Pediatric Sarcoidosis 

Updated: Feb 01, 2016
Author: Girish D Sharma, MD, FCCP, FAAP; Chief Editor: Michael R Bye, MD 

Overview

Background

Sarcoidosis, a systemic, granulomatous disease, can occur in adult and pediatric patients, but it is nonetheless relatively rare in children. The description of sarcoidosis goes back to 1899, when Caesar Boeck described the skin nodules characterized by epithelioid cells with large, pale nuclei and giant cells as "multiple benign sarcoid of skin," due to its resemblance to sarcoma.

Sarcoidosis, the etiology of which is unknown, most commonly affects young adults, who frequently present with hilar lymphadenopathy, pulmonary infiltration, and ocular and cutaneous lesions. Although the lung is most frequently involved, the disease can affect any organ system of the body. Infants and children younger than age 4 years present with the triad of skin, joint, and eye involvement without typical pulmonary disease; in older children, involvement of the lungs, lymph nodes, and eyes predominates (see the image below). (See Clinical and Workup.)

Chest radiograph showing bilateral hilar lymphaden Chest radiograph showing bilateral hilar lymphadenopathy in a 10-year-old girl with sarcoidosis.

Despite various hypotheses regarding causative agents, the cause of sarcoidosis still is unknown. The diagnosis of sarcoidosis is established when histopathologic evidence of noncaseating granulomata in affected organs and reasonable exclusion of other granulomatous diseases support compatible clinical and radiographic findings. (See Etiology, Clinical, and Workup.)[1]

Frequently observed immunologic features include depression of cutaneous delayed-type hypersensitivity and a heightened helper T-cell type 1 (Th1) immune response at sites of disease. Circulating immune complexes, along with signs of B-cell hyperactivity, may also be found. The illness can be self-limited or chronic, with episodic recrudescence and remissions. The course and prognosis may correlate with the mode of onset and the extent of the disease. (See Prognosis and Treatment.)

Complications

Because sarcoidosis can involve any organ in the body, potential complications can include a gamut of abnormalities. Progressive interstitial lung disease with restrictive ventilatory pattern can occur. Untreated ocular disease may result in synechiae, glaucoma, and blindness.

Unusual, but serious, complications described in childhood sarcoidosis include nephrolithiasis, nephrocalcinosis, cranial nerve palsies, and cardiac disease, including vasculitis involving the aortic arch. (See Prognosis.)

Etiology

Sarcoidosis is a chronic inflammatory disease characterized by a highly focused, exaggerated immune response to an unknown antigen at the target organs. The hallmarks of the disease, sarcoid granulomas, most likely are formed in response to a persistent, poorly degradable, antigenic stimulus. Macrophages bearing increased expression of major histocompatibility class (MHC) II molecules most likely initiate the inflammatory response of sarcoidosis by presenting an unidentified antigen to CD4+ Th (helper-inducer) lymphocytes. This results in proliferation and activation of the T cell.

Iannuzzi et al hypothesized a possible role of infectious, organic and inorganic agents in the immunopathogenesis of sarcoidosis.[1] Any causative microbe, if present, is probably cleared, leaving behind an undegradable product. This process may initiate a cross-reacting immune response to self-antigen. Antigen-presenting cells (APC), in addition to producing high levels of tumor necrosis factor alpha (TNF-α), secrete interleukin (IL)-12, IL-15, and IL-18; macrophage inflammatory protein 1 (MIP-1); monocyte chemotactic protein 1 (MCP-1); and granulocyte macrophage colony-stimulating factor (GM-CSF).

The lung lymphocytes usually consist of CD4 memory T cells. Activated CD4+ T cells interact with APCs to initiate the formation and maintenance of granulomas. CD4+ T cells release IL-2 and interferon-γ. Activated CD4+ cells differentiate into type 1 helper (Th1) ̶ like cells and secrete predominantly IL-2 and interferon-γ. The efficiency of antigen processing, antigen presentation, and cytokine release is probably under genetic control. Evidence supports a role for macrophage human leukocyte antigen (HLA) and BTNL2 alleles in sarcoidosis susceptibility and phenotypic presentation.[2, 3]

Sarcoidal granulomas are organized, structured masses composed of macrophages and their derivatives, epithelioid cells, giant cells, and T cells. Sarcoidal granulomas may persist, resolve, or lead to fibrosis. Alveolar macrophages activated in the context of a predominant type 2 helper (Th2) T-cell response appear to stimulate fibroblast proliferation and collagen production, leading to progressive fibrosis.

The immunopathology has been best studied in lung disease in which early lesions consist of an alveolitis with a high proportion of activated CD4+ Th1 cells, which may precede granuloma formation. Although the lung lymphocytes usually consist of CD4 memory T cells, in some patients they are predominantly CD8 cells. The CD4+ lymphocytes, in association with other immune effector cells, such as macrophages, mast cells, and natural killer cells, perpetuate the inflammatory response by release of cytokines, monocyte chemotactic factors, macrophage migration inhibitory factor, leukocyte inhibitory factor, adhesion molecules (CD49a, CD54, CD102), and growth factors.

The appearance of worsening of sarcoidosis in the immune reconstitution inflammatory syndrome after treatment with antiretroviral therapy in patients with human immunodeficiency virus (HIV) infection underscores the central pathogenic role of CD4+ cells in sarcoidosis.[1]

As a result of these various immunologic interactions, an acute and often a chronic cascade of inflammation occurs. This is characterized by changes in tissue permeability, cellular influx, and local cell proliferation, resulting in a granuloma. Persistent antigenic stimulation is believed to maintain the pathogenic processes.

Other immunologic abnormalities observed in patients with sarcoidosis include circulating immune complexes, B-cell hyperactivity, spontaneous in situ production of immunoglobulins, and depression of cutaneous delayed-type hypersensitivity reactions.

Although sarcoidosis most commonly involves the lungs, it can affect nearly any organ system; products injure local tissues, and elaborating growth factors cause fibrosis. Sarcoid granulomas either resolve or heal by fibrosis. This fibrotic response can be severe and include the lymph nodes,[4] ears,[5] eyes,[6] skin, liver, spleen, kidneys, bone, joints, nervous system, and heart. Granulomas mediate disease by compressing tissues, secreting cytokines that provoke constitutional symptoms, and recruiting inflammatory cells that cause often irreversible organ damage and physiologic dysfunction.

Causes

Despite the world occurrence of sarcoidosis, the cause of the disease is still unknown. Attempts to elucidate the cause of sarcoidosis have been disappointingly thwarted by lack of an animal model and the failure to identify the antigen.

Despite extensive research, no identifiable agent has been demonstrated to account for the granulomata that characterize the disease. Infectious agents, chemicals, drugs, autoimmunity, and genetic factors have all been explored as potential causes. Most experts think that sarcoidosis results from exposure of genetically susceptible hosts to specific environmental agents that trigger an exaggerated cellular immune response, leading to granuloma formation. Case clustering suggests that an infectious agent may be responsible.

Mycobacteria, including Mycobacterium tuberculosis and other atypical species, have received the greatest amount of attention. The detection of mycobacterial deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in sarcoid lesions by polymerase chain reaction (PCR) assay, demonstration of components of the mycobacterial cell wall (eg, tuberculostearic acid, muramyl dipeptide) in sarcoid nodules, and the growth of acid-fast L-forms from the blood of patients with sarcoidosis lend support to that association. However, several investigators have fiercely contested the results obtained by PCR assay. Furthermore, attempts to fulfill the Koch postulates have failed, and the role of mycobacteria in sarcoidosis remains a controversial issue.

Besides M tuberculosis, many other antigens are under suspicion, including other bacteria, such as Propionibacterium acnes, Streptococcus species, Borrelia burgdorferi, Mycoplasma species, and Nocardia species. Viruses (eg, Epstein-Barr virus, herpesvirus, Coxsackie B virus, cytomegalovirus, retrovirus) and noninfectious environmental chemicals (eg, beryllium, aluminum, zirconium, titanium, pine pollen, peanut dust, clay ingestion) are also under suspicion.

Case reports from Scandinavia suggesting that rickettsiae may contribute to a granulomatous process as seen in sarcoidosis[7] were not supported by a prospective study in Danish patients with sarcoidosis.[8]

Variant human herpesvirus 8 (HHV-8) DNA sequences were detected from multiple sample sites in all patients with sarcoidosis. The significance of this finding is not clear and further studies are necessary to determine whether the association between HHV-8 and sarcoidosis is causal.

The striking racial variation in sarcoidosis incidence suggests a genetic predisposition to develop sarcoidosis. The strongest support for a genetic susceptibility to sarcoidosis comes from numerous reports of familial clustering of cases. In the United States, familial clusters more frequently are observed in blacks, with a rate of at least 19% in affected black families, compared with 5% in white families. Segregation and linkage analyses have not been performed.

When sarcoidosis has been observed in twins, monozygotic twins have been 2-4 times more concordant for disease than have dizygotic twins. The most common familial relationship is sibling pairs, followed by parent-offspring.

The hereditary differences in candidate genes that promote susceptibility may reside in loci that influence regulation of antigen presentation or recognition, T-cell function, or the regulation of matrix deposition that favors granuloma formation and progressive fibrosis. Genetic factors may also be important in defining the pattern of disease presentation, its severity, and the prognosis.

Several investigators have searched for associations with human leukocyte antigen (HLA)–related genes that may confer susceptibility to sarcoidosis. HLA analyses of affected families suggest a polygenic mode of inheritance of risk for sarcoidosis; the most commonly found alleles include class I HLA-A1 and B8 and class II HLA-DR3 in whites. Reports have demonstrated that association studies may be performed best with families in whom the ethnic background can be controlled.

HLA-DRB1*1101 is a significant risk factor for sarcoidosis in blacks. The rates for HLA DRB1 are reported to be 16% in blacks and 9% whites. In African American population, DQB1*0201 has no effect, while DQB1*0602 is associated with radiographic disease progression.[9] A 2011 study reports that HLA-DRB1*04 is associated with symptoms of Heerfordt syndrome (uveitis, parotid or salivary gland enlargement, and cranial nerve palsy) in a Scandinavian sarcoidosis population.[10]

Examination of other genetic loci, such as those encoding polymorphisms for immunoregulatory cytokines, growth factors, and angiotensin-converting enzyme (ACE), may prove equally important. A recent review article highlights recently performed genome-wide association studies (GWAS) and influence of genetic factors on phenotypic presentation of sarcoidosis; for example, HLA-DRB1*03 is both a risk factor for sarcoidosis and a determinant of good prognosis.[11]

Epidemiology

Occurrence in the United States

The prevalence of sarcoidosis in the adult population ranges from less than 1 case to 40 cases per 100,000 population, with an age-adjusted annual incidence rate of 10.9 per 100,000 for white people and 35.5 per 100,000 in black people. True incidence and prevalence is unknown because of the rarity of the disease and the small number of reported cases in childhood. As in adults, many children with sarcoidosis may be asymptomatic and the disease may remain undiagnosed.

More than 70% of childhood cases in the United States have been reported primarily in Virginia, North Carolina, South Carolina, and Arkansas, suggesting that the southeastern and south central states are an endemic area for childhood sarcoidosis.

International occurrence

In the United Kingdom, the overall prevalence of sarcoidosis is approximately 20 per 100,000 population. In Europe, the prevalence ranges from 3-50 cases per 100,000 population, with the disease most frequently affecting persons aged 20-40 years. Sweden has the highest reported incidence of sarcoidosis in Europe, ranging from 64 cases per 100,000 population using mass radiographic screening to 641 cases per 100,000 population using autopsy studies.

One review reported that the approximate incidence of clinically recognized sarcoidosis in Danish children younger than age 15 years was 0.22-0.27 per 100,000 children per year, corresponding to approximately 3 new cases in Denmark each year. In many other countries, such as Spain, Portugal, India, Saudi Arabia, or South America, the prevalence of sarcoidosis is low, possibly because of the absence of mass chest radiographic screening and also because of the presence of other more commonly recognized granulomatous diseases, especially tuberculosis, that mimic sarcoidosis.

Race-related demographics

In the United States, the lifetime risk of sarcoidosis on the basis of cumulative incidence estimates is 2.4% for black people and 0.85% for white people. The racial distribution of sarcoidosis varies with geographic location. In the pediatric series reported from the southeastern United States, sarcoidosis had a higher incidence among blacks.

In children aged 4 years or younger with sarcoidosis, 7-28% are black, whereas in children aged 8-15 years, the percentage of blacks increases to 72-81%. Studies in military and veteran populations showed that black people are 10-17 times more commonly affected by sarcoidosis than are white people. Outside the United States, sarcoidosis most frequently occurs in the predominant race of the country. Thus, in Scandinavian countries where sarcoidosis is common, almost all cases occur in white people, while in Japan, most patients are Asian.

Sex-related demographics

No clear sex predominance is recognized in childhood sarcoidosis, although a Japanese study reported a higher incidence of sarcoidosis in males than in females. In a study from Denmark, the male/female gender ratio was close to 1. Adult studies have reported a slightly higher disease rate for women. A population-based study of incidence and survival in adults with sarcoidosis reported incidence rates of 5.9 per 100,000 person-years for men and 6.3 per 100,000 person-years for women.

Age-related demographics

Most reported childhood cases have occurred in patients aged 13-15 years. The disease has also been reported in very young children. A recent report describes sarcoidlike granulomatous disease in an 11-month-old girl.[12] The prevalence increases until adulthood, when the disease most frequently is found in patients aged 20-30 years. A bimodal distribution has been reported in Scandinavian countries and Japan, with a secondary peak occurring primarily in females older than age 50 years.

Prognosis

Very few studies of the prognosis and natural history of sarcoidosis in children are available because of the rarity of the disease and the small number of reported cases. Thus, long-term prognosis is only speculative.[13] However, the overall prognosis of childhood sarcoidosis is reported to be good, with most children demonstrating considerable improvement in clinical manifestations and in findings on chest radiographs and pulmonary function tests.[14]

Although most children apparently improve, a significant number of patients have sequelae or experience major complications; however, the mortality rate is low. A review of 5 large series of childhood cases of sarcoidosis showed that 6 of 176 patients died, for an overall mortality rate of 3%. Asymptomatic cases usually have a favorable outcome, with spontaneous regression in many patients. Symptomatic patients with multisystemic involvement often experience chronic disease, with residua in about 20%, mainly involving the eyes and lungs.

Early onset sarcoidosis with involvement of the eyes, joints, and skin suggests a guarded prognosis, with the likelihood existing of a chronic, progressive course and even life-threatening complications; 80-100% of these children develop residua of uveitis, polyarthritis, and other organ involvement. Progressive ocular disease may produce severe disability, with the occurrence of secondary glaucoma resulting in blindness. Periodic ophthalmologic evaluations are essential in all cases of childhood sarcoidosis to identify ocular disease and prevent further morbidity.

Currently, longitudinal clinical assessment focusing on the severity of the disease in affected organs remains the best approach to prognosis. An acute onset with erythema nodosum indicates a good prognosis and spontaneous resolution, whereas an insidious onset may be followed by relentless, progressive fibrosis.[15]

A study by Nathan et al collected information on a large cohort of pediatric thoracic sarcoidosis to provide information on disease presentation, management and outcome. The study found that common prognosis factors are not suitable in pediatric patients, and a young age at diagnosis does not seem to be associated with a poorer prognosis; the study found that patients diagnosed before 10 years of age had lower frequency of relapses and were more likely to recover.[16]

Morbidity

Marcille et al performed a follow-up study on 19 individuals in whom sarcoidosis had been diagnosed in childhood, with a mean follow-up period of 21 years (range 8-35 y), and found that 7 patients (37%) had persistent abnormalities on chest radiograph, 68% had impaired lung function, and 63% had abnormal findings on echocardiography.[14]

Although most older children appear to improve, a significant number have sequelae or experience major complications; however, the mortality rate is low. Asymptomatic cases with hilar adenopathy have a very favorable outcome, with spontaneous resolution in many patients, whereas those with stage IV disease have a poor prognosis. Symptomatic patients with multisystemic involvement often experience chronic disease, with residua in about 20%, mainly involving the eyes and lungs.

As stated above, early onset sarcoidosis with involvement of the eyes, joints, and skin suggests a guarded prognosis. A series of 6 patients with early onset sarcoidosis and a long follow-up with a mean of 14 years (range 0-23 y) reported on the severe outcome of the disease, including blindness (4 patients), growth retardation (3 patients), cardiac involvement (2 patients), renal failure (1 patient), and even death (1 patient).

 

Presentation

History

Because sarcoidosis is a multisystem disease and affects most organs, the clinical presentation can widely vary. In most children, the disease frequently involves the lungs, lymph nodes, eyes, skin, liver, and spleen. A recent study of lung sarcoidosis in children reported that 85% presented with a multi-organ disease[16] similar findings were reported by a recent retrospective study.[17] Almost all childhood cases of sarcoidosis are symptomatic. In asymptomatic cases, the diagnosis may be made by chance.

Most of the reported cases of childhood sarcoidosis are accompanied by nonspecific constitutional symptoms, such as fever, fatigue, malaise, and weight loss, as well as symptoms from particular organs, such as lungs, eyes, skin, and lymph nodes.

Pulmonary symptoms are usually mild and often consist of a dry, hacking cough with or without mild to moderate dyspnea and occasionally chest pain. Less common symptoms include bone pain, headache, dyspnea, and abdominal pain. Patients with sarcoidosis may in rare cases present with fever of unknown origin.

Physical Examination

Two distinct forms of childhood sarcoidosis are noted. Older children usually present with a multisystem disease similar to the adult manifestation, with frequent lymphadenopathy and pulmonary involvement, as well as generalized signs and symptoms, such as fever and malaise. In contrast, early onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis[6] in presenting patients who are younger than age 4 years.

Lung

The lung is the organ most commonly involved in sarcoidosis. Nearly half of all children with sarcoidosis demonstrate restrictive lung disease on static and dynamic pulmonary function tests, including a reduction in total lung capacity (TLC), forced vital capacity (FVC), functional residual capacity (FRC), and transfer factor (DL CO). These changes are believed to be secondary to early alveolitis progressing to fibrosis.

An obstructive ventilatory pattern has been reported in approximately 15% of children with sarcoidosis. Airway obstruction may be secondary to airway hyperactivity, intrabronchial sarcoid granuloma, hilar and/or mediastinal lymph node compression of the airways, or bronchiectasis.

Lymphatic system

The most common clinical feature in childhood sarcoidosis is peripheral lymph node enlargement. About 40-70% of children with sarcoidosis have palpable peripheral lymph glands. Lymph nodes are typically firm, nontender, discrete, and freely movable. They do not ulcerate and do not form draining sinuses. The most frequently involved glands are the cervical, axillary, epitrochlear, and inguinal glands. In the neck, the posterior triangle nodes are affected more commonly than the nodes in the anterior triangle. The enlarged peripheral lymph nodes are the most accessible tissue for biopsy, providing a high diagnostic yield.[4]

Liver and spleen

Hepatosplenomegaly occurs in as many as 43% of children with sarcoidosis at some point in their clinical course; however, clinically significant hepatic dysfunction is rare. Mild elevation in biochemical liver function test values (eg, serum bilirubin, serum alanine transferase, alkaline phosphatase) is common, but severe liver involvement with cirrhosis and portal hypertension or splenic involvement with red blood cell (RBC) sequestration is unusual in children.

Eyes

Ocular involvement is extremely common in children with sarcoidosis, and a complete ophthalmologic evaluation, including a slitlamp examination, is crucial, particularly in young children. Any part of the eye or orbit may be affected.

Anterior uveitis (also known as iritis or iridocyclitis) is the most frequently observed lesion, occurring in about 58-90% of early-onset sarcoidoses, as compared with 24-54% of sarcoidosis cases in older children. The frequency of ocular involvement in adults with sarcoidosis ranges from 25-50% in most series.

Sarcoid-associated uveitis can be acute or chronic and can vary from an isolated iridocyclitis to a bilateral panuveitis syndrome.

Chronic granulomatous uveitis of sarcoidosis is characterized by firmly edged "mutton-fat" keratitic precipitates occurring preferentially in the limbus, but they may be present as a ring or confluent cellular aggregates and form "snow banking" inferiorly. These precipitates of inflammatory cells can also be present on the iris pupil margin, where they are called Koeppe nodules, and they become a site of synechia formation.

The iritis of juvenile rheumatoid arthritis (JRA) may also produce few symptoms; however, the corneal cellular aggregates are more centrally located and the edges are less firm and distinct. In addition, the synechia formation is more diffuse in JRA and tends to be more focal in sarcoidosis. If left untreated, the disease may result in synechiae, corneal opacities, glaucoma, and, eventually, blindness.

An acute nongranulomatous type of anterior uveitis may also occur, which typically is characterized by eye pain, blurred vision, photophobia, redness, and excessive lacrimation.

Conjunctival granulomas are the second most common ocular manifestation in sarcoidosis, and they may appear as tiny, translucent, pale yellow nodules. A bulbar conjunctival biopsy can be valuable, yielding a diagnosis in 50% of cases.

Other forms of ocular lesions include interstitial keratitis, band keratopathy (because of calcium deposition), dacryocystitis, retinal vasculitis, lacrimal gland enlargement, choroiditis, and orbital infiltration, which may result in proptosis

Skin

Cutaneous involvement occurs in about 24-40% of older children with sarcoidosis and in 77% of young children with sarcoidosis. The most frequent cutaneous eruptions include soft, red to yellowish brown, or violaceous, flat-topped papules, most frequently found on the face. In children, erythematous macular lesions with scarring and ichthyosiform rashes are frequently encountered. Larger, violaceous, plaquelike lesions may be found on the trunk, extremities, and buttocks.

Other skin lesions of sarcoidosis include nodules, hyperpigmented lesions, hypopigmented lesions, ulcers, subcutaneous tumors, and erythema nodosum. Rarely, "scar sarcoidosis" (ie, infiltration of old scars with sarcoid granuloma in the active phase of the disease) may present in children.

Cutaneous involvement occurs in about 25% of all adult patients with sarcoidosis. Two clinically important and easily identifiable sarcoid skin lesions in adults (but unusual in children) are erythema nodosum and lupus pernio. Lupus pernio, a violaceous, indurated skin lesion occurring principally on the cheeks, nose, lips, and ears, represents chronic sarcoidosis in older women, especially West Indian and black women.

Erythema nodosum, the hallmark of acute sarcoidosis, is commonly observed in European, Puerto Rican, and Mexican patients, particularly in women of childbearing age. The entity is rare in Japanese and African American patients. Erythema nodosum consists of ill-defined, tender, red nodules on the anterior aspects of the legs and may be associated with swollen and painful adjacent joints. The lesions typically resolve over 2-3 weeks, with characteristic bruising. Rarely, erythema nodosum may be a presenting sign of childhood sarcoidosis.

Lofgren syndrome is a classic presentation of acute sarcoidosis that is typically observed in young adult females, primarily white females; it is characterized by fever, bilateral hilar adenopathy, erythema nodosum, and arthralgia. The ankle and knee joints are most frequently involved. This presentation remains less common in children than in adults. Prognosis is excellent, and complete resolution is observed in more than 90% of patients.

Musculoskeletal system

In childhood sarcoidosis, arthritis occurs with a frequency of 45-58%. Musculoskeletal features of sarcoidosis include joint pain, joint effusions, and, rarely, bone lesions. Bone lesions are more likely to be found if chronic cutaneous lesions are present. The arthritis of childhood sarcoidosis, which can easily be confused with JRA in preschool-aged children, is characterized by boggy tenosynovitis with relatively painless effusion and good range of movement. Multiple large joints on the upper and lower extremities are often involved. The joints are swollen but are usually without tenderness or erythema of the skin.

Bone involvement is rarely noted in children with sarcoidosis; the common sites include the hands and feet. When small, destructive cystic lesions are present in the distal ends of the phalanges, metacarpals, and metatarsals, a lacy, reticular trabecular pattern or acro-osteolysis has been noted. Sarcoid lesions have also been reported to occur in the long bones, spine, and skull. Osteolytic bone lesions or erosive changes are rarely observed today in association with musculoskeletal manifestations of childhood sarcoidosis.

Symptomatic muscle involvement in sarcoidosis is unusual in children. Adult studies have reported symptomatic muscle involvement in 1.4% of known cases of sarcoidosis. The clinical spectrum most frequently can vary from an asymptomatic state to nodular myopathy (in which findings on magnetic resonance imaging [MRI] and gallium scintigraphy, acute myositis, and chronic myopathy may indicate the lesions). In symptomatic cases, muscle involvement may be evident because of pain, tenderness, weakness, and elevated muscle enzymes (eg, creatine kinase, aldolase). The presence of sarcoid granulomas can be detected in 50% of affected adults on muscle biopsy.

Renal and endocrine systems

Renal involvement occurs infrequently in children and adults with sarcoidosis. Renal disease can be attributed to granulomatous interstitial infiltration or to disorders of calcium homeostasis, including hypercalcemia and hypercalciuria with or without nephrocalcinosis and nephrolithiasis. Clinically, variable renal disease occurs in 5-10% of adult cases. Renal involvement is not well characterized in the published series of childhood sarcoidosis. Only 32 isolated cases of sarcoidosis with renal involvement have been reported in children since 1941.

The clinical manifestations in reported cases of renal granulomatous sarcoidosis include proteinuria, leukocyturia, hematuria, concentration defect, hypertension, and renal failure.

Heart

Sarcoidosis involving the heart has been well documented in adults but rarely in children. The most common cardiac abnormalities include conduction abnormalities and dysrhythmias due to granulomatous infiltration of the heart. Sudden deaths have been reported in as many as 60% of adults with untreated cardiac sarcoidosis.

Nervous system

Little is known about neurosarcoidosis in children because of the rarity of the disorder in this age group. Sarcoidosis may affect virtually any axis of the nervous system in adults. The disease is apparent in approximately 5% of patients of all ages, often in a clinically silent form.

In a review of 29 pediatric neurosarcoid cases, the authors noted that the clinical presentation of neurosarcoid in prepubertal children is different when compared with that in adults. Children are more likely to have seizures, less likely to have cranial nerve palsies, and more likely to present with space-occupying lesion. The pediatric cases evolve into adult patterns of disease, with more frequent cranial nerve palsies and fewer seizures as children progress to adulthood.

Cranial neuropathies are the most common manifestation of adult neurosarcoidosis, and facial nerve palsy is the most frequent abnormality, followed by abnormalities that affect the optic and acoustic nerves.

Sarcoid granulomas primarily involve the basilar leptomeninges, leading to obstructive hydrocephalus and seventh nerve palsy. Other reported manifestations of neurosarcoidosis include meningitis, seizures, hypopituitarism, diabetes insipidus, cerebellar ataxia, isolated intramedullary spinal cord or cauda equina involvement, and peripheral neuritis.

Parotid glands

Parotid gland enlargement is a frequent finding in children with sarcoidosis. In early-onset sarcoidosis, involvement of the parotid gland is reported in 13% of cases. A recent report describes bilateral parotitis as the initial presentation of childhood sarcoidosis.[18] Unilateral or bilateral parotitis with swollen, painful enlargement of the gland occurs in less than 6% of adult patients with sarcoidosis and is self-limiting in about 40% of these patients. Heerfordt syndrome (a combination of fever, parotid enlargement, anterior uveitis, and cranial nerve palsies) is often observed in adult patients and has been reported in childhood sarcoidosis.

Other sites of involvement

The incidence of gastrointestinal (GI) tract sarcoidosis is reported to be less than 1% in adults. The stomach is the most frequent site of involvement, whereas the esophagus, small bowel, appendix, rectum, and pancreas are very rarely affected. Involvement of the GI tract in childhood sarcoidosis is very unusual.

Rarely, the sarcoid granulomatous process may involve the reproductive system in adults and children, often mimicking a tumor. A few cases of isolated laryngeal sarcoidosis have been described in the pediatric literature.[19] Endocrine manifestations, such as anterior pituitary involvement, growth hormone deficiency, and delayed puberty, are rare.

Early onset childhood sarcoidosis

Early onset childhood sarcoidosis (ie, with onset in the first 4 y of life) is a rare disease and appears to be different from sarcoidosis in older children and adolescents. A striking predominance of white patients is observed in early onset disease, in contrast to older children with sarcoidosis. Patients with early onset sarcoidosis frequently present in the first year of life, with the characteristic triad of rash, uveitis, and arthritis occurring in children younger than 4 years.

Hetherington et al reviewed 28 cases of early onset disease and noted that a red maculopapular rash (78%) may precede joint symptoms (58%) by months.[20] Uveitis, which occurs in about 58-90% cases of early onset disease, is described in about 20-30% of patients with later-onset disease. Pulmonary involvement, the leading feature of late-onset disease, is unusual in early onset sarcoidosis and was noted in only 22% of children.

Early onset sarcoidosis may be overlooked because of its similarity to systemic-onset JRA. Both entities may be associated with systemic manifestations such as fever, weight loss, and fatigue. Skin changes may help to distinguish between the 2 diseases at the onset. The rash of JRA is pink, evanescent, and macular, whereas the rash of sarcoidosis usually is a persistent follicular or nodular rash with scaling.

Joint involvement in early onset sarcoidosis typically begins as early morning stiffness with minimal functional impairment and is characterized by painless, boggy effusions with synovial thickening that commonly affects the wrists and knees. Fusiform swelling of the finger joints and skeletal abnormalities are more common in this age group. Sarcoid arthritis typically is persistent and nondestructive, affecting predominantly the large joints; however, painful destructive polyarthritis with functional impairment indistinguishable from that associated with JRA has also been described in early onset sarcoidosis.

Uveitis is a useful differentiating feature. In JRA, the corneal cellular aggregates are more centrally located and the edges are less firm and distinct. In addition, the synechia formation is more diffuse in JRA and tends to be more focal in sarcoidosis. Furthermore, uveitis is very unusual in systemic-onset JRA, which is most often confused with early onset sarcoidosis.

The other organs involved in preschool children with sarcoidosis include liver and spleen (52%), lymph nodes (42%), parotid gland (13%), bones (13%), and lungs (13%). Because liver involvement occurs in approximately half of the cases, liver biopsy is an important diagnostic tool in patients in whom findings on other tissue biopsies are not helpful or in whom affected organs are not easily accessible.

Cardiac, renal, and central nervous system (CNS) involvement have been reported infrequently in early onset disease. The cardiac manifestations include pericarditis, myocarditis, and intraventricular thrombosis with significant clinical effects. A few case reports describing vasculitis involving renal arteries and aortic arch disease also appear in the literature. Blindness is a rare, but severe, late complication in early onset sarcoidosis.

 

DDx

Diagnostic Considerations

The differential diagnosis of sarcoidosis depends largely on the clinical presentation of the disease. Rule out granulomatous pulmonary infections, especially those caused by mycobacteria and fungi. Exclude neoplastic diseases, such as lymphoma, in cases with hilar adenopathy. Hypercalcemia in sarcoidosis may mimic metabolic disorders, such as primary hyperparathyroidism. Early onset sarcoidosis is often misdiagnosed as systemic-onset JRA.[21] Rarely, severe symptomatic bone marrow involvement may mimic numerous infectious and neoplastic disorders.

Differential Diagnoses

 

Workup

Approach Considerations

No definitive laboratory test diagnostic of sarcoidosis has been identified. In the absence of a known etiologic agent, sarcoidosis often remains a diagnosis of exclusion, although a typical presentation may strongly suggest the diagnosis. The diagnosis of sarcoidosis is established when a compatible clinical and radiographic picture is supported by histologic evidence of noncaseating granulomas in affected tissues and exclusion of other granulomatous diseases capable of producing a similar histologic or clinical picture.

Other tests that may provide supportive evidence for sarcoidosis include measurement of serum ACE level, gallium-67 (67 Ga) scan,[22] bronchoalveolar lavage (BAL) lymphocyte count, and CD4+/CD8+ T-lymphocyte ratio; however, tissue biopsy is required for a definitive diagnosis.

Laboratory evaluation may reveal an elevated erythrocyte sedimentation rate (ESR) or other acute-phase reactants. Anemia, leukopenia, and eosinophilia are commonly observed on blood cell counts. Hypergammaglobulinemia can occur in 75% of children with sarcoidosis. The presence of impaired delayed hypersensitivity on skin testing is typical, but not diagnostic, of sarcoidosis. Hypercalcemia and/or hypercalciuria may be found in as many as 30% of cases.

Renal and endocrine systems

In a review, decreased creatinine clearance was found in more than 60% of children with sarcoidosis, although other evidence of renal dysfunction, such as abnormal urinalysis results, elevated blood urea nitrogen (BUN) levels, and elevated serum creatinine values were found in less than 40% of children.

Histopathologic studies have revealed epithelioid granuloma formation, interstitial infiltration by mononuclear cells, interstitial fibrosis, tubulitis, tubular atrophy, mesangial hyperplasia, glomerular fibrosis, membranous nephropathy, and vascular involvement.

Granulomas have been found in the kidneys in 15-40% of adult patients with sarcoidosis. Incidence in children is unknown but is believed to be lower. Children who have a partial response to corticosteroid therapy and who develop arterial hypertension have a poor prognosis.

Derangement in calcium metabolism manifesting as hypercalcemia and/or hypercalciuria occurs in up to 30% of children. In vitro experiments of cultured alveolar macrophages from patients with sarcoidosis and of homogenized sarcoid lymph node tissue have demonstrated that the sarcoid macrophage is able to synthesize 1,25-dihydroxyvitamin D via 25-hydroxyvitamin D3-1-alpha hydroxylating activity. The excess circulating 1,25-dihydroxyvitamin D produced extrarenally causes increased intestinal absorption of calcium, enhanced bone resorption, and resultant hypercalciuria with or without hypercalcemia.

Additionally, granulomatous production of parathyroid hormone–related protein may also play a role. This process can ultimately result in nephrocalcinosis and renal failure. Nephrolithiasis and nephrocalcinosis have been reported in several cases of childhood sarcoidosis with hypercalcemia and hypercalciuria.

Hypercalcemia of sarcoidosis often becomes clinically manifest during the summer months, because the production of provitamin D in the skin is accelerated by exposure to sunlight. Intense sunlight exposure, as occurs during prolonged sunbathing in subtropical or tropical countries, may induce severe hypercalcemia in some patients with sarcoidosis. Hypercalcemic crisis has been reported as the presenting sign in childhood sarcoidosis.

Heart

Half of the patients with cardiac sarcoidosis have electrocardiographic abnormalities of rhythm, conduction, and repolarization, warranting 24-hour Holter monitoring. A high index of suspicion and early diagnosis is crucial, because aggressive treatment with prolonged steroids may result in decreased mortality rates.

Other manifestations of cardiac sarcoidosis include infiltrative cardiomyopathy with congestive heart failure, valvular disease, pericardial effusion, and papillary-muscle dysfunction. A combination of myocardial scintigraphy with thallium-201 (201 Tl) and67 Ga is recommended to evaluate disease status and predict possible response to corticosteroids.

Hematologic manifestations

Sarcoidosis can affect the bone marrow. The toxicity may result from mechanical disruption of the marrow by granulomas as well as from an indirect effect from the variety of cytokines released. Several studies of adult patients with sarcoidosis have shown 1 or more hematologic abnormalities in over half of the cases. Anemia occurs in 4-20% of patients with sarcoidosis. Leukopenia occurs in as many as 40% of patients but rarely is severe. In the absence of splenomegaly, leukopenia may reflect bone marrow involvement. Other hematologic abnormalities, such as leukemoid reaction, eosinophilia, autoimmune hemolytic anemia, and thrombocytopenia, are rare.

Bone marrow involvement in sarcoidosis often is asymptomatic. In severe cases, children may present with fever of unknown origin, localized bone pains, anemia, and leukopenia, mimicking a number of infectious, inflammatory, and neoplastic processes. In such cases, MRI may reveal multiple small, nodular lesions within the marrow, even in the presence of normal findings on plain radiographs and normal findings on bone scan. MRI can help to localize sarcoid lesions for diagnostic marrow biopsy.

Angiotensin-Converting Enzyme

ACE is produced by the epithelioid cells of granulomas and, thus, may be elevated in the serum of sarcoid patients. ACE serum level is typically elevated in as many as 80% of older children and in 60% of adults with sarcoidosis. Healthy children have higher ACE levels than adults, and, thus, results must be compared with age-matched controls.

ACE is found in many organs and body fluids, especially in the lungs, kidneys, and seminal fluid. At the cellular level, serum ACE is secreted by pulmonary capillary endothelial cells, alveolar macrophages, and epithelial cells of the renal proximal tubule. However, the test is not specific for sarcoidosis, and a wide variety of disorders, including tuberculosis, leprosy, primary biliary cirrhosis, diabetes mellitus, pulmonary neoplasm, lymphoma, Gaucher disease, and hyperthyroidism, may be associated with increased serum ACE activity, making it a supportive test rather than a diagnostic one.

ACE serum level is often associated with active disease and routinely decreases with corticosteroid therapy in pediatric and adult sarcoidosis patients. Although proven not to be very sensitive in early onset sarcoidosis, one report found serum ACE levels to correlate well with disease activity and effects of therapy in older children with sarcoidosis. However, in adult patients with sarcoidosis, serum ACE levels generally have not been a useful guide to predict the clinical course and the response to therapy, because ACE measurements do not necessarily correlate with symptoms, findings on pulmonary function testing, or findings on chest radiographs and they do not assist in determining prognosis.

Chest Radiography

The most helpful noninvasive test to support the diagnosis of sarcoidosis is chest radiography, which typically shows bilateral hilar lymph node enlargement, frequently with right paratracheal enlargement but normal lungs. (See the images below.)

Chest radiograph showing bilateral hilar lymphaden Chest radiograph showing bilateral hilar lymphadenopathy in a 10-year-old girl with sarcoidosis.
Chest radiograph showing patchy diffuse pulmonary Chest radiograph showing patchy diffuse pulmonary infiltrates involving both lung fields in a 12-year-old girl at onset of her sarcoidosis (left). A repeated study 6 months later showing almost complete resolution of the infiltrates (right).

Pulmonary disease and abnormal findings on chest radiography are more common in children with sarcoidosis who are aged 8-15 years, occurring in 94-100% of patients. In contrast, approximately 22% of children with sarcoidosis who are younger than age 4 years have pulmonary involvement.

Bilateral hilar adenopathy is the most common chest radiographic finding in children and occurs in almost all cases. Other radiographic findings include paratracheal adenopathy (75-88%) and subcarinal adenopathy (42%). The hilar lymphadenopathy is typically symmetrical, although it may appear unilateral in rare instances.

Pulmonary parenchymal involvement is common and predominantly appears radiographically as an interstitial pattern, although nodular, alveolar, and fibrotic patterns have also been described. Uncommon manifestations include pleural effusion, pneumothorax, pleural thickening, calcification, atelectasis, and cor pulmonale.

Exclude other diseases, including tuberculosis, histoplasmosis or other fungal infection, or lymphoma, that can also demonstrate hilar adenopathy similar to sarcoidosis. In one series of consecutive cases of bilateral hilar adenopathy, sarcoidosis accounted for 74% of cases and lymphoma accounted for 20% of cases.

Staging

Traditionally, pulmonary involvement in sarcoidosis has been classified into 5 stages based on chest radiography findings; however, the prognostic value of this classification in children is uncertain.

  • Stage 0 - Normal findings on chest radiograph

  • Stage I - Bilateral hilar lymphadenopathy, which may be accompanied by paratracheal adenopathy

  • Stage II - Bilateral hilar adenopathy with pulmonary infiltrates

  • Stage III - Parenchymal infiltrates without hilar adenopathy

  • Stage IV - Advanced fibrosis with evidence of honey-combing, hilar retraction, bullae, cysts, and emphysema

CT Scanning and Scintigraphy

High-resolution CT scanning

High-resolution computed tomography (HRCT) scanning of the chest may be helpful in delineating the distribution of the parenchymal lung lesions and of hilar adenopathy. Characteristic HRCT scan findings include smooth or nodular peribronchovascular interstitial thickening; small, well-defined nodules in relation to the pleural surfaces; interlobular septa or centrilobular structures; and peribronchovascular distribution of nodules in the central lung and upper lobes.[23] . A recent study found no correlation between HRCT and pulmonary function tests; forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), forced expiratory flow during mid half of the FVC (FEF25-75) and specific dynamic compliance (SpecCLdyn) at the time of diagnosis, however use of linear mixed models showed a significant association between HRCT and pulmonary function tests thus reducing the needs of HRCT during follow up.[24]

Gallium-67 scanning

67 Ga scanning shows increased isotope uptake in the affected organ; however, increased uptake can occur with any inflammatory disease. These findings are present in a small number of cases. Furthermore, because of its expense, nonspecificity, and significant radiation exposure, gallium scanning is not recommended as a diagnostic tool. Several adult studies have shown a poor correlation between gallium scans and clinical course and other objective measures.

Kveim-Siltzbach Test

The historic Kveim-Siltzbach skin anergy test is performed by the intradermal injection of homogenized spleen or lymph node obtained from a patient with sarcoidosis. Biopsy of the skin site 4-6 weeks later shows typical sarcoid granulomas in a high percentage of affected patients, especially those with lymphadenopathy and skin lesions. The Kveim-Siltzbach test is not approved for general use by the US Food and Drug Administration (FDA) because of difficulty in obtaining standardized test material and reports of varying sensitivity and specificity of the test.

Biopsy

Tissue biopsy findings that confirm the diagnosis of childhood sarcoidosis have been documented in 90% of cases reported in the literature. Obtain biopsy specimens from the most readily accessible organ with the least invasive method. Preferred sites of biopsy in children include palpable peripheral lymph nodes, superficial skin lesions, and, occasionally, the conjunctiva, because performing biopsy on these tissue sites is easy and biopsies performed on these sites have a high sensitivity rate.

Other potential biopsy sites include enlarged lacrimal or parotid glands, lung tissue (by transbronchial biopsy), mediastinal lymph nodes (by mediastinoscopy), and lung tissue (by open or thoracoscopic lung biopsy). A diagnostic liver biopsy may be useful if no peripheral lymphadenopathy is present and hepatomegaly or abnormal liver function test findings occur. Bone marrow biopsy specimen may reveal sarcoid granulomas in some cases. Do not perform biopsy on erythema nodosum lesions, because they do not show granulomas.

In adult patients, transbronchial lung biopsy is the recommended procedure, yielding positive results in 40-90% of cases when 4-5 biopsy specimens are obtained from different sites. Transbronchial lung biopsy may be performed in adolescents, but it is technically difficult in younger children. If bronchoscopic findings are negative and mediastinal adenopathy is documented on the conventional CT scan, perform mediastinoscopy.

Data suggest that CT scan ̶ guided transthoracic biopsy can be helpful in the diagnostic evaluation of children who present with nonmalignant pulmonary disease. Some investigators have demonstrated that multidetector CT scan ̶ guided transthoracic lung biopsy may be helpful in evaluating pulmonary manifestations of childhood sarcoidosis, enabling accurate diagnosis and prompt initiation of appropriate therapy.[25]

Thoracoscopic lung biopsy or open lung biopsy is indicated in rare cases, that is, when bronchial or transbronchial biopsy results are nondiagnostic, no other accessible sites for biopsy are identified, and parenchymal involvement is observed on the chest radiograph or lung CT scan.

Bronchoalveolar Lavage

BAL performed through a flexible fiberoptic bronchoscope has proven to be a safe and well-tolerated procedure to assess the intensity of alveolitis in children, as measured by the BAL lymphocyte count and CD4+/CD8+ T cell ratio. However, defining the normal cellular and noncellular components of BAL fluid in children has been difficult.

Lymphocytic alveolitis precedes granuloma formation in the lungs and is the earliest sign of disease activity in pulmonary sarcoidosis in older children, as reported in adults. BAL fluid typically demonstrates an increased number of T lymphocytes (ranging from 20-70%), most of which are activated helper-inducer T lymphocytes that can cause the CD4+/CD8+ T lymphocyte ratio to be markedly increased (in the range of 2-13). The increased CD4+/CD8+ ratio may help in differentiating sarcoidosis from tuberculosis, as well as from Hodgkin lymphoma and non-Hodgkin lymphoma.

Other investigators have studied BAL fluid variables, such as yield, cell count, and proportions of cellular components, to differentiate sarcoidosis from other interstitial lung disorders. However, none of the BAL fluid findings are specific for sarcoidosis, including the CD4+/CD8+ cell ratio, and, although BAL is a useful research tool, its usefulness as a diagnostic test is limited, especially in children.

Histologic Findings

The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. Very active disease may be accompanied by some fibrinoid necrosis. To further support the diagnosis of sarcoidosis, exclude infectious granulomatous conditions (eg, histoplasmosis, blastomycosis, tuberculosis) by special stains and cultures.

An experienced pathologist must review characteristic pathologic changes. Clinical history, system review, and detailed physical examination should guide the clinician to choose the biopsy site that can be reached in the least invasive fashion.

 

Treatment

Approach Considerations

The goal of therapy in sarcoidosis is to prevent or minimize inflammation and granuloma formation (ie, disease activity) leading to organ system dysfunction, which may ultimately cause end-stage organ destruction by the development of hyaline fibrosis. Treatment is symptomatic and supportive.

Glucocorticoids remain the therapy of choice for children with multisystem involvement. However, because the disease clears spontaneously in approximately 50% of patients and because permanent organ dysfunction often does not improve with glucocorticoids, no clear consensus has been established among clinicians as to the criteria for treatment.

Some reports suggest that methotrexate (MTX) administered orally in low doses in childhood sarcoidosis is effective, safe, and exhibits steroid-sparing properties. Data regarding efficacy of other immunosuppressive agents, such as azathioprine, cyclophosphamide, chlorambucil, and cyclosporine in adult sarcoidosis, have been limited to anecdotal, uncontrolled reports.

Consultations

Pulmonologist

Determining the extent and activity of the inflammatory process in the organs at greatest risk, such as the lung, is critical to make decisions regarding therapy in sarcoidosis. A complete medical history and physical examination in conjunction with chest radiography and pulmonary function tests are helpful in evaluating the pulmonary disease.

Ophthalmologist

Referral to a pediatric ophthalmologist is invaluable in suspected cases of childhood sarcoidosis, because eye lesions frequently occur. Decisions concerning therapy are based on slitlamp examination and tests for visual acuity.

Rheumatologist

All suspected cases of childhood sarcoidosis necessitate prompt referral to a pediatric rheumatologist for the initial diagnostic evaluation and subsequent management, including long-term follow-up.

 

Medication

Medication Summary

The current therapy of choice for childhood sarcoidosis with multisystem involvement is corticosteroids, whereas a patient with anterior uveitis may be a candidate for topical steroids alone. The optimal corticosteroid dose and the duration of corticosteroid therapy for sarcoidosis have not been studied in randomized, controlled trials. Dose and duration of therapy must often be individualized.

Oral prednisone or prednisolone is usually initiated at 1-2 mg/kg/day for 4-8 weeks as induction treatment. This treatment is continued until the clinical manifestations of the disease resolve or show significant improvement.

Slowly taper the dose in patients who respond to steroids over a period of 2-3 months to an appropriate maintenance dose (ie, the lowest dose that controls the activity of the disease, which often is in the range of 10-15 mg/d or a qod regimen). Depending on which organs are involved and on the activity of the disease, maintenance treatment is usually required for at least 6 months for most age groups and is then tapered if possible.

Some patients may relapse, either during steroid taper or after discontinuation of the drug. In such cases, resume treatment with a dosage similar to that used in the induction treatment. In a few cases, patients are steroid-dependent and need long-term treatment with relatively high doses to achieve satisfactory responses. In such cases, serious complications due to chronic corticosteroid therapy, such as growth failure and bone disease, may occur. Moreover, a subset of patients with persistent active or progressive sarcoidosis may be unresponsive to corticosteroids; therefore, steroid-sparing agents are needed.

Methotrexate

Immunosuppressive agents, such as low-dose MTX, have been used to treat rheumatoid arthritis for the last 2 decades. In patients with JRA, a double-blind, controlled study showed that MTX was efficacious and had little toxic effect. Randomized, controlled trials have demonstrated that MTX has clinically important benefits and steroid-sparing properties in many chronic inflammatory disorders, including Crohn disease, multiple sclerosis, and asthma. Most reports on MTX therapy in sarcoidosis have involved adults.

Lacher's initial case report in 1968 described the successful use of MTX in a 27-year-old woman with sarcoidosis who was unresponsive to glucocorticoids and vinblastine treatment. Since this report, numerous small, uncontrolled clinical trials have consistently shown MTX to be beneficial in patients with steroid-resistant disease or in those with unacceptable adverse effects from glucocorticoids.

Lower and Baughman treated 15 adult patients on prednisone who had progressive disease or excessive steroid adverse effects with MTX for 6 months and found that 12 patients had improvement in objective parameters. Five relapses occurred as treatment was withdrawn.[26]

In a larger, subsequent series, these investigators treated 50 symptomatic patients for 2 years with MTX and showed an improvement in pulmonary function and a reduction in steroid dosage in 66% of patients. Although MTX is steroid-sparing, however, its use has been associated with significant adverse effects, including hepatotoxic effects (it may lead to fibrosis or cirrhosis), neutropenia, cough, obstructive lung disease, and hypersensitivity pneumonitis. It is also teratogenic and has been shown to cause spontaneous abortions in early pregnancies.

Advise male and female patients to use appropriate birth control for as long as 6 months after discontinuation of MTX. Although some concern exists that the drug has the potential to cause malignancy, several large series have failed to show an increase in malignancy in cases of MTX-treated patients followed for up to 10 years.

In a study, Gedalia et al found symptom improvement in pediatric patients treated with MTX. In the report, the investigators described their experience with 6 months of low-dose oral MTX following a strict protocol in 7 children with biopsy-proven sarcoidosis.[27] Corticosteroids were used for the first 6 weeks only in 6 of 7 cases. The patients were treated with low-dose MTX for 1 year, and the clinical response was scored using a composite of the various symptoms encountered.

In the study, MTX therapy resulted in improvement in clinical symptom score and decreased mean daily steroid dosage. Additionally, parallel decreases in the ESR and the mean serum ACE concentrations were observed. No adverse effects occurred in these patients, all of whom received folate supplementation. The authors suggested that MTX administered orally in low doses in childhood sarcoidosis was effective, safe, and had steroid-sparing properties.

However, because of significant concerns regarding the risk of long-term adverse effects of MTX therapy and the lack of a randomized, controlled trial, some experts have questioned the therapeutic index of MTX for corticosteroid-resistant sarcoidosis in children. Liver biopsy performed after a cumulative MTX dose of 1-1.5 g has been proposed to monitor liver toxicity. MTX toxicity can be minimized by the use of folic or folinic acid. Successful steroid-sparing treatment with mycophenolate mofetil was described in an adolescent with renal-limited sarcoidosis complicated by renal failure.

Additional medications

Alternative immunosuppressive agents, such as azathioprine, cyclophosphamide, chlorambucil, and cyclosporine, have been tried in adult cases of sarcoidosis with questionable efficacy. The high toxicity profile of these agents, including an increased risk of lymphoproliferative disorders and carcinomas, has limited their use to patients with severe disease that is refractory to other agents. Studies have failed to demonstrate any beneficial effect of inhaled corticosteroids in pulmonary sarcoidosis.

Hydroxychloroquine has been used with success in adults for chronic disfiguring cutaneous sarcoidosis that is unresponsive to corticosteroids, with serial monitoring for ocular toxicity. The quinolones also are efficacious in the management of hypercalcemia in sarcoidosis. Although clinical trials and case reports support the use of antimalarial agents in sarcoidosis, no double-blind placebo-controlled studies have been conducted. Several other agents, such as melatonin, thalidomide, and pentoxifylline, have been reported as useful in some adult patients with refractory sarcoidosis.

Newer treatment strategies have included the use of monoclonal antibodies to TNF-α, such as infliximab. Anecdotal case reports about the use of infliximab in renal sarcoidosis are found in the literature.

Corticosteroids

Class Summary

Pharmacologic therapy inhibits the lymphokine IL-2 from activated helper T lymphocytes (CD4), which controls T cell proliferation and recruitment of these cells from the blood. Therapy decreases the release of IL-1 monocyte chemotactic factor, an initiating event in granuloma formation.

Prednisone

Oral corticosteroids are indicated in patients with pronounced symptomatic disease and/or evidence of progressive damage to involved organs. Systemic therapy is clearly indicated for extrapulmonary sarcoidosis (eg, cardiac disease, neurologic disease, eye disease not responding to topical therapy, hypercalcemia, hepatosplenomegaly, sarcoid hepatitis, marked lymphadenopathy).

Corticosteroid therapy is not indicated for asymptomatic patients with isolated bilateral hilar adenopathy. In contrast, severe respiratory symptoms, decreasing lung function, and progressive pulmonary infiltrates on chest radiograph warrant corticosteroid therapy.

Immunosuppressive agents

Class Summary

These agents have been proposed as an alternative therapy for refractory sarcoidosis in adults, particularly low-dose MTX. Although randomized controlled trials are lacking, recent reports in adults and children suggest that low-dose MTX is effective, safe, and has long-term corticosteroid-sparing properties. Because low-dose MTX displays far fewer adverse effects than other alternative agents, such as cyclosporin A or cyclophosphamide, select MTX first in refractory sarcoidosis.

Methotrexate (Trexall, Rheumatrex)

Low-dose MTX therapy has been used to treat various manifestations of sarcoidosis in adult patients, such as skin disease, musculoskeletal complications, progressive pulmonary sarcoidosis, and neurosarcoidosis. In pediatric sarcoidosis, low-dose MTX has been used to treat a subset of patients with persistent active or progressive disease that is unresponsive to corticosteroids.