagnostic criteria for ReA are also based upon clinical criteria [268]. Nonspecific laboratory findings are common including elevated ESR and CRP; especially in cases of severe disease [306]. Children with ReA may have mild leukocytosis and elevated neutrophil counts. Testing for HLA-B27 is generally not useful since greater than 50 % of children will have a negative result [327]. Urinalysis may reveal pyuria due to urethritis. Cultures of urine or stool should be obtained based upon the clinical manifestations. In children with chronic disease, conventional radiography may show periostitis, sacroiliitis , joint erosions , and joint space narrowing [327]. MRI may also be useful to identify early joint involvement in these children

The treatment of children with JSpA is challenging due to the variable clinical course and limited reports of efficacy of many drugs used to treat these diseases. NSAIDs are often used to provide symptomatic relief of arthritis and enthesitis . Continuous treatment with NSAIDs may be more beneficial than intermittent therapy based upon studies in adults [328]. Sulfasalazine is also frequently used in children with resistant arthritis and enthesitis [306, 329, 330]. Systemic corticosteroids may be required for patients with severe disabling disease not controlled with NSAIDs. Methotrexate may be useful for patients with anterior uveitis or inflammatory bowel disease [253]. More recently, the TNFα inhibitors etanercept and infliximab have demonstrated significant improvement in disease activity in patients with JSpA [104, 331–333].

Currently there are no guidelines for the use of antibiotics in children with ReA. Many studies have demonstrated no benefit from the use of various antibiotics [327]. However, children with acute Chlamydia trachomatis infection should be treated; as well as their sexual partners based upon the most current recommendations [304]. A recent study has also shown that a 10–14 day course of amoxicillin alone or combined with clavulinic acid may be useful during the early stages of ReA prior to identification of the underlying organism [334].

Children with acute anterior uveitis are initially treated with topical corticosteroids and cycloplegics [335]. If the inflammation is especially severe or persists despite frequent topical corticosteroids, periocular corticosteroids are often used. Systemic corticosteroids are reserved for recalcitrant cases [273]. Methotrexate may be considered as a corticosteroid-sparing agent in children requiring prolonged systemic therapy. Complications of chronic anterior uveitis such as cataracts, posterior synechiae, band keratopathy, and glaucoma may require surgical intervention.

Conjunctivitis in children with ReA typically resolves without therapy [317, 335]. Mild episcleritis may require no treatment if asymptomatic. For those with symptoms, artificial tears are often useful. Initial treatment of scleritis is systemic NSAIDs. Systemic corticosteroids or systemic immunomodulator therapy may be necessary in children with refractory disease [336]. Keratitis may be self-limited requiring no therapy in children with ReA [317, 335]. If symptomatic or persistent, treatment with topical corticosteroids is often useful.

Sarcoidosis is a chronic multisystem disease characterized by the presence of granulomatous inflammation [337]. The diseases is most common among young adults who typically present with hilar adenopathy, pulmonary infiltrates, as well as skin and ocular lesions [338]. Sarcoidosis is uncommon in children [339]. Most affected children are 13–15 years of age although very young children can also develop the disease [340–342].

Blau syndrome , an autosomal dominant form of the disease is similar to sporadic early onset sarcoidosis (EOS) [343, 344]. Both are characterized by the presence of polyarthritis, rash, and recurrent uveitis. In addition, both are associated with missense mutations of the caspase recruitment domain gene (NOD2/CARD15) [345, 346].

The etiology of sarcoidosis is unknown but may involve environmental or infectious risk factors that trigger the abnormal immune response in genetically susceptible patients [347, 348]. Environmental factors such as insecticides, pesticides , mold, and mildew may increase the risk for sarcoidosis [349]. Mycobacterium tuberculosis and Proprionibacterium acnes have also been suggested as possible infectious etiologies [350].

The characteristic feature in sarcoidosis is the presence of epithelioid granulomas with associated mononuclear cell infiltration. Granulomas develop in response to a persistent poorly soluble antigenic material. Phagocytic cells of the innate immune system surround the antigenic stimulus and initiate an immune response ultimately leading to the formation of a granuloma. Granulomas in sarcoidosis ultimately resolve or heal by fibrosis [349, 350].

The first description of sarcoidosis was by Hutchison in 1877 [351]. In 1899 Caesar Boeck described the skin lesions of the disease and was the first to provide histologic confirmation of granulomatous inflammation [352]. Boeck also proposed terminology ultimately leading to the current term of sarcoidosis. The systemic manifestations of the disease were recognized in 1915 [353]. Initial reports of pediatric sarcoidosis appeared during the 1950s [354].

Childhood sarcoidosis is a rare disease and epidemiologic data are limited. A study of Danish children found an estimated incidence of 0.22–0.27 per 100,000 children per year [355]. The incidence in children 4 years of age or younger was 0.06 per 100,000 person years. The incidence among children 14–15 years of age was 1.02 per 100,000 person years [356].

There is no gender predilection in children with sarcoidosis . In the United States, approximately 81 % of older children with sarcoidosis are African American, however less than 30 % of young children with the disease are African American [340, 342, 357–359]. Most children with Blau syndrome are Caucasian [343, 345, 360]. In other countries, sarcoidosis is more common in the major racial groups of the country.

Systemic manifestations vary in children with sarcoidosis based upon the presence of or absence of the NOD2/CARD15 mutation. Children without the NOD2/CARD15 mutation usually present with fever, malaise, and weight loss [344]. Pulmonary manifestations such as cough, dyspnea, and chest pain occur in virtually all affected children [344, 361–363]. Bilateral hilar adenopathy is the most common finding with chest radiography [350, 355, 364]. Pulmonary parenchymal involvement includes interstitial, nodular, alveolar, and fibrotic patterns [364, 365]. Restrictive lung disease is relatively common in children [366, 367]. Peripheral lymphadenopathy and hepatosplenomegaly are also common. Parotid gland enlargement is another common finding in children [357, 368]. The most common skin manifestation is an erythematous rash seen in up to 77 % of children (Fig. 20.5) [355, 358]. Flat papules typically located on the face as well as macules and plaques are also common. Erythema nodosum occurs in approximately one-third of children. Arthritis affects over one-half of children with sarcoidosis. It is typically a boggy tenosynovitis with effusion and good range of motion. Multiple large joints of the upper and lower extremities are most commonly involved [350, 357, 368, 369]. Renal involvement including interstitial and granulomatous nephritis can rarely occur [350]. Neurosarcoidosis is also rare in children [370]. Mass-like lesions may be seen with imaging of the CNS [344]. Other manifestations include seizures, meningitis, and cranial neuropathies, especially involving the facial nerve [365].

Children with the NOD2/CARD15 mutation include those with Blau syndrome and EOS. Polyarthritis, rash, and recurrent uveitis are the characteristic clinical features among these children [344]. Most patients present with a rash involving the trunk with extension to the face and extremities. Early in the course, the rash my exhibit fine desquamation. Eventually after several years, the rash may appear similar to ichthyosis vulgaris. Subcutaneous nodules similar in appearance to erythema nodosum may also occur. Most children develop polyarthritis within months following the onset of the rash. Large and small peripheral joints are most commonly affected. The proximal interphalangeal joints may exhibit a characteristic flexion contracture known as camptodactyly (Fig. 20.6) [344]. Granulomatous nephritis, small vessel vasculitis, lymphadenitis, pericarditis, and cranial neuropathy have been rarely reported [371–373].

Ophthalmic manifestations have been reported in up to 80 % of children with sarcoidosis [374–379]. Anterior uveitis is the most common manifestation in both older and younger children occurring in up to 48 % of children [358, 380, 381]. Presenting symptoms in these children were eye pain and loss of vision. Anterior uveitis can be granulomatous or nongranulomatous. Fine or mutton fat keratic precipitates as well as iris nodules may be present (Fig. 20.7). Complications of anterior uveitis are not uncommon including band keratopathy, synechiae, glaucoma, and cataract [382, 383]. Complications are a significant cause of morbidity among children who are inadequately treated [358, 380, 381, 384].

Intermediate, posterior and panuveitis have also been reported. Posterior uveitis is more common in older children [385, 386]. Specific manifestations reported include vitritis, multifocal chorioretinal granulomas, choroiditis, optic disc edema or granuloma, chorioretinal scars, and choroidal neovascularization (Fig. 20.8) [312, 382, 383, 387].

Conjunctival nodules and cysts are not infrequent in children with sarcoidosis (Fig. 20.9) [382, 388–390]. Less common manifestations have been reported in a number of cases reports and limited series such as orbital inflammation with proptosis, small eyelid nodules, sicca syndrome and interstitial keratitis [387, 391–394].

Ocular manifestations of Blau syndrome have been described in a number of families. Manifestations in these children consist of panuveitis with multifocal choroiditis, subretinal exudates, chorioretinal lesions, anterior uveitis, ischemic optic neuropathy and retinal vasculopathy (Fig. 20.10) [395, 396]. Complications associated with uveitis are common including band keratopathy, anterior and posterior synechiae, iris bombé, glaucoma, cataracts, cystoid macular edema, optic disk edema and subretinal fibrosis [395–397].

The definitive diagnosis of sarcoidosis is established by biopsy of involved tissue demonstrating noncaseating epithelioid cell granulomas and exclusion of other causes of granulomatous inflammation [398–401]. In young children, the skin may be the best site for biopsy while in older children any enlarged lymph nodes may be preferred [382]. No laboratory tests are diagnostic for sarcoidosis. Non-specific laboratory findings include elevated ESR and CRP as well as mild anemia and leukopenia [344]. Hypergammaglobulinemia is relatively common. Angiotensin converting enzyme (ACE) may be elevated in some children, however normal levels vary with age in children [342, 344, 401]. As a result, ACE levels may have limited utility in children with suspected sarcoidosis. Liver function tests are often elevated. Hypercalcemia and or hypercalcuria is found in up to 35 % of children [402].

Chest radiography may reveal bilateral hilar adenopathy especially in older children [342, 380, 381]. These children may have parenchymal involvement as well. Osteopenia and punched out lesions may occur in younger children and visible with radiographs of the hand [357]. Pulmonary function tests are often abnormal in children with sarcoidosis [402].

There are no current guidelines for the treatment of children with sarcoidosis. Treatment should be based upon the severity of the disease as well as the organs involved. Most children with multisystem involvement are initially treated with corticosteroids [337, 344, 366, 403–405]. Methotrexate is an effective steroid sparing agent that has been used to treat a variety a variety of disease manifestations [406–409]. The TNFα antagonists are also useful in the treatment of children with sarcoidosis [410]. Infliximab appears effective in controlling arthritis and visceral manifestations [344, 411].

Management of the ophthalmic manifestations should begin with a comprehensive ophthalmic examination at the time of initial diagnosis and at regular intervals thereafter due to the lack of symptoms in some children. Although no recommendations exist regarding the frequency of ophthalmic examination, it would seem reasonable for older children without uveitis to be followed at 6 month intervals. Younger children may require more frequent follow-up to ensure uveitis or other ocular manifestations are detected and treated early.

Treatment of the ophthalmic manifestations is based upon the specific condition. Children with anterior uveitis are initially treated with topical corticosteroids with or without cycloplegics [382]. Periocular corticosteroids and or systemic corticosteroids may be necessary in severe or recalcitrant cases [341]. Methotrexate may also be considered as a steroid sparing agent in children to avoid serious side effects from prolonged corticosteroid therapy.

Children with intermediate uveitis may be treated with periocular corticosteroids. If the inflammation is not controlled, systemic corticosteroids and or methotrexate may be necessary. Patients with posterior or panuveitis will likely require systemic therapy to control the inflammation [336].

Children with Blau syndrome and panuveitis with multifocal choroiditis or subretinal exudates or chorioretinal lesions will typically require systemic therapy. Initial short-term treatment in most cases consists of oral corticosteroids with or without adjunctive periocular corticosteroids. Long-term treatment should include a steroid-sparing agent such as methotrexate or other immunosuppressive agent [336, 395].

Interstitial keratitis is usually treated with topical corticosteroids [392, 393]. Symptomatic sicca syndrome therapy consists of artificial tear preparations for most cases. Many children with symptomatic band keratopathy treated with EDTA chelation experience improvement in symptoms and visual acuity [412, 413]. Glaucoma is initially treated with topical anti-glaucoma therapy, followed by oral medications. Children with progressive glaucoma may ultimately require glaucoma surgery [382]. Cataract surgery may be necessary in children with visually significant cataracts. To ensure the best possible outcome, the eye should be completely free of inflammation for at least 3 months prior to surgery [382, 414]. There is little data regarding management of cataracts in childhood sarcoidosis compared to other children with uveitic cataracts such as those with JIA. Therefore, it is unclear if an intraocular lens should be implanted in these children.

Juvenile dermatomyositis (JDM) is a rare autoimmune small vessel vasculopathy that primarily affects skin and muscle [415]. It is the most common inflammatory myopathy in children and characterized by proximal muscle weakness as well as characteristic skin rashes [416]. Arthritis as well as gastrointestinal, pulmonary, neurologic, and cardiac manifestations may occur but are much less common. Unlike adult dermatomyositis, JDM results in less functional disability and mortality compared to adults with dermatomyositis. Associated malignancy is also rare in children with JDM [417]. The clinical course is monocyclic in 41 % of children with permanent remission occurring 2–3 years after disease onset. The remaining 59 % of children have a polycyclic chronic course characterized by disease exacerbations and remissions [418–420].

The etiology of JDM remains uncertain although a genetic predisposition is likely in affected children [415]. Environmental triggers, innate and adaptive immune responses, and specific tissue responses are likely involved in the pathogenesis of the disease [415, 416]. Type 1 interferons (IFN-α and IFN-β) and TNFα are important cytokines in the pathogenesis of JDM [421].

The Bohan and Peter criteria are used to classify children with JDM (Table 20.10) [422, 423]. A diagnosis of definite JDM requires the presence of a typical rash and at least three of the other criteria. Children with “probable” JDM have a typical rash and two other criteria while those classified as “possible” JDM have a typical rash with one other criteria [422]. Magnetic resonance imaging of the hip girdle muscles with fat-suppressed T2 weighted or Short Tau Inversion Recovery (STIR) sequences that demonstrate symmetric muscle edema is now often used to confirm the diagnosis of JDM in place of electromyography or muscle biopsy since it is less invasive [424].

The first clinical descriptions of JDM were reported in 1877 [425–428]. In 1912, the first postmortem examination of a child with JDM was described and noted vascular abnormalities including perivascular infiltrations of small round cells, thickening of vessel walls, and luminal occlusion [429]. Bruce was the first to describe retinitis in JDM [430].

The incidence of JDM in children is 2–4 children per million per year [431, 432]. It is more common in girls with a female to male ratio of 2.3:1 [431, 433]. The mean age of onset is 7 years with up to 25 % of children developing the disease prior to the age of 4 years [434]. In the United States and United Kingdom, 65–83 % of children with JDM are Caucasian [431, 433].

Proximal muscle weakness is the usual presenting symptom, often manifested by difficulty climbing stairs or frequent falls [435, 436]. Malaise and easy fatigability usually precede obvious muscle weakness by days to months. Muscle pain is seen in a majority of patients, and back pain may be an early symptom in up to 20 % of cases [435, 436].

The rash of JDM is characteristic and may precede or follow the onset of muscle weakness [417, 435, 436]. The most typical cutaneous manifestations include: heliotrope rash, Gottron’s papules, and periungal erythema or nailfold capillary loop abnormalities. The heliotrope rash presents as a violaceous discoloration of the upper eyelids with or without edema (Fig. 20.11). It is erythematous with a varying degree of violaceous or heliotrope tint in most cases [417]. Gottron papules are raised erythematous papules on the extensor surfaces of joints, especially the proximal interphalangeal and metacarpophalangeal joints (Fig. 20.12) [437]. Periungal erythema can be seen by the naked eye. Capillary loop abnormalities surrounding the nail can be seen using an ophthalmoscope for magnification or nailfold capillaroscopy. A photosensitive rash can be seen on sun exposed areas such as the chest and posterior aspect of the neck (V- and shawl sign) and the malar eminences which may be indistinguishable from the malar rash of SLE [438].

Fever is reported in 50–75 % of children [435, 436]. Other constitutional symptoms include anorexia and lymphadenopathy. Calcinosis occurs in up to 70 % of cases, typically at least 2 years following initial diagnosis of the disease [417, 435, 436]. Acquired lipodystrophy has been reported in up to 40 % of children [439–441]. Nondestructive arthritis similar to that in children with SLE can also occur [417, 442].

Gastrointestinal involvement may manifest as dysphagia and dysphonia in severe cases [417]. Gastrointestinal ulceration, perforation, or hemorrhage may occur due to vasculopathy [443, 444]. Malabsorption has also been reported in children with JDM [445].

Up to one-third of children with JDM develop pulmonary manifestations [417]. Respiratory muscle weakness and impaired chest wall compliance may result in reduced ventilatory capacity [446]. Interstitial lung disease may also occur. Some asymptomatic children may have abnormal pulmonary function tests [447].

Central or peripheral nervous system manifestations may occur secondary due to vasculopathy. Seizures, pseudoseizures, and psychosis have been reported. Peripheral polyneuropathy may also occur [417].

Cardiac involvement is very rare in children. Hypertension, pathologic/borderline electrocardiogram, diastolic dysfunction, and pericarditis have been reported but most children have subclinical disease [448].

One of the most striking features of JDM is the periorbital violaceous or heliotrope rash that may be seen in up to 80 % of cases (Fig. 20.11) [416]. Periorbital edema occurs in 50–90 % of children [449, 450]. Scaly erythema and edema of the eyelids are also relatively common. Well circumscribed atrophic lid scars likely due to cutaneous vasculopathy have also been described [451]. Eyelid telangiectasias also occur and may persist long after apparent resolution of other symptoms [416]. Extraocular muscle dysfunction and convergent strabismus have been reported [430, 452, 453].

Conjunctival and episcleral vessel tortuosity are relatively common in JDM [453–455]. Avascular areas of conjunctiva have been described in patients with dermatomyositis and may be due to the associated vasculopathy [456]. Additional anterior segment manifestations include episcleritis, scleritis, membranous conjunctivitis, uveitis, and secondary glaucoma [457–459]. Ocular complications of high-dose corticosteroids may develop including glaucoma and posterior subcapsular cataracts [416, 451, 460].

Retinal manifestations are rare in JDM [417, 451]. Children are more likely than adults to develop retinal manifestations because of the systemic vasculitis associated with the childhood form of the disease [423, 453]. The retinal manifestations of JDM may be indistinguishable from those seen in SLE [452]. Most of the retinal manifestations are the result of ischemic retinopathy such as diffuse cotton wool spots, deep and superficial retinal hemorrhages, retinal edema, retinal exudates, and retinal neovascularization [430, 452, 453, 458, 461–464]. The retinopathy may be transient, lasting several weeks or persistent with permanent visual loss. Optic atrophy has been reported following severe cases of retinopathy [453, 465].

The diagnosis of JDM is based upon clinical features and many clinicians utilize the Bohan and Peter criteria to aid in establishing the diagnosis. Muscle enzymes should be obtained in all children suspicious for JDM including lactate dehydrogenase, creatinine kinase, aldolase, alanine aminotransferase, and aspartate aminotransferase [437]. Up to 75 % of children with JDM will have elevations of at least one of these enzymes. Antinuclear antibodies occur in up to 85 % of patients with JDM [438]. The myositis specific antibodies anti-p155/140 and anti-p140 (MJ) are present in up to 29 and 23 % of children respectively [421].

Magnetic resonance imaging is used to document muscle involvement and myositis [437, 466]. Muscle biopsy is used less often than in the past but should be obtained in atypical cases. Electromyography (EMG) is included in the Bohan and Peter criteria although it is no longer widely used. Baseline chest radiography and pulmonary function studies should be considered in all children with JDM due to the risk of pulmonary involvement [437].

There have been no published clinical trials regarding the treatment of children with JDM. As a result, most treatment recommendations are based upon expert opinion [437]. To assist clinicians with treatment decisions, the Children’s Arthritis and Rheumatology Research Alliance (CARRA) has described the typical care of JDM [467, 468]. Initial treatment of moderate disease is oral or intravenous corticosteroids. Most children are treated with corticosteroids for up to 2 years followed by tapering and discontinuation over 12 months. Methotrexate is also recommended as part of the initial therapeutic regimen in addition to corticosteroids [466]. Other medications that may be considered, especially in severe disease are intravenous immunoglobulin, cyclosporine, mycophenolate mofetil, and cyclophosphamide.

Little information exists relating to the treatment of ocular manifestations of JDM. Nevertheless, therapy should be individualized based upon the specific manifestation. Eyelid and periorbital manifestations typically require no therapy. Conjunctivitis and episcleritis are often self-limited conditions but artificial tears may be helpful in children who are symptomatic. Scleritis is usually treated with NSAIDs and occasionally systemic corticosteroids [469]. Children who develop glaucoma are initially treated with topical glaucoma medications although surgery may be required in patients with progressive disease. Cataract surgery may be necessary in some cases if there is a risk of amblyopia or visual impairment.

Most of the retinal manifestations described in the English literature occurred at the time of initial disease presentation [451]. Since the retinal findings are very rare, there are no recommendations regarding their treatment in children. However, since the retinopathy may be associated with the vasculopathy, treatment of the underlying disease may result in resolution of the retinopathy [458].

Juvenile scleroderma is a rare disease characterized by fibrosis of the involved organs [470–472]. The mechanism of the disease likely involves vascular damage, autoimmunity with immune activation, and excessive deposition of collagen in affected organs [473]. Localized and systemic forms of the disease occur in all age groups but the localized form is most common among children [470, 474]. Manifestations of juvenile localized scleroderma (JLS) are typically limited to the skin while the systemic form known as systemic sclerosis (JSSc) can involve other organs. Juvenile systemic sclerosis can be a life-threatening disease due to cardiac, pulmonary, or renal involvement [470].

Since 1995, localized scleroderma (LS) has been classified into five types: plaque morphea, generalized morphea, bullous morphea, linear morphea, and deep morphea [475, 476]. To develop a more comprehensive system for JLS, this classification has been modified. The revised criteria often referred to as the Padua criteria include circumscribed morphea, linear scleroderma, generalized morphea, pansclerotic morphea, and mixed morphea [477].

In 2007, the Committee on Classification Criteria for JSSc published provisional criteria for the diagnosis of JSSc (Table 20.11). These criteria were developed to enhance and standardize the classification of children for research purposes [478]. To establish a diagnosis of JSSc requires the child to be less than 16 years of age with proximal skin sclerosis or induration (major criterion) and at least two minor criteria.

The first description of a patient with scleroderma-like manifestations was by Curzio in 1753 [479]. The term scleroderma was subsequently introduced by Giovambattista Fantonetti in 1836 [480]. Numerous early reports of ocular involvement in scleroderma began to appear around 1948 but the first series of patients was reported by Stucchi and Geiser in 1967 [481]. Decreased tear production and conjunctival fornix shortening were described in a number of these patients.

Both the localized and systemic forms of scleroderma are rare in children [482]. The estimated annual incidence of JLS is 1–3/100,000 while JSSc is 1 per million children [483, 484]. The mean age of onset of juvenile scleroderma is 8–9 years [470, 474]. Females are more commonly affected than males with a female-to-male ratio of 2:1 in JLS and 4:1 in JSSc [482, 485]. Over 90 % of affected children are Caucasian. Delays in diagnosis are common ranging from 1.2 to 2.8 years [482, 485–488].

Juvenile localized scleroderma is a group of conditions affecting the skin and subcutaneous tissues [477]. Circumscribed morphea lesions are round or oval and can involve the epidermis or subcutaneous tissues. Linear scleroderma is the most common type in children; affecting the trunk, limbs or head [489]. Facial or scalp involvement has been termed en coup de sabre (ECDS) based upon its similarity to the appearance of someone struck on the head with a sword. The Parry-Romberg syndrome (PRS) is another linear form with progressive hemifacial atrophy below the forehead involving the subcutaneous tissues, muscle, mandible, maxilla, and tongue (Fig. 20.13) [474]. In some cases, there appears to be overlap between ECDS and PRS prompting some authors to suggest they represent a spectrum of disease while others believe they are two distinct disorders [490–493]. Children with ECDS or PRS are at increased risk for central nervous system involvement including seizures, chronic headaches, and neuropsychiatric disorders [490, 494]. Generalized morphea is characterized by four or more large plaques at least 3 cm wide affecting at least two anatomic areas. Pansclerotic morphea is a rare form of JLS that manifests as circumferential involvement of the limbs with sparing of the distal fingers and toes. Mixed morphea includes a combination of at least two of the previously described subtypes.

Juvenile systemic sclerosis is a multisystem fibrosing disease that can be divided into three clinical subtypes. Diffuse cutaneous JSSc has extensive rapidly progressive skin thickening with early cardiac, renal and hepatic involvement. Limited cutaneous JSSc has limited nonprogressive skin thickening with late gastrointestinal and pulmonary involvement. The third subtype, overlap JSSc includes diffuse or limited cutaneous JSSc with features of another disease such as SLE or JDM [474, 495].

Children with JSSc often present with Raynaud phenomenon and skin changes involving the hands [485]. Raynaud phenomenon is a reversible vasospasm affecting the fingers and toes characterized by a triphasic color change of white to blue as the tissues become cyanotic and finally red with reperfusion [470]. Numbness and tingling of the digits are common during the cyanotic phase. Skin involvement is typically subtle resulting in delayed diagnosis in many children. Edema of the skin is one of the earliest signs of cutaneous involvement typically affecting the distal extremities. Later, fibrosis leads to increased skin thickness with a shiny appearance and loss of hair follicles [474]. As the skin thickens, the underlying tendons are affected leading to shortening with reduced range of motion. Tightness of the skin of the midface produces the characteristic small mouth, prominent teeth, pinched nose, and expressionless appearance.

Children with JSSc can also develop gastrointestinal, pulmonary, cardiac, musculoskeletal, and renal manifestations. Gastrointestinal involvement affects up to 50 % of children often presenting with dysphagia and gastroesophageal reflux [474]. Pulmonary disease is also common including interstitial lung disease and pulmonary arterial hypertension. Slowly progressive dyspnea with exertion suggests interstitial lung disease while pulmonary hypertension typically presents with rapidly progressive dyspnea [474]. Cardiac involvement is uncommon but a major cause of mortality due to pericarditis, arrhythmia, cardiomyopathy, and heart failure [470, 475]. Up to 40 % of children with JSSc develop inflammatory arthritis as well as synovitis associated with fibrosis of tendons. Tendon friction rubs may be noted with flexion or extension of involved joints [474, 496]. Renal disease is uncommon in children with JSSc. Mild renal dysfunction secondary to vasculopathy may occur but severe scleroderma renal crisis with accelerated arterial hypertension is extremely rare [482, 485].

Numerous ocular manifestations of scleroderma have been described in adults [497]. The most common ocular manifestation among adults is KCS [498–501]. Eyelid skin changes and telangiectasia are also common especially among patients with extensive skin disease [497]. Fibrosis of the skin can manifest as tightness of the lids, blepharophimosis, or rarely lagophthalmos [499–501]. Superficial punctate keratopathy may occur in patients with KCS or as a result of eyelid fibrosis. Increased central corneal thickness has been described in patients with systemic sclerosis [502]. Iris transillumination defects have been described in many patients and may be due to defects in the iris pigment epithelium [497, 499, 501]. Cataracts may be seen in longstanding disease. Retinopathy has rarely been reported although most patients had advanced disease with renal involvement and hypertension [503, 504]. Several reports have described superior oblique palsy, Brown syndrome, and ophthalmoplegia due to orbital myositis [497]. There also have been suggestions that there may be an increased risk of normal tension glaucoma among patients with scleroderma [505, 506].

Reports describing ocular complications in children are very limited. In a retrospective study of 750 patients with JLS from centers in Europe, North America, South America, Asia, and Australia, ocular manifestations were noted in 3.2 % of children [487, 507]. Ocular manifestations were more common among children with ECDS compared with the other types of JLS. Overall, the most common manifestations were ocular adnexal disorders in 42 % including eyelid and eyelash abnormalities. Asymptomatic anterior uveitis or episcleritis was noted in 29 % of children. Pupillary mydriasis was noted in two patients; one with pseudotumor cerebri and orbital myositis and the other with epilepsy. One patient had multiple ocular manifestations including enophthalmos, iris atrophy, neuroretinitis, and retinal telangiectasia. Other ocular abnormalities included an abducens palsy and pseudopapilledema. One of these reports also describes additional ocular manifestations such as KCS, keratitis, and acquired glaucoma [487].

A number of case reports have described additional ocular manifestations in children with scleroderma. Among these, the most common are enophthalmos, ptosis, eyelid atrophy, pupil abnormalities, iris heterochromia, uveitis , strabismus, and pigmentary changes in the fundus in children with ECDS or PRS [508, 509]. Orbital myositis, retinal vasculitis, and amblyopia have also been described in single case reports [510–512].

The diagnosis of juvenile scleroderma is based upon the characteristic clinical manifestations. The provisional criteria for the classification of JSSc may be useful to establish a diagnosis in many children. Biopsy of skin lesions can be considered in cases when the diagnosis is uncertain. No laboratory studies are diagnostic for the disease; however there are a number of autoantibodies that have been associated with juvenile scleroderma. In children with JSSc, autoantibodies have been reported in 81 % of patients. These include ANA, anti-topoisomerase (SCl-70) and anticentromere antibodies [485]. Children with JLS also have positive ANA tests but anti-topoisomerase and anticentromere antibodies are less common [486]. Rheumatoid factor may also be present in 16–17 % of children with JSSc and JLS. Nonspecific acute phase reactants such as ESR and CRP may be also be elevated. Serum immunoglobulin levels, especially IgG may be increased in some children.

Currently there are no guidelines for ongoing diagnostic evaluation of visceral involvement in JSSc. Evaluation of cardiac and pulmonary status with echocardiography and pulmonary function testing should be considered at the time of initial diagnosis for most children [470]. Additional follow-up evaluations should be performed to screen for development of cardiac and or pulmonary disease. MRI of the head and orbits should be considered in children with ECDS or PRS to detect possible CNS or orbital involvement.

There are no current guidelines for the treatment of juvenile scleroderma but therapy should be based upon the specific organ system involvement. In North America, most children with moderate to severe JLS are treated with a combination of methotrexate and systemic corticosteroids [513]. The optimal dosage and duration of this combination has not been established since treatment protocols vary between centers [514–517]. Treatment of children with JSSc is similar to that of adults based upon the specific disease manifestations. Raynaud phenomenon and digital ulcers are typically treated with oral nifedipine or intravenous prostanoids, usually iloprost, if active severe ulceration is present [470, 518]. Methotrexate is recommended for early diffuse skin involvement. Proton pump inhibitors should be used to prevent gastroesophageal reflux, esophageal ulcers and strictures [518]. Rotating antibiotics are recommended for children with malabsorption due to bacterial overgrowth [470]. Endothelin receptor antagonists and phosphodiesterase inhibitors have been recommended for the treatment of pulmonary hypertension including bosentan and sildenafil [518]. Patients with interstitial lung disease are treated with cyclophosphamide with or without low dose corticosteroids [519–521].

Ocular involvement in juvenile scleroderma is rare and at present there are no specific recommendations for the treatment of these conditions. Management should be individualized based upon the specific condition; however a few general principles may be considered for some of these manifestations. Children with KCS are treated with artificial tear preparations and or punctal plugs [497]. Anterior uveitis is typically treated with topical corticosteroids with or without cycloplegics. Periocular or intraocular corticosteroid injections are beneficial in cases of severe uveitis not controlled with topical therapy. Methotrexate may allow reduction or elimination of topical corticosteroids in some patients. Children with symptomatic episcleritis are often treated with artificial tears or mild topical corticosteroids until the symptoms resolve.

Henoch-Schönlein purpura (HSP) is an acute, self-limited, small vessel leukocytoclastic vasculitis. It is the most common primary vasculitis in children [522]. Characteristic clinical manifestations are palpable purpura, arthritis, colicky abdominal pain, gastrointestinal bleeding and nephritis [523, 524].

The etiology of HSP is unclear although many cases follow an upper respiratory tract infection suggesting infectious agents may be possible triggers. This is further supported by the seasonal nature of the disease with most cases developing in the winter and spring [525–528]. Group A β-hemolytic streptococcus, Staphylococcus aureus , viral infections and Mycoplasma pneumonia are the most commonly suspected organisms [529–539]. Several autoimmune disorders may also be risk factors for HSP including complement deficiencies as well as hereditary fever syndromes [540–542].

Since 1990, the ACR criteria for HSP were used to classify children with HSP; however these criteria were developed by analyzing adults with the disease [543]. The most recent proposed EULAR/PRES criteria for HSP are based upon children with vasculitides [544]. The updated criteria requires the presence of purpura or petechiae predominantly affecting the lower extremities plus one of the following manifestations: abdominal pain, arthritis or arthralgias, renal involvement, or histopathology demonstrating immunoglobulin A deposition.

In 1802, Heberden first described the disease later termed HSP [545]. Schlönlein in 1837 described the association of purpura, arthritis, and urinary abnormalities [546]. Henoch in 1874 subsequently reported gastrointestinal and renal manifestations of the disease [547].

Henoch-Schönlein purpura is primarily a disease of childhood and most cases occur in children less than 10 years of age. The mean age at onset of the disease is 7 years with a range of 1–16 years [538, 539, 548]. Boys are more commonly affected with a male to female ratio of 1:5:1 [539, 549]. In children, the estimated annual incidence of HSP is 13.5–20 per 100,000 [522, 549, 550]. The highest reported incidence is among Caucasians while African Americans have the lowest [522].

The disease onset is acute or subacute with most children presenting with palpable purpura, arthritis and abdominal pain. Low-grade fever and malaise are also common [551]. Some children may have a maculopapular or urticarial rash prior to developing purpura [540]. The purpura may be concentrated in dependent areas such as the lower legs but can also occur on the face and arms. Arthritis occurs in approximately 80 % of children, is typically transient and primarily affects the knees, ankles, and feet [540, 548, 552]. In some children, arthritis may involve the joints of the upper extremities as well. Gastrointestinal involvement occurs in up to 75 % of children. These manifestations typically occur within a week following the onset of the rash although abdominal pain may be the initial manifestation in up to one-third of cases [553–555]. Intermittent colicky abdominal pain, vomiting, hematemesis, and melena are common [548, 556]. Intussusception, pancreatitis, cholecystitis, and bowel perforation may rarely occur [548, 552]. Renal disease occurs in 40–60 % of patients, typically within one to 3 months after onset of the disease [524, 528, 557]. Microscopic hematuria is the most common manifestation although gross hematuria can also occur [538]. Proteinuria is present in over one-half of children with hematuria [558]. Children who develop nephritis are at increased risk for developing hypertension as well as renal impairment [559]. Orchitis has been reported in up to 38 % of boys. Scrotal pain and swelling are also common in HSP [560, 561].

Ocular manifestations are uncommon in HSP [538, 562]. Episcleritis , scleritis, anterior uveitis, keratitis, and central retinal vein occlusion have been described in children with HSP [548, 562–564]. Cortical blindness has been reported in 5 % of HSP patients with neurologic manifestations [565]. A case of transient conjugate eye deviation associated with cortical blindness has also been described in HSP [566]. Orbital subperiostial hematomas presenting with bilateral exophthalmos and eyelid ecchymoses has been described in a 5-year-old boy [567]. Bilateral central retinal artery occlusion was reported in a 6-year-old girl who subsequently developed cerebral vasculitis [568].

Diagnosis of HSP is based upon clinical manifestations. Acute phase reactants ESR and CRP may be elevated, especially during the active phase of the disease. Serum IgA and IgM are elevated during the acute phase in approximately one-half of children with HSP [569]. Anemia and leukocytosis may also be present [570]. Platelet counts are normal or elevated [556]. Urinalysis may reveal microscopic hematuria and or proteinuria in patients with renal involvement [570]. Weekly urinalysis is recommended during the active phase of the disease and then monthly for the subsequent 3 months [523].

Conventional radiography is useful in children with gastrointestinal involvement. Abdominal ultrasound or computed tomography may also be useful in children with possible cholecystitis, pancreatitis, or intussusception [523].

Treatment of mild HSP is mainly supportive typically with analgesics and NSAIDs [523, 556]. Corticosteroids are useful for management of gastrointestinal symptoms, arthritis, and renal disease. In severe cases, intravenous corticosteroids are commonly used [530, 540, 571–575]. Patients with acute renal failure or life-threatening manifestations may require plasmapheresis followed by azathioprine, cyclophosphamide, or cyclosporine [540]. Rituximab has been used in a small number of patients with severe disease refractory to traditional immunosuppressive therapies [576].

With few reports describing ocular manifestations in children with HSP, recommendations for the treatment of these disorders is based upon the treatment of children with other rheumatic diseases. Children with episcleritis may require no therapy but symptomatic patients are usually treated with artificial tears or systemic NSAIDs if symptoms are severe [185]. Scleritis often responds to treatment with systemic NSAIDs but short-term systemic corticosteroids may be necessary if NSAIDs are ineffective [336]. Keratitis and anterior uveitis are both treated with topical corticosteroids. Cycloplegics may be considered in children with severe anterior uveitis or those with photophobia.

Granulomatosis with polyangiitis (Wegener, GPA) is a chronic necrotizing primary systemic vasculitis involving small and medium sized arteries [577, 578]. The classic triad of inflammation of the upper and lower respiratory tract and glomerulonephritis is characteristic of GPA [579]. Most patients present with upper and lower respiratory tract involvement such as sinusitis, epistaxis, oral and nasal ulcers, otitis media, pulmonary hemorrhage, and pulmonary nodules [578]. Renal involvement occurs in up to three-quarters of children.

In 2010, the term granulomatosis with polyangiitis (Wegener, GPA) was introduced as a replacement for the eponym Wegener granulomatosis [580–582]. This change was based upon recommendations by the American College of Rheumatology, American Society of Nephrology, and European League Against Rheumatism to progressively shift from honorific eponyms to disease-descriptive or etiology-based terminology [581, 582].

There is no single widely accepted classification of childhood GPA . The 1990 American College of Rheumatology (ACR) criteria are based on adult data and therefore may not be ideal for use in children [577, 583, 584]. In 2006, the European League Against Rheumatism and the Pediatric Rheumatology European Society (EULAR/PRES) proposed modified criteria in an effort to improve the classification of GPA in children (Table 20.12) [585]. However, in the cohort described by Cabral, the EULAR/PRES classification did not demonstrate a significant improvement compared with the ACR criteria [586]. At this time, both sets of criteria are used in the classification of children with GPA.

McBride was the first to describe a patient with the midfacial granuloma syndrome in 1896 [587]. In 1931, a medical student, Heintz Klinger first described the disorder ultimately known as GPA [588, 589]. The diffuse systemic form of the disease was described in detail by Wegener in 1936 and 1939 [589–591]. The term Wegener granulomatosis first appeared in the English literature in 1954 [592].

Childhood GPA is a rare disease but one of the most common primary systemic vasculitides seen in children [586]. The incidence in children ranges from 0.03 to 3.2 per 100,000 children per year [38, 522]. Two single center studies describing forty children with GPA found that females were more commonly affected than males [584, 593]. A larger study of 65 children with GPA from the United States and Canada reported 63 % of patients were females and over two-thirds were Caucasian [586]. Among these children, the median age at diagnosis was 14.2 years (range 4–17 years).

In children with GPA, multiple organ involvement is common [577]. The most common features at presentation are constitutional symptoms such as fatigue, malaise, fever, and weight loss [586, 594]. Pulmonary and ear, nose and throat involvement occurs in 80 % of children at presentation [578, 586]. Pulmonary manifestations including hemorrhage, nodules, infiltrates, pleurisy, and abnormal pulmonary function studies are relatively common. Upper airway involvement is also common such as sinusitis, nasal septal perforation, saddle nose deformity, otitis, mastoiditis, hearing loss, and subglottic stenosis. Renal involvement occurs in 75–88 % of children at presentation with most having abnormal urinalysis or glomerulonephriti s [578, 586]. Up to 24 % of children ultimately develop renal failure requiring dialysis. Arthritis or arthralgias may be present at the time of initial diagnosis or develop later in 20–54 % of children [578, 586]. Petechiae and palpable purpura are also common in childhood GPA.

Ophthalmic manifestations are common in patients with GPA. Numerous reports have noted that 50–60 % of patients have ophthalmic involvement [595–600]. Most of these studies consist of adults with GPA although a few children are included in some series. Nonetheless, the most common ocular manifestations in these reports are orbital disease and scleritis. Orbital disease may represent focal inflammation or extension of adjacent disease of the paranasal sinuses or nasopharynx [595]. Other common manifestations include episcleritis, interstitial and peripheral ulcerative keratitis, and optic neuropathy [589]. Uveitis is uncommon and retinochoroidal involvement is rare in patients with GPA [601–604].

There are limited reports describing the ophthalmic manifestations of GPA in children. In the cohort described by Akikusa, one-half of the children had ocular manifestations; mostly conjunctivitis [578]. Scleritis, episcleritis, and proptosis were also noted in this group of children. In a larger study of 65 children, 37 % of patients had ocular involvement [586]. Non-specific red eye was most the most common finding followed by conjunctivitis and scleritis. Among six patients from various institutions, ocular findings included proptosis, eyelid edema and erythema, limited extraocular muscle motility, dacryoadenitis, conjunctivitis, scleritis with limbal infiltrates, iritis, and disc edema [605]. Numerous case reports and smaller series have also described proptosis, orbital inflammation, orbital tumor, lacrimal mass, nasolacrimal duct obstruction and motility disturbances [600, 606–610]. Additional manifestations from these reports include conjunctivitis, episcleritis, scleritis, uveitis, papillitis, and vasculitis affecting the retina, choroid and optic nerve [605, 611, 612].

The diagnosis of childhood GPA is based upon characteristic clinical manifestations, serologic markers, and histopathologic features [577]. Elevated ESR and anemia are common in childhood GPA [578]. Antineutrophil cytoplasmic antibodies are found in up to 90 % of children with GPA. Of these, 86 % have cytoplasmic antineutrophil cytoplasmic antibody (cANCA) and 13 % have perinuclear antineutrophil cytoplasmic antibody (pANCA) [577]. In addition, anti-proteinase-3 (PR-3) is found in 68 % of children [586]. Rheumatoid factors are present in 50 % while antinuclear antibodies are present in up to 36 % of children [586]. Anticardiolipin antibodies or lupus anticoagulants are found in approximately one-half of children. Antiphospholipid antibodies are rarely present but may increase the risk for thrombosis [578].

Urinalysis is frequently abnormal in childhood GPA. Proteinuria, hematuria, and red cell casts are commonly found in patients with glomerulonephritis [599]. Elevated serum creatinine and BUN are present in patients with renal disease.

Abnormal chest radiographs are common in children with GPA . Pulmonary nodules and infiltrates are the most common findings [578, 586]. High resolution CT may be useful for detecting additional pulmonary manifestations. Conventional sinus radiographs of CT are useful to detect sinus inflammation. Magnetic resonance imaging may be more sensitive for demonstrating sinusitis as well as soft tissue changes involving the upper airways [613, 614]. Computed tomography and MRI are useful for evaluation and management of orbital disease [613, 615, 616].

In some children, orbital biopsy may be necessary to exclude other diseases and to guide therapy, however orbital biopsy has a low sensitivity and should not be used to exclude GPA if the classic histopathologic features are not present [600, 617, 618].

With no controlled trials in childhood GPA, most of the treatment recommendations are based on studies of adults with GPA [597, 599]. In a study of 23 children, treatment with cyclophosphamide and corticosteroids achieved remission in 89 % of patients [593]. In a larger cohort of 65 children, 83 % of children were treated with combination cyclophosphamide and corticosteroids but no follow-up data was reported [586]. Methotrexate has also been used as an alternative to cyclophosphamide in children with GPA [578, 619]. The anti-CD20 monoclonal antibody rituximab may also have a role in the treatment of patients with GPA. The RAVE trial compared rituximab with cyclophosphamide for remission induction in adults with ANCA positive GPA or microscopic polyangiitis. The results of this trial demonstrated that rituximab was not inferior to cyclophosphamide and may be superior in patients with relapsing disease [620]. Treatment options for maintenance therapy in adults include azathioprine, leflunomide, and mycophenolate mofetil [577, 621, 622]. The TNFα antagonist infliximab has also been shown to be effective in adults [623].

Initial therapy of the ophthalmic manifestations of GPA is based upon treatment of the underlying disease. Although isolated ocular disease may be the initial manifestation of GPA, most patients will have multiple organ involvement requiring systemic therapy. Combination therapy with cyclophosphamide and corticosteroids should be considered as initial therapy for most children. Rituximab is an alternative therapy in patients with refractory orbital disease [624–626]. Maintenance therapy is ultimately required and the choice is often dependent upon other systemic manifestations. Adjunctive topical corticosteroid therapy may be needed in children with uveitis or inflammatory keratitis [596].

Dacryocystorhinostomy is recommended for patients with nasolacrimal duct obstruction [627]. Dacryocystectomy may be required in refractory cases [627, 628]. Orbital decompression may be necessary in some patients with optic nerve compression, severe pain or proptosis who do not respond to typical medical therapy [600, 629].

Treatment of retinal vasculitis is combination systemic therapy for the underlying disease. Some patients may benefit from periocular corticosteroids. Panretinal photocoagulation may be necessary if retinal neovascularization develops [593, 630].

Kawasaki disease (KD) is an acute febrile illness of childhood typically affecting young children less than 5 years of age. It is the second most common childhood vasculitis; primarily affecting medium-sized arteries. The disease is characterized by fever, rash, conjunctivitis, oropharyngeal changes, extremity changes and lymphadenopathy [540, 631]. Previously termed mucocutaneous lymph node syndrome, KD is the leading cause of acquired heart disease in children from Japan and North America [632, 633].

The cause of KD is unknown but the disease may be associated with an infectious trigger in a genetically predisposed child [631, 634]. This suspicion is based upon the clinical manifestations, epidemiology, and increased risk in certain ethnic groups as well as children with a parent with a history of KD [635–640]. It has been suggested that the vasculitis may be caused by conventional antigens or superantigens that initiate an immune response directed against endothelial cells [641].

Several classification criteria have been developed to aid in the diagnosis of KD [585, 634]. All of these classifications require the presence of fever for at least 5 days with additional manifestations. The American Heart Association criterion categorizes KD as classic/complete, incomplete, or atypical (Table 20.13). However, in some cases there may not be a clear distinction between incomplete and atypical KD [642]. On the other hand the 2006 EULAR/PRES classification has similar criteria but does not use these three categories [585]. At present, there is no consensus as to which classification performs best when categorizing these children.

Kawasaki disease was first described in the Japanese medical literature in 1967 by Kawasaki and in the American literature by Melish and colleagues in 1977 [643, 644]. In 1974, Kawasaki described bilateral congestion of the ocular conjunctivae as a prominent manifestation of the disease [645]. The first reports of uveitis associated with KD were in 1980 by Germain [646].

Kawasaki disease is more common in eastern Asia [647]. In 2008, the incidence in Japan was 218.6 per 100,000 children; an increase when compared to previously reported epidemics [648]. In 2006, the estimated incidence of KD in the United States was 20.8 per 100,000 children [649]. In American populations, KD is most common among children with Asian and Pacific Island ancestry. Most patients are less than 5 years of age, but KD occurs most commonly in children from age 6 to 11 months. Cases in children over 5 years of age are much less common [649–651]. It is more common in boys with a male to female ratio of 1.62:1 [648, 649, 652]. Disease recurrence occurs in 3.5 % of children [648].

Kawasaki disease is characterized by three clinical phases. The acute febrile period typically lasts up to 2 weeks. Resolution of fever signals the beginning of the subacute phase which ends when all of the clinical features resolve. In most children, this phase lasts 2–4 weeks. Following the end of the subacute phase, the convalescent phase begins and can last for months to years. The convalescent phase ends when the platelet count and ESR return to normal [540, 653].

The fever in KD is high, spiking in character , poorly responsive to antipyretics and lasts up to 14 days [540, 653]. Rash, oropharyngeal changes, and conjunctivitis are the most common manifestations during the acute phase. The rash may resemble measles, scarlet fever, or erythema multiforme, although most frequently described as diffuse, erythematous and maculopapular [631, 634]. It may be prominent in the perianal region and desquamation is frequent during the acute phase [654]. Diffuse erythema of the oropharynx is common as well as erythema, fissuring, cracking and bleeding of the lips. A “strawberry tongue” similar to that of scarlet fever may be present.

Edema and or erythema of the hands and feet sometimes with induration, usually occurs during the acute phase. Periungal lifting or detachment of the skin below the nail plate may also develop during the acute phase [631]. Periungal desquamation usually begins during the second week of the illness.

Some children may have cervical adenopathy; typically unilateral with nodes exceeding 1.5 cm in diameter. Fever and cervical adenopathy may be the initial manifestations of KD in a small number of children and may be confused with a bacterial infection [655].

Additional manifestations that are not included in the diagnostic criteria may also occur. Severe irritability is a common finding in children. This is probably due to aseptic meningitis Oligoarticular and polyarticular arthritis as well as arthralgias are present in up to 8 % of children [656]. Abdominal pain, vomiting, and diarrhea are also common. Cholecystitis or gallbladder hydrops can be seen. Upper respiratory symptoms occur in approximately one-third of children [657]. Urethritis and meatitis are also common findings and may be associated with white blood cells in the urine [631, 653].

Cardiac manifestations may develop during the acute phase. Myocarditis may occur in up to one-half of children [658]. Pericarditis may also develop in children with KD. Coronary artery aneurysms develop in up to 25 % of children without treatment and are a leading cause of morbidity and mortality [659]. Treatment with intravenous immune globulin (IVIG) markedly decreases the risk for developing coronary aneurysms [634, 660]. Although less common, peripheral arterial complications may also occur [631].

Ocular manifestations are common in children with KD. Bilateral bulbar conjunctivitis (Fig. 20.14) is the most common manifestation with almost all children affected during the acute phase of the disease [661–663]. Onset usually occurs within a day or two after the onset of fever and may last for several months [664]. The conjunctivitis primarily involves the bulbar conjunctiva; frequently with sparing of the limbus [644, 645, 665]. Chemosis and purulent discharge are not characteristic features. However, palpebral conjunctival scarring has been rarely reported [666].

Anterior uveitis is seen in over 75 % of cases of KD [662, 665]. These children may complain of photophobia; especially during the first week of the illness. Similar to the conjunctivitis, most cases are bilateral. Anterior chamber cells and flare as well as keratic precipitates are common. The uveitis is usually mild and resolves with the other manifestations of disease without sequelae or recurrence [646, 661, 667, 668]. Complications of uveitis such as posterior synechiae, cataract and glaucoma have not been reported [661]. Significant correlation has been reported between uveitis and the ESR and CRP [662].

Less common manifestations include superficial punctate keratitis, vitreous opacities, optic disc swelling, and subconjunctival hemorrhage [662, 669]. In addition, isolated cases of disciform keratitis and periorbital vasculitis have been reported [670, 671]. A single child has been reported with choroidal, retinal and vitreous changes resulting in severe visual impairment [661]. In addition, postmortem findings in a child with KD noted multiple areas of thrombotic occlusion of ophthalmic artery branches due to vasculitis resulting in bilateral retinal ischemia [672].

The diagnosis of KD is based upon clinical manifestations. Initial laboratory evaluation should include baseline complete blood count with differential, platelet count, ESR, and CRP. In addition, serum electrolytes, BUN, creatinine, serum transaminases, serum albumin, bilirubin and urinalysis are obtained. During the acute phase of the disease, increased ESR, CRP and white blood cell count are common. Anemia and thrombocytosis may be seen, especially following the acute phase. Elevated serum transaminase levels and decreased albumin are also common [631, 634].

Initial evaluation of children with KD or suspected KD should also include a baseline electrocardiogram and echocardiogram [631]. A repeat echocardiogram should be performed after 6–8 weeks.

Based upon recommendations by the American Heart Association, all children with suspected KD should be treated within the first 7–10 days of the disease with IVIG and high dose aspirin (80–100 mg/kg daily) [634]. Some clinicians reduce the aspirin dosage after the child is afebrile for at least 48 h while others continue the original dose of aspirin through day 14 of the illness and at least 48 h following resolution of the fever. Low dose aspirin (3 to 5 mg/kg per day) is typically continued until there is no evidence of coronary changes 6–8 weeks after disease onset [634]. Up to 38 % of children have persistent or recurrent fever after treatment with IVIG. These children are at increased risk for development of coronary artery aneurysms and should be retreated with IVIG [634]. Less than 5 % of children fail to respond to two courses of IVIG and these patients are typically treated with intravenous methylprednisolone. Infliximab has also been shown to be effective in treating KD unresponsive to IVIG [673–675].

Children with coronary artery abnormalities are usually treated with antithrombotic agents until the lesions resolve. Anticoagulation with warfarin is necessary for children with large aneurysms. Thrombolytic agents may also be used in patients with coronary or peripheral arterial obstructions [634].

Most of the ocular manifestations of KD are self-limited and resolve as the underlying disease improves [667]. Thus, specific treatment of these conditions is not required in most children. Children with symptomatic conjunctivitis may be treated with artificial tear preparations or topical corticosteroids in cases with significant symptoms. The treatment of anterior uveitis consists of short-term topical corticosteroids in most cases.

Polyarteritis nodosa (PAN) is a necrotizing vasculitis affecting medium and small arteries. It is the third most common vasculitis in children although it is very uncommon in this age group [540]. Characteristic manifestations are fever, weight loss, livedo reticularis, painful cutaneous nodules or ulcers, myalgias, leukocytosis and elevated ESR [676].

Polyarteritis nodosa is characterized by focal necrosis of the walls of small and medium-sized arteries [677]. The etiology of PAN is unknown although association with hepatitis B or other viruses including parvovirus B19 and cytomegalovirus has been described. These associations are much less common in children with PAN [678]. Isolated cases of PAN associated with familial Mediterranean fever have also been described [679–681]. In some cases, superantigens may be involved in the pathogenesis of PAN [682].

The diagnosis of PAN is often difficult and several classification criteria have been proposed for children. The most recent EULAR/PRES classification for childhood PAN has been validated in children with vasculitis (Table 20.14) [544]. In this classification, histopathologic confirmation of necrotizing vasculitis involving medium or small arteries or angiographic demonstration of aneurysm, stenosis , or occlusion of these arteries is required plus one other criterion to establish the diagnosis of PAN.

Polyarteritis nodosa was originally described in 1866 by Kussmaul and Maier [683]. Although the original designation was periarteritis nodosa, descriptions of involvement of the entire wall of the vessel led to widespread use of the preferred term polyarteritis nodosa.

There are no reports describing the epidemiology of childhood PAN while the incidence in adults from Europe and the United States is estimated to be 2.0–9.0/1,000,000 per year [684]. In children, the disease typically develops between 7–11 years of age with a mean age of 9 years [676, 684]. Some authors describe a greater frequency of boys with PAN, similar to adults, while others report a similar incidence among boys and girls [676, 677, 685, 686].

The clinical manifestations of PAN are diverse and vary depending on the regions of vascular involvement. The skin, musculoskeletal system, kidneys, and gastrointestinal system are most commonly affected [678]. Neurologic, pulmonary, and cardiac involvement occurs less commonly [676, 684, 687, 688].

The key features of PAN are fever, malaise, weight loss, abdominal pain, rash, myalgia, and arthropathy [677, 684, 685, 688–692]. Skin lesions are highly variable and may appear similar to those in HSP. Livedo reticularis is a characteristic finding in children with PAN. Tender subcutaneous nodules may be present overlying the affected arteries. Myalgias and arthropathy are seen in approximately one-third of children [676]. Neurologic manifestations include hemiplegia, focal defects, mononeuritis multiplex, and psychosis [693, 694]. Children with renal involvement may have proteinuria, hematuria, and hypertension [688, 695, 696]. Testicular pain has also been described in boys with PAN. Peritoneal hemorrhage may result from rupture of arterial aneurysms [697]. Pulmonary symptoms such as asthma, rhinitis, or pulmonary infiltrates are uncommon [677].

Common manifestations in infants are transient prolonged fever, macular exanthum, cardiomegaly, congestive heart failure, electrocardiogram changes and an abnormal urinalysis [698]. Hypertension and gangrene of the extremities is not uncommon in infants with PAN [698, 699]. Coronary arteritis has been noted in 90 % of all fatal cases of infantile PAN at autopsy.

Ophthalmic manifestations occur in up to 20 % of patients with PAN [700, 701]. Most studies describing ocular findings consist of adults with PAN. In these reports, manifestations include episcleritis, scleritis, interstitial keratitis, peripheral ulcerative keratitis, anterior uveitis, retinal vasculitis, cotton-wool spots, retinal exudates and hemorrhages, retinal edema, serous retinal detachment, retinal arterial occlusion and papilledema or papillitis [700–702]. The retinal findings can occur with or without hypertension [703]. Exophthalmos may also occur due to inflammation of the orbital vasculature [700]. Extraocular muscle palsies, amaurosis, nystagmus, and visual field defects have also been reported [700, 704]. Central retinal vein occlusion has been described in a single patient with marked thrombocytosis [705]. Approximately one-half of infants with PAN have transient conjunctivitis [698].

The EULAR/PRES criteria for childhood PAN requires histopathologic evidence of necrotizing vasculitis or angiography demonstrating aneurysm, stenosis, or occlusion of medium or small arteries [544]. Additional clinical manifestations are necessary to establish the diagnosis. The acute phase reactants including ESR and CRP are frequently elevated. In addition, leukocytosis, thrombocytosis, and mild anemia are relatively common [678]. Children with renal involvement may have proteinuria, hematuria, and decreased glomerular filtration rate. Conventional angiography remains the best vascular imaging technique however magnetic resonance angiography may be useful in selected cases [678]. Fluorescein angiography is used for patients with suspected retinal vasculitis.

There are no widely accepted recommendations for the treatment of childhood PAN. In general, treatment is based on the severity of the disease. Patients with mild PAN may be treated with corticosteroids while those with more severe disease are typically treated with cyclophosphamide and corticosteroids to induce a remission [540, 684, 706, 707]. Plasmapheresis has been used in cases of organ or life-threatening disease [540]. Maintenance therapy for most children is a traditional immunosuppressive agent such as azathioprine, methotrexate, mycophenolate mofetil, or IVIG. Biologic agents may be considered for children who fail to respond to these traditional therapies [708].

Systemic corticosteroids with or without immunosuppressive agents are typically required for the treatment of the ocular manifestations of PAN. With few reports describing ocular manifestations in children, recommendations regarding additional therapy are based upon experience in adults with PAN. Children with anterior uveitis and interstitial keratitis may benefit from topical corticosteroids. Cycloplegics are useful for children with photophobia or severe uveitis. Periocular corticosteroids may be considered in children with severe uveitis or retinal vasculitis. Patients with retinal vein occlusion should be monitored closely for the development of macular edema and secondary glaucoma.

Takayasu arteritis (TA) is a rare, relapsing vasculitis of unknown etiology affecting large arteries, particularly the aorta, its main branches and the pulmonary arteries. Any portion of the aorta may be involved although the renal, subclavian and carotid arteries are most commonly affected in children [709]. Early reports suggested that TA was primarily a disease of East Asian females, although it is now evident that the disease occurs throughout the world and affects both males and females [710]. The clinical manifestations of TA vary depending on the specific arteries involved. Fatigue, fever, weight loss, hypertension, arthritis/arthralgias, abdominal pain and ischemic strokes are common [577].

Criteria for the classification of childhood TA were developed by the EULAR/PRES [544]. The diagnosis of TA in children requires angiographic evidence of aneurysm/dilation of the aorta or it branches plus at least one of the following: decreased peripheral pulses or claudication, blood pressure discrepancy of greater than 10 mm Hg in any extremity, bruits of large arteries, hypertension, or elevated acute phase reactants. Unfortunately, the diagnosis of TA is often delayed by months to years in many children [711–714].

The disease is characterized by granulomatous periarteritis with adventitial thickening, leukocyte infiltration of the tunica media, as well as intimal hyperplasia [713, 715]. Fibrosis of the media and intima ultimately leads to fixed stenosis or arterial occlusion [716]. Most patients have stenotic lesions while aneurysms occur in up to 25 % of cases [714, 717–721]. The etiology of TA is unknown but exposure to Mycobacterium tuberculosis may be associated with the development of TA [722–724].

There are currently no studies describing the incidence of TA in children. However, 20–30 % of patients with TA may be less than 20 years of age [725–728]. The median age in studies including only children was 8–14 years [729]. The youngest patient reported was 2.4 years old [730]. The incidence in adults ranges from 0.8–2.9 per 1,000,000 per year [728, 729, 731, 732]. Females are more commonly affected with a female to male ratio of 1.2:1 to 6.9:1 [731, 733, 734].

The first description of pulseless disease was in 1908 by the Japanese ophthalmologist Takayasu [735, 736]. He noted ocular changes in a 21 year old woman which consisted of a peculiar capillary flush in the ocular fundi, wreath-like arteriovenous anastomosis around the optic disk, and blindness due to cataracts. The first report of corticosteroid therapy in Takayasu arteritis was in 1954 by Ask-Upmark [737].