Today, it is recognized that intrathoracic manifestations of sarcoidosis are most common; involvement of other organs such as the lymph nodes, skin, eyes, central nervous system, bones, and joints is also common [50]. Sarcoidosis is most common in young adults between the ages of 20–40 years, who frequently present with hilar lymphadenopathy, pulmonary infiltration, and ocular and cutaneous lesions. The prevalence of the disease varies across ethnic groups and geographic location, with African Americans being affected 10–20 times more often than Caucasians in the United States [51]. Sarcoidosis is relatively rare in childhood, and its clinical presentation tends to be quite different from that of adults. Children younger than 5 years often present with the triad of skin, joint, and eye involvement, which can be confused with JRA. Sarcoidosis in older children most closely clinically resembles the disease in adults.

19.4.4.2  Clinical Findings/Natural History

There appears to be two distinct clinical presentations of childhood sarcoidosis. In children less than 5 years of age the disease most often presents with the triad of rash, uveitis, and arthritis. In contrast, children age 8–15 years old usually present with a multisystem disease similar to the adult manifestation with pulmonary involvement, lymphadenopathy, and often constitutional signs and symptoms such as fever and malaise [52]. Ocular involvement occurs with a higher frequency in early-onset sarcoidosis, but is still common with disease onset in older childhood and adults.

Uveitis is the most frequent ocular manifestation of sarcoidosis, with anterior uveitis occurring more commonly in younger children than in older children and adults [53]. Since they only rarely have pulmonary ­disease, the disease in younger children can be easily misdiagnosed as JRA, which can also present with symptoms of the joints and eyes [54]. Anterior uveitis can present acutely, accompanied by eye pain, blurred vision and photophobia, or as a chronic granulomatous iridocyclitis that presents with few symptoms. The frequency of asymptomatic anterior uveitis in younger children with sarcoidosis highlights the need for frequent ophthalmologic evaluations, particularly at the slit-lamp. Typical findings of the chronic granulomatous uveitis of sarcoidosis include aqueous cells and flare in the anterior chamber with “mutton-fat” keratic precipitates on the corneal endothelium. Additionally,

nodules at the iris pupillary margin (Koeppe) or on the iris surface (Busacca) are commonly seen.

Posterior segment involvement is more common in older children than those under 5 years of age (Fig. 19.3) [55]. Vitreous inflammation can be diffuse, but classically appears as yellow-white aggregates (“snowballs”) or linearly in a “string of pearls” configuration. Nodular granulomas can occur in both the posterior and peripheral retina and choroid, as well as on the optic nerve head. Irregular nodular granulomas along venules are referred to as “candlewax drippings.” Linear or segmental periphlebitis along venules presents clinically as perivascular sheathing. CME is common when there is posterior segment involvement of ocular sarcoidosis [56, 57].

The prognosis for sarcoidosis with onset in childhood is generally better than for adult disease, with pediatric sarcoidosis often being self-limited after 2–3 years.

Pathophysiology

The epithelioid granuloma, a cluster of closely packed epithelioid histiocytes, macrophages, and multinucleated giant cells along with interspersed lymphocytes, monocytes, and fibroblasts, is the characteristic lesion of sarcoidosis. It is believed that this highly focused immune reaction is an antigenic response, but to date there is no definitively identified causal agent or trigger.

It is hypothesized that macrophages initiate the inflammatory response in sarcoidosis through the release of interleukins that promote the activation and proliferation of T-helper cells (CD4+) [57]. Liberation of mediators such as interleukin-2 (IL-2) and gamma interferon from these T-helper cells leads to clonal proliferation of T-lymphocytes and additional activation of macrophages. A cascade of inflammation from these and other immune effector cells ultimately leads to the release of additional cytokines, chemotactic factors, migration inhibition factors, adhesion molecules, and growth factors. As a result of the amplified immune response, changes in tissue permeability, cellular influx, and local cell proliferation results in a noncaseating granuloma at site of disease activity. It is believed that persistent antigenic stimulation maintains the pathogenic process and leads to chronic inflammation. Disease manifestations result from local tissue injury, compression, and fibrosis, and through cytokines that incite constitutional symptoms.

Fig. 19.3  (a) Vitreous inflammation can be diffuse in sarcoidosis. (b) This patient presented with retinal granulomas. (c) The figure shows a nodular granuloma in the posterior pole.

(d) Fluorescein angiogram reveals optic nerve inflammation and periphlebitis

a

c

b

d

Eyes with active sarcoidosis demonstrate the presence­ of activated T-lymphocytes, macrophages, epithelioid cells, and lymphokine production [58]. Granulomata of the iris, ciliary body, retina, choroid, sclera, optic nerve, and extra-ocular muscles have been identified.

Genetics

Racial variation in the incidence of sarcoidosis and familial clustering suggests a genetic predisposition. Recent evidence indicates increased frequency of HLA-DRB1 in patients with biopsy-confirmed sarcoidosis [59]. It has been suggested that HLA-B8 may be associated with early resolution of sarcoidosis [60].

Diagnosis/Treatment/Complications

The evaluation of children with suspected sarcoidosis is different from that of adults. Careful rheumatologic evaluation for systemic disease, including the skin and joints, is a necessary part of the evaluation. Younger

children do not commonly have pulmonary involvement, so chest roentgenograms are thus less likely to be of value. Older children may show the typical chest radiographic findings of adult disease. ACE levels are more variable in children, and are thus not helpful in most cases. Roentgenograms of the hands may aid in the diagnosis in children.

Early-onset sarcoidosis in children must be differentiated from JRA-associated iridocyclitis and from familial juvenile systemic granulomatosis. Anti-nuclear antibodies, which are usually positive in JRA but rarely in sarcoidosis, can help in the distinction. Additionally, a rash is a common findings in sarcoidosis of children but uncommon in JRA. Lastly, the arthritis of JRA is usually pauciarticular, while joint involvement in younger children with sarcoidosis is often polyarticular.

Both acute and chronic anterior uveitis in pediatric sarcoidosis are treated with topical corticosteroids and cycloplegic agents. Therapy can be tapered when the anterior chamber reaction has subsided.

Periocular and systemic corticosteroids are the mainstays of therapy with posterior involvement; visionthreatening posterior segment lesions such as visually significant vitreous opacities, CME, or optic disc edema