Extrapulmonary Manifestations of Sarcoidosis




Sarcoidosis is a systemic disease characterized by the development of epithelioid granulomas in various organs. Although the lungs are involved in most patients with sarcoidosis, virtually any organ can be affected. Recognition of extrapulmonary sarcoidosis requires awareness of the organs most commonly affected, such as the skin and the eyes, and vigilance for the most dangerous manifestations, such as cardiac and neurologic involvement. In this article, the common extrapulmonary manifestations of sarcoidosis are reviewed and organ-specific therapeutic considerations are discussed.


Key points








  • Sarcoidosis is a systemic granulomatous disease that most commonly affects the lungs, skin, and eyes.



  • All patients with sarcoidosis should be evaluated for cardiac involvement, which may lead to life-threatening arrhythmias.



  • Although many patients can be monitored without treatment, those with worsening pulmonary disease or cardiac, neurologic, or vision-threatening ocular disease require prompt therapy.



  • Most manifestations of sarcoidosis can be treated with corticosteroids, with the highest doses used for cardiac and neurologic involvement.



  • Disease-modifying antirheumatic drugs such as methotrexate and biological therapies such as antitumor necrosis factor agents are increasingly being used for refractory disease.






Introduction


Sarcoidosis is a systemic disorder characterized by the aberrant development of granulomas within various organs in the body. The lungs are involved in 90% of patients, and the skin, eyes, and heart are affected in a significant fraction of patients. The disease remits within 3 years in most patients, whereas 10% to 30% of patients develop chronic disease requiring ongoing treatment. Significant variation in disease incidence and manifestations is well recognized. The incidence rate of sarcoidosis in Northern Europe is between 5 and 40 cases per 100,000 people, compared with a rate of 1 to 2 cases per 100,000 in Japan. Cardiac and ocular disease are more common in Japanese patients, whereas joint symptoms and erythema nodosum are more common in northern Europeans. In the United States, the age-adjusted annual incidence of sarcoidosis in black patients is 35.5 per 100,000, 3 times higher than that of white patients (10.9 per 100,000). Black patients are more likely to develop ocular and granulomatous skin involvement and more frequently suffer chronic, debilitating disease.


Although there are no universal criteria for the diagnosis of sarcoidosis, a diagnosis is likely when a patient presents with signs or symptoms consistent with sarcoidosis and has granulomas shown on tissue biopsy. Most patients with sarcoidosis develop pulmonary involvement, which may be asymptomatic or may cause dyspnea, dry cough, or chest discomfort. Chest radiographs show abnormalities classified into 5 stages ( Table 1 ). Laboratory testing may reveal an increased angiotensin-converting enzyme (ACE) level; however, this test lacks sufficient specificity to make a diagnosis of sarcoidosis. Examination of bronchoalveolar lavage fluid may help in the diagnosis, because a markedly increased ratio of CD4+ T cells to CD8+ T cells in the bronchoalveolar lavage fluid is relatively specific for sarcoidosis; however, diagnosis is generally confirmed by showing epithelioid granulomas on transbronchial biopsy. Diagnosis of sarcoidosis also requires the exclusion of other causes of granulomatous disease, including mycobacterial infections such as tuberculosis and leprosy, fungal infections such as coccidiomycosis and histoplasmosis, syphilis, exposures to particulates such as beryllium, and granulomatosis with polyangiitis.



Table 1

Chest radiographic staging






















Stage Radiographic Findings
Stage 0 Normal radiograph
Stage I Bilateral hilar lymphadenopathy
Stage II Bilateral hilar adenopathy and parenchymal infiltrates
Stage III Parenchymal infiltrates alone
Stage IV Pulmonary fibrosis


Extrapulmonary disease may manifest before, concurrent with, or after development of pulmonary disease, thus patients with sarcoidosis come to the attention of a range of providers depending on the location of symptoms. Awareness of the common and protean manifestations of sarcoidosis is required to recognize the disease and monitor for additional disease complications. In this article, first, the immunopathology of sarcoidosis is reviewed. The common extrapulmonary manifestations of sarcoidosis are then reviewed, and organ-specific considerations in treatment are discussed.




Introduction


Sarcoidosis is a systemic disorder characterized by the aberrant development of granulomas within various organs in the body. The lungs are involved in 90% of patients, and the skin, eyes, and heart are affected in a significant fraction of patients. The disease remits within 3 years in most patients, whereas 10% to 30% of patients develop chronic disease requiring ongoing treatment. Significant variation in disease incidence and manifestations is well recognized. The incidence rate of sarcoidosis in Northern Europe is between 5 and 40 cases per 100,000 people, compared with a rate of 1 to 2 cases per 100,000 in Japan. Cardiac and ocular disease are more common in Japanese patients, whereas joint symptoms and erythema nodosum are more common in northern Europeans. In the United States, the age-adjusted annual incidence of sarcoidosis in black patients is 35.5 per 100,000, 3 times higher than that of white patients (10.9 per 100,000). Black patients are more likely to develop ocular and granulomatous skin involvement and more frequently suffer chronic, debilitating disease.


Although there are no universal criteria for the diagnosis of sarcoidosis, a diagnosis is likely when a patient presents with signs or symptoms consistent with sarcoidosis and has granulomas shown on tissue biopsy. Most patients with sarcoidosis develop pulmonary involvement, which may be asymptomatic or may cause dyspnea, dry cough, or chest discomfort. Chest radiographs show abnormalities classified into 5 stages ( Table 1 ). Laboratory testing may reveal an increased angiotensin-converting enzyme (ACE) level; however, this test lacks sufficient specificity to make a diagnosis of sarcoidosis. Examination of bronchoalveolar lavage fluid may help in the diagnosis, because a markedly increased ratio of CD4+ T cells to CD8+ T cells in the bronchoalveolar lavage fluid is relatively specific for sarcoidosis; however, diagnosis is generally confirmed by showing epithelioid granulomas on transbronchial biopsy. Diagnosis of sarcoidosis also requires the exclusion of other causes of granulomatous disease, including mycobacterial infections such as tuberculosis and leprosy, fungal infections such as coccidiomycosis and histoplasmosis, syphilis, exposures to particulates such as beryllium, and granulomatosis with polyangiitis.



Table 1

Chest radiographic staging






















Stage Radiographic Findings
Stage 0 Normal radiograph
Stage I Bilateral hilar lymphadenopathy
Stage II Bilateral hilar adenopathy and parenchymal infiltrates
Stage III Parenchymal infiltrates alone
Stage IV Pulmonary fibrosis


Extrapulmonary disease may manifest before, concurrent with, or after development of pulmonary disease, thus patients with sarcoidosis come to the attention of a range of providers depending on the location of symptoms. Awareness of the common and protean manifestations of sarcoidosis is required to recognize the disease and monitor for additional disease complications. In this article, first, the immunopathology of sarcoidosis is reviewed. The common extrapulmonary manifestations of sarcoidosis are then reviewed, and organ-specific considerations in treatment are discussed.




Immunopathology


The hallmark of sarcoidosis is the development of epithelioid granulomas. Autopsy and imaging studies suggest that granulomatous involvement can be more widespread in patients with sarcoidosis than is apparent clinically. Granulomas in different organs tend to conform to a similar histologic pattern, consisting of a dense collection of epithelioid macrophages and CD4+ T cells, with fewer CD8+ T cells restricted to the periphery. Part of the diagnostic challenge is that similar appearing granulomas may form in response to several different stimuli, some of which must be excluded to diagnose sarcoidosis. Exposure to beryllium causes a granulomatous disease similar in appearance to sarcoidosis; however, chronic beryllium disease is generally considered a distinct entity.


Hints as to the cause of sarcoidosis have been derived from observations about the localization of lesions, spatial-temporal patterns of disease, immunophenotyping, and genetics; however, a cohesive understanding of the disease remains elusive. The pattern of tissue involvement, with a predominance of symptoms in the lungs, skin, and eyes, suggests that exposure to an external trigger plays a key role in initiating the disease. One potential set of triggers is environmental particulate matter. Just as particles of beryllium clearly cause a granulomatous reaction, other types of particulate matter have also been suspected in sarcoidosis. The most comprehensive evaluation for such a trigger was ACCESS (A Case Control Etiologic Study of Sarcoidosis), which evaluated exposure histories of more than 700 patients with recently diagnosed sarcoidosis. The study found no association of sarcoidosis with occupational exposure to wood dust, metal, silica, or talc but did report that occupational exposure to insecticides was associated with a modestly increased risk of sarcoidosis. The increased frequency of sarcoidosis in people exposed to dust and debris from the World Trade Center collapse further supports the association between particulates and sarcoidosis.


An infectious cause of sarcoidosis has also been long suspected, in particular because certain well-characterized infections, such as tuberculosis and leprosy, also induce granulomas. Presentations of Löfgren syndrome were noted to cluster in the spring and early summer, suggesting a possible infectious agent. Person-to-person transmission was suggested by observations from the Isle of Man that patients diagnosed with sarcoidosis were more likely than healthy control patients to have been previously in contact with another person with sarcoidosis. The ACCESS study also noted a positive association between sarcoidosis and occupational exposure to areas with musty odors, which perhaps carry higher loads of bioaerosols containing molds and mycobacteria.


The case for a mycobacterial infection underlying at least some cases of sarcoidosis is particularly strong. Several reports have described isolation of mycobacterial DNA from patients with sarcoidosis, and a meta-analysis of 31 studies showed that detection of mycobacterial DNA by polymerase chain reaction (PCR) has been reported in about one-quarter of patients with sarcoidosis tested, although evidence of publication bias was noted. Propionibacterium , Mycoplasma , viruses, and Borrelia have been implicated in some patients. Given the variety of possible exposures associated with this disease, it seems unlikely that a single trigger explains all of sarcoidosis. Rather, it is more likely that several triggers may be able to initiate a granulomatous response in a susceptible host, causing a clinical presentation of sarcoidosis.




Extrapulmonary manifestations


Cardiac


Cardiac sarcoidosis is a leading cause of death in sarcoidosis, responsible for 13% to 25% of deaths caused by sarcoidosis in US patients with sarcoidosis, and strikingly, 58% to 85% of deaths in Japanese patients with sarcoidosis. Thus, evaluation for cardiac disease in all patients with sarcoidosis is particularly important. Cardiac involvement does not correlate with the severity of pulmonary involvement and can be difficult to diagnose in the context of active pulmonary disease. In the United States, about 5% of patients with sarcoidosis have clinical manifestations of cardiac sarcoidosis; however, autopsy analyses show that myocardial granulomas can be found in 20% to 30% of patients. More severe cardiac disease correlates with an increased risk of severe arrhythmias. Symptoms suggestive of conduction disease include significant palpitations, presyncope, and syncope. The presence of such symptoms increases the likelihood of cardiac sarcoidosis by 8-fold, with significant palpitations being the most informative symptom. Sarcoidosis has been found as a cause of previously unexplained atrioventricular block or early pacemaker dependence. Sarcoidosis may also cause a dilated cardiomyopathy, associated with typical symptoms of heart failure such as dyspnea, weight gain, and edema, and can rarely cause valvular involvement.


All patients with sarcoidosis should have an electrocardiogram as part of the initial evaluation, although electrocardiograms are an insensitive method of evaluating for cardiac sarcoidosis. Electrocardiographic abnormalities may include PR prolongation, atrioventricular nodal blockade, or atrial or ventricular premature beats. Patients suspected of having conduction disease from symptoms or an abnormal electrocardiogram should also undergo Holter monitoring. Rhythm abnormalities detected by Holter monitoring increase the likelihood of finding imaging abnormalities consistent with sarcoidosis by almost 20-fold. The presence of ventricular dysfunction can be evaluated by a transthoracic echocardiogram.


Imaging by cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) have facilitated detection of cardiac sarcoidosis, and the combination of clinical assessment plus imaging has been reported to show cardiac involvement in almost 40% of patients with sarcoidosis. Cardiac MRI may show a pattern of late gadolinium enhancement in the basolateral area of the left ventricle, with lesions most frequently seen in the midcardial to epicardial regions, distinct from the subendocardial regions commonly affected by ischemia. The ability of cardiac MRI to differentiate active inflammation from previous injury is not fully defined; however, serial cardiac MRI evaluation has been suggested to have usefulness in following the response of cardiac sarcoidosis to corticosteroid treatment.


Nuclear imaging by PET shows focally increased uptake of the radioactive tracer 18 F-fluorodeoxyglucose (FDG), most often in the basal and midanteroseptal-lateral areas of the left ventricle. This method seems more sensitive than cardiac MRI in detecting cardiac sarcoidosis, with a reported sensitivity of 89% and specificity of 78%. Because FDG PET theoretically depends on the presence of inflammatory cells to take up the radiolabeled tracer, this modality may be particularly useful in monitoring disease activity. Recently, high-sensitivity cardiac troponin T has also been suggested as a means of assessing the presence and activity of cardiac sarcoidosis.


The presence of granulomatous disease infiltrating the myocardium may be confirmed by endocardial biopsy. However, cardiac sarcoidosis is patchy and favors areas of the left ventricle, whereas endocardial biopsies are typically taken from the right side of the interventricular septum; thus, false-negative results are common because of limitations of sampling.


Cutaneous


The skin is affected in 20% to 35% of patients with sarcoidosis, and skin lesions are often present at the time of diagnosis. Cutaneous manifestations of sarcoidosis that are caused by granulomas are referred to as specific for sarcoidosis, whereas other lesions are considered nonspecific. The most common nonspecific cutaneous manifestation is erythema nodosum, which typically manifests as painful nodules on the lower legs, usually in the setting of an acute presentation of sarcoidosis. Erythema nodosum is more common in women and northern Europeans, and is associated with a favorable overall prognosis. Histologically, the lesions show a septal panniculitis rather than granulomas.


Specific forms of cutaneous sarcoidosis occur in many patterns, with the most common being papular, maculopapular, and plaque lesions. Papular lesions occur commonly on the face, often around the eyes, whereas maculopapular lesions tend to favor the neck and trunk ( Fig. 1 ). Both are associated with milder pulmonary disease and a good prognosis, whereas plaque lesions are more often associated with chronic disease requiring steroid treatment. Variants of papular and plaque sarcoidosis can take on many forms, including lesions that resemble psoriasis, lichen planus, verrucae, and lupus.




Fig. 1


Examples of cutaneous sarcoidosis. ( A ) Waxy papules over the eyelid of a patient with systemic sarcoidosis. ( B ) Granulomatous inflammation within the area of 1 color of a tattoo in a patient with systemic sarcoidosis.

( Courtesy of Dr J. Merola, Brigham and Women’s Hospital, Boston, MA.)


A unique lesion of sarcoidosis, termed lupus pernio (unrelated to systemic lupus erythematosus) causes distinctive violaceous, indurated lesions on the face, often on the nasal alae. These lesions are often disfiguring and may damage underlying soft tissue and bony structures, causing nasal ulcerations, septal perforation, and deformity. Bony cysts may develop under affected areas. Lupus pernio occurs more frequently in female patients and is associated with more frequent pulmonary parenchymal involvement and more aggressive systemic disease.


Cutaneous lesions in sarcoidosis may also be precipitated by skin trauma. So-called scar sarcoidosis can occur in response to abrasions, punctures, or tattoos. Reactions to tattoos may form in response to 1 or multiple colors within a tattoo, and may develop even years after placement of the tattoo. Such reactions can be the initial presentation of sarcoidosis and should prompt the investigation of systemic manifestations of sarcoidosis. Granulomas may also occur in the subcutaneous tissue below otherwise normal-appearing skin, causing painless or only mildly tender nodules. Such nodules, which may be the presenting sign of sarcoidosis, can be evaluated by ultrasonography or MRI, and biopsy reveals granulomas within the panniculus. Most patients with subcutaneous sarcoidosis have hilar lymphadenopathy, and many are subsequently found to have granulomas in other organs. Recognition of skin lesions is important in sarcoidosis, because identification of the disease by skin biopsy may obviate more invasive diagnostic procedures.


Ophthalmologic


The eye is the third most frequently involved organ, affected in between 10% and 60% of patients. Granulomatous disease may cause inflammation either within the eye or in adnexal structures. Ocular involvement occurs at higher rates in women and African Americans, and seems more common in Japanese cohorts.


Uveitis is the most common ocular manifestation and can be vision-threatening; thus, all patients diagnosed with sarcoidosis should have an ophthalmologic evaluation ( Fig. 2 ). Symptoms of uveitis may include tearing, photophobia, pain, and injection; however, about one-third of patients with uveitis caused by sarcoidosis have no ocular symptoms. There are 2 peaks of incidence: the first in the third decade (more often associated with an acute course) and the latter in the sixth to seventh decade (more often associated with a chronic course). Ocular inflammation is most often bilateral, and the anterior segment is involved in 70% to 85% of cases. Involvement of the posterior segment occurs less frequently but is seen more often in whites, particularly elderly women, and is associated with a higher risk of central nervous system (CNS) involvement. Symptoms of blurry vision, hyperopia, visual field deficits, or floaters may suggest the development of retinal vasculitis, which in sarcoidosis is usually a retinal periphlebitis, sparing the retinal arteries. Uveitis occurring concomitant with fever, parotitis, and facial nerve paralysis has been termed uveoparotid fever or Heerfordt syndrome.




Fig. 2


Examples of ocular sarcoidosis. ( A ) Scleritis in a patient with sarcoidosis. ( B ) Optic nerve swelling on fundoscopic exam.

( Courtesy of Dr G. Papaliodis, Massachusetts Eye and Ear Infirmary, Boston, MA.)


Ocular inflammation may be the presenting symptom of sarcoidosis; however, showing granulomatous disease in the eye is often not feasible, because biopsy is generally not pursued in patients presenting with uveitis. Biopsy of another involved site, if available, is useful. Given the frequent lack of ocular histologic evidence, an international consensus conference delineated criteria for the diagnosis of ocular sarcoidosis, which include a description of 7 clinical signs on ophthalmologic examination suggestive of ocular sarcoidosis. The conference also outlined different levels of certainty regarding the diagnosis of ocular sarcoidosis based on ophthalmologic evaluation, laboratory investigation, and imaging ( Table 2 ).



Table 2

Diagnosis of ocular sarcoidosis



















Certainty of Ocular Sarcoidosis Diagnosis Findings
Definite


  • Uveitis compatible with sarcoidosis



  • Biopsy of another organ supporting sarcoidosis

Presumed


  • Uveitis compatible with sarcoidosis



  • Biopsy not performed



  • Bilateral hilar adenopathy on chest imaging

Probable


  • 3 signs of uveitis compatible with sarcoidosis



  • Biopsy not performed



  • 2 other investigations supporting sarcoidosis:




    • Chest computed tomography abnormalities



    • Increased ACE or lysozyme level



    • Abnormal liver enzyme tests



    • Negative PPD in a BCG-vaccinated or previously PPD-positive patient


Possible


  • 4 signs of uveitis compatible with sarcoidosis



  • Lung biopsy negative



  • 2 other investigations supporting sarcoidosis:




    • Chest computed tomography abnormalities



    • Increased ACE or lysozyme level



    • Abnormal liver enzyme tests



    • Negative PPD in a BCG-vaccinated or previously PPD-positive patient



In all cases, alternative causes of uveitis, in particular tuberculosis, must be excluded.

Abbreviations: BCG, bacille Calmette-Guérin; PPD, purified protein derivative.


Involvement of the orbit and adnexal structures is less common than uveitis, occurring in 8% to 27% of cases, and occurs independently of uveitis. Adnexal involvement occurs in the form of lacrimal gland infiltration, formation of an orbital mass, or less commonly, involvement of the lacrimal sac. The lacrimal gland is the most commonly affected site, with an estimated incidence of 5% to 16% in sarcoidosis. Patients may present with edema or erythema of the eyelid or symptoms of dry eye, which may mimic Sjögren syndrome. Progressive lacrimal gland disease may cause insufficient tear production; however, sicca symptoms do not necessarily correlate with lacrimal gland infiltration. Occasionally, patients may present with a palpable eyelid mass. A solid orbital mass may be caused by sarcoidosis; however, it is debated whether an isolated, solitary orbital granulomas should be considered sarcoidosis or a distinct entity.


Neurologic


Neurologic symptoms affect an estimated 5% of patients with sarcoidosis and may also be the presenting manifestation of systemic sarcoidosis. Granulomatous inflammation can affect the cranial nerves, peripheral nerves, or brain parenchyma, and autopsy studies suggest that granulomas are frequently present in these areas in the absence of symptoms. Cranial nerve dysfunction is the most common neurologic manifestation. The facial nerve is the most frequently affected cranial nerve, followed by the optic and vestibulocochlear nerves, although any cranial nerve can be involved.


Lesions occurring in the peripheral nervous system most often cause an axonal or sensory peripheral neuropathy, although sensory-motor and myopathic patterns are also seen. Suspected peripheral nerve lesions can be confirmed by evaluation with nerve conduction studies and electromyography. Histologically, granulomas form within the epineurium or perineurinum, frequently accompanied by some component of granulomatous angiitis. Involvement of the endoneurium may also occur, perhaps via inflammatory cell invasion along septae or via microvessels, which inflicts more severe injury to the nerve. Peripheral nervous system involvement tends to respond to corticosteroid treatment and carries a better prognosis than does CNS involvement.


Granulomatous involvement of the brain parenchyma is one of the most serious complications of sarcoidosis. However, attributing neurologic dysfunction to sarcoidosis is challenging, particularly in the absence of identifiable granulomatous disease in other organs. Symptoms of headache, nausea, and ataxia raise suspicion for cerebellar or brainstem involvement. Visual impairment, diplopia, and seizures may also occur. The base of the brain is frequently affected, often with granulomatous infiltration of the hypothalamus and pituitary, leading to dysfunction of the hypothalamic-pituitary axis. Leptomeningeal involvement may yield an appearance of aseptic meningitis, and involvement of the spinal cord may result in myelopathy. Spinal cord involvement tends to occur in older patients with sarcoidosis and can be difficult to distinguish from cervical spondylosis. Neuropsychiatric symptoms are uncommon.


Evaluation for neurosarcoidosis typically includes a lumbar puncture and brain MRI ( Fig. 3 ). Cerebral spinal fluid analysis may reveal an increased cell count with a lymphocytic pleiocytosis, increased protein levels, and oligoclonal bands. A variety of lesions can be seen on brain MRI, including enhancing parenchymal lesions, leptomeningeal thickening or enhancement, and dural involvement. Periventricular white matter lesions may be easily mistaken for lesions from multiple sclerosis. A set of diagnostic criteria has been proposed to help classify patients as having definite, probable, or possible neurosarcoidosis ( Table 3 ).




Fig. 3


Examples of neurosarcoidosis. ( A ) Orbital and dural involvement ( arrow ) on gadolinium-enhanced T1-weighted fat-saturated MRI. ( B ) Diffuse nodular meningeal lesions on gadolinium-enhanced T1-weighted fat-saturated MRI. ( C ) Involvement of the pituitary infundibulum ( arrow ) on gadolinium-enhanced T1-weighted fat-saturated MRI. ( D ) Involvement of the foramen of Magendie ( arrow ) causing hydrocephalus.

( Courtesy of Dr K. Talekar, Thomas Jefferson University Hospital, Philadelphia, PA.)


Table 3

Diagnosis of neurosarcoidosis
















Certainty of Neurosarcoidosis Diagnosis Findings
Definite


  • Presentation suggestive of neurosarcoidosis



  • Nervous system histology with granulomatous disease

Probable


  • Presentation suggestive of neurosarcoidosis



  • One abnormality indicating CNS inflammation:




    • Increased CSF protein or cells



    • CSF oligoclonal bands



    • MRI findings consistent with sarcoidosis




  • Either biopsy of another organ supporting sarcoidosis or 2 of the following a :




    • Increased ACE level



    • Abnormal chest imaging



    • Abnormal gallium scan


Possible


  • Presentation suggestive of neurosarcoidosis



  • Criteria for probable neurosarcoidosis not met

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Extrapulmonary Manifestations of Sarcoidosis

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