sarcoidosis is a systemic inflammatory disease of unknown etiology that can target almost any organ of the body . the most commonly involved organs include the lungs , lymph nodes , skin , and eyes . the clinical presentation and disease course can be extremely variable depending upon the patient population and organ involvement . more than half of patients diagnosed with sarcoidosis experience a limited disease course and remission within 3 years . up to a third of patients develop chronic disease and require long - term therapy . patients with severe pulmonary disease , cardiac disease , or neurosarcoidosis have an increased mortality risk   and often require aggressive immunosuppression . patients suspected of having sarcoidosis may undergo a battery of diagnostic tests that are not specific for sarcoidosis , but rather markers of granulomatous inflammation . angiotensin converting enzyme ( ace ) may be elevated in 6070% of patients with sarcoidosis . lysozyme is another marker of disease activity that , when elevated , might suggest a diagnosis of sarcoidosis . hypercalcemia and hypercalciuria are present in 10% and 30% of patients , respectively , and are thought to be associated with increased calcium absorption . vitamin d dysregulation with hypervitaminosis has also been measured in patients with active disease . because the lungs are the most common site of involvement , chest x - ray or computerized tomography is performed on most patients to aid in diagnosis and identify possible sites for biopsy . positron emission tomography ( pet ) is a more comprehensive study that helps clinicians to understand the extent of organ involvement and to identify possible sites for biopsy . while various diagnostic tests can support a diagnosis , none are confirmatory , and , thus , sarcoidosis is considered a diagnosis of exclusion . experts agree that three criteria must be met prior to assigning a diagnosis of sarcoidosis : ( 1 ) clinical or radiologic findings consistent with sarcoidosis , such as pulmonary disease , uveitis , mediastinal hilar lymphadenopathy , or erythema nodosum ; ( 2 ) tissue biopsy with histologic evidence of noncaseating granulomas ; ( 3 ) absence of other causes of granulomatous disease . a diagnosis of sarcoidosis can be made based solely on clinical features in select cases , such as lfgren 's syndrome . the classic triad of lfgren 's syndrome is fever , bilateral hilar lymphadenopathy , and polyarthralgias ; erythema nodosum is now considered additional diagnostic criterion . in these patients , a diagnosis of sarcoidosis can be made in lieu of biopsy [ 1214 ] . in patients who are unable to undergo biopsy or who do not have appropriate sites for biopsy , ocular involvement occurs in 1183% of cases of sarcoidosis patients and can lead to significant morbidity [ 1618 ] . the diagnosis of sarcoidosis in patients with ocular disease can be complicated , as intraocular biopsy is not commonly performed for this disease . one retrospective review of patients with biopsy - proven sarcoidosis and uveitis suggested that although the sensitivities of ace and lysozyme are low in isolation , when both tests are used in combination with chest x - ray , over 80% of patients had at least one marker suggestive of sarcoidosis . the rate increases to over 90% when ace and lysozyme are combined with a chest ct . initial management of patients with systemic sarcoidosis is challenging because evidence exists that the use of systemic corticosteroids actually increases the likelihood of relapse . in patients with chronic systemic disease who are effectively treated with corticosteroids , as many as 74% may relapse within 1 month of stopping the medication . in contrast , only approximately 14% of patients who go into spontaneous remission without treatment relapse . in the case of active ocular disease , patients are treated if symptomatic or if they develop vision threatening sequelae of ocular inflammation , such as cystoid macular edema or retinal ischemia . understanding the epidemiology of sarcoidosis is complicated by the variability in presentation and diagnostic criteria and the disease is certainly underdiagnosed . as an example , one recent study reported sarcoidosis in 22% of patients with mediastinal incidentalomas identified on chest ct . sarcoidosis presents most often in young adults under the age of 50 , with the highest incidence reported in patients between 20 and 39 years of age . countries with a high prevalence of sarcoidosis include scandinavian countries [ 23 , 24 ] , which include predominantly white patients , and the united states , where black patients are more often affected [ 22 , 25 ] and are diagnosed almost 10 years earlier than whites . black americans are also more likely to have extrapulmonary disease and a chronic disease course [ 1 , 26 ] . as with many inflammatory diseases , sarcoidosis affects women more than men . three population - based studies performed in three different countries have produced similar findings . in japan , the rates were 1.2 versus 1.4 per 100,000 in males versus females   and , in the united states , the rates were 5.9 versus 6.3 cases per 100,000 person - years in males versus females . a much higher incidence was measured in sweden , and again the rate was higher in females ( 21.7 per 100,000 person - years ) versus males ( 16.5 per 100,000 person - years ) . a more recent study of patients evaluated at a tertiary referral center found that 65.5% were female . interestingly , men developed symptoms of sarcoidosis and were diagnosed approximately 2 years earlier than women . the increased incidence of sarcoidosis in females has led some to hypothesize that hormones may be a compounding factor . the black women 's health study ( bwhs ) followed black women between 1995 and 2009 and determined that factors not associated with an increase in incidence of sarcoidosis included age at menarche , age at menopause , and parity . a reduced incidence of sarcoidosis was noted with a later age at first birth , and a weak association was suggested between recent birth and reduced incidence of sarcoidosis , although other studies have shown an increase in disease onset in the first postpartum year . one danish cohort study reported a positive association between the number of children and risk of erythema nodosum . the relative risk of a hospital contact for sarcoidosis was 1.61 in patients with 4 or more children versus women without children . a second trend is the recognized second peak of sarcoidosis diagnosed in patients over 50 years of age [ 25 , 27 , 32 ] . late - onset sarcoidosis is more common in women than men , which may factor into the increased mean age of diagnosis reported in women versus men . one study reported a rate of 70.3% females in a study of patients with systemic sarcoidosis diagnosed at 70 years of age or older . a second study compared patients with sarcoidosis who were diagnosed at 65 years of age or older with younger patients . in this study , 83.3% of patients in the older cohort were female versus 50% in the younger group ( p = 0.003 ) . uveitis was more common in the elderly group versus the younger group ( 33.3% versus 8.6% , resp . ; p = 0.002 ) , and 80% of the patients with uveitis in the study were female . white males reportedly have a higher relapse rate of sarcoidosis than white females and african americans of either gender . in this same study , patients with musculoskeletal sarcoidosis as their presenting disease were more likely to develop recurrence , while patients with asymptomatic disease identified on chest imaging were most likely to remain in remission . the array of clinical manifestations associated with sarcoidosis is quite varied and includes both constitutional and organ - specific presentations . in any patient with suspected sarcoidosis , a complete review of systems is essential to help characterize the systemic disease and direct diagnostic testing and management . generalized symptoms of sarcoidosis include fatigue , night sweats , weight loss , arthralgia , and exercise intolerance . gender differences in complaints of fatigue , anxiety , or depression   have been measured in patients with sarcoidosis , but they ultimately paralleled similar studies of the general population . therefore , the authors concluded that sex differences are not specific to sarcoidosis . organ - specific involvement is easier to characterize and several sex differences have been identified in this regard . males tend to have higher rates of pulmonary and cardiac involvement , while females are more prone to peripheral lymph node , skin , eye , and liver disease [ 26 , 38 , 39 ] . the most common cutaneous manifestation is erythema nodosum ( en ) , which consists of red , tender bumps or nodules on the anterior aspect of the leg . lupus pernio , a chronic manifestation of sarcoidosis , is characterized by indurated plaques and discoloration of the skin . it often presents on the nose , cheeks , lips , and ears , most commonly in women of african descent . a prospective study of patients with newly diagnosed sarcoidosis conducted in the united states reported that women are more likely to have en than men , although no significant variation was measured for other cutaneous manifestations . en can be associated with joint swelling , and men with lfgren 's syndrome are more likely to experience periarticular inflammation or arthritis of the ankles . hypercalciuria and hyperprolactinemia have been reported in up to 30% of patients with sarcoidosis [ 9 , 42 ] . . clinical manifestations of hyperprolactinemia are certainly sex - dependent , with men experiencing decreased libido , impotence , and gynecomastia and women complaining of secondary amenorrhea , galactorrhea , or decreased libido . patients with abnormal 67ga - citrate uptake at initial presentation of sarcoidosis , particularly females with anti - thyroid peroxidase antibodies , are at risk of aggressive autoimmune thyroiditis and hypothyroidism and should be carefully monitored . . among men , clinical signs include testicular swelling and a painless mass in the scrotum , while women may experience granulomatous inflammation of the uterus , abnormal bleeding , or erosion of the cervix . genitourinary sarcoidosis affects less than 0.2% of men with sarcoidosis , although evidence of subclinical involvement is present in up to 5% of patients . sarcoidosis can involve almost any ocular structure , including the globe , orbit , and adnexa . as with systemic sarcoidosis , ocular manifestations of the disease are more common in women [ 4648 ] . in african americans , anterior uveitis is the most common ocular manifestation of sarcoidosis   and posterior segment involvement carries a worse visual prognosis . sex - specific differences in posterior segment disease have been described , with a higher rate of cystoid macular edema ( cme ) and worse visual acuity in women [ 51 , 52 ] as well as a trend toward a higher rate of periphlebitis vitreous opacity in men . several studies have demonstrated a second peak of uveitis in patients over the age of 50 , and the vast majority of patients in this subset are female [ 19 , 49 , 50 ] . one consideration in any patient over 50 who presents with newly diagnosed uveitis must be malignancy . in one series , nine patients over the age of 50 were initially diagnosed with primary intraocular lymphoma , but the diagnosis was later determined to be ocular sarcoidosis . seven of the patients had multifocal choroiditis and six had cystoid macular edema , both of which are rare in lymphoma . this highlights two considerations in female patients over the age of 50 that posterior multifocal choroiditis may be more common in women over age of 50   and that chest x - ray is often not sufficient to identify associated pulmonary sarcoidosis . in one study , 11 of 17 patients with a negative chest x - ray had findings suggestive of sarcoidosis on chest computed tomography ( ct ) . this finding has been supported by others   and has led to the recommendation that women over 50 years of age with a clinical presentation consistent with ocular sarcoidosis should undergo chest imaging with ct rather than chest x - ray . patients with sarcoidosis have been successfully treated with numerous anti - inflammatory agents , ranging from topical and systemic corticosteroids to antimetabolites and monoclonal antibodies . because sarcoidosis often occurs in patients of childbearing age , special considerations must be made in patients who may have planned or unplanned pregnancy . the pregnancy class of many medications used to treat sarcoidosis is listed in table 1 . a recent international poll of sarcoidosis specialists found that 80% of physicians considered mtx their preferred second - line treatment option for sarcoidosis , after systemic corticosteroids . they also reported that , in cases of ocular sarcoidosis refractory to topical corticosteroids , mtx is their preferred first - line drug rather than systemic corticosteroids . patients should be adequately educated on the risk of birth defects associated with use of mtx and provided with information on appropriate birth control . although women who plan to get pregnant are at a greater risk of causing direct harm to their unborn fetus , experts agree that both men and women should stop the medication at least 3 months prior to any planned pregnancy . topical and periocular corticosteroids are commonly used to treat uveitis during pregnancy . in the case of topical administration , patients should be educated on punctual occlusion after administering the medication to reduce systemic absorption . intravitreal bevacizumab , a class c drug , has reportedly been used for choroidal neovascularization , a potential complication of posterior segment inflammation which can lead to significant and permanent vision loss , in pregnant patients . in a small series of 4 patients treated off - label with intraocular bevacizumab the use of medications during pregnancy should be individualized and must include discussions regarding the risks and benefits of treatment . patients with sarcoidosis often report a diminished health - related quality of life , with a range of symptoms such as emotional distress , lung problems , pain , physical limitations , fatigue , social limitations , eye issues , skin disorders , and sleep disruption . side effects of treatments for sarcoidosis may also negatively impact quality of life for these patients . patients with ocular sarcoidosis have a significantly diminished quality of life based on a visual questionnaire when compared to patients without ocular disease . , cross - sectional survey study found that women with sarcoidosis showed a greater degree of functional impairment than men , particularly with regard to physical health . there was no difference found in emotional and daily quality of life in men versus women . a recent study demonstrated that female smokers were more likely to have a reduced diffusion capacity for carbon monoxide than male smokers , and both female sex and smoking are associated with the development of extrapulmonary manifestations of the disease . death from sarcoidosis is closely associated with respiratory , cardiac , neurologic , and hepatic involvement . a recent report highlighted an increased rate of mortality in recent years , specifically citing a 30% increase in men and 50% increase in women in 2007 compared to 1988 . although sarcoidosis deaths were most common in younger patients ( 3544 years ) , the increase in mortality was greatest in older individuals ( 5574 years ) , specifically among non - hispanic black females . the cause of death was determined to be sarcoidosis in almost 60% of patients , while other causes included ischemic heart disease , cardiomyopathy , lung cancer , and pneumonia . in fact , autoimmune disease is the fifth leading cause of death among women . proposed reasons for sex differences in incidence of autoimmune disease have included environmental factors such as hormonal and genetic effects , gender - biased activities , occupational exposure , medications , smoking , and vitamin d deficiency in women . women may be more likely to develop autoimmune disease due to hormonal variation during menstruation , pregnancy , and childbirth . the natural breakdown of epithelial tissue that occurs during these events may increase a woman 's exposure to triggers of autoimmune inflammation [ 68 , 69 ] . in the case of sarcoidosis , this may be of particular importance , as a 2011 study into risk of sarcoidosis among adults exposed to the world trade center ( wtc ) catastrophe found that firefighters , police officers , lower manhattan residents , area workers , and even passers - by were found to have an increased risk of sarcoidosis . this study specifically concluded that working on the wtc debris pile was associated with an increased rate of post-9/11 sarcoidosis diagnosis . a recent brazilian study found that certain hla alleles were more likely to be found in mestizos and blacks with sarcoidosis . microchimerism and epigenetics have also been implicated in the reason behind female predominance in many autoimmune diseases , including sarcoidosis . almost every aspect of sarcoidosis , from epidemiology and clinical presentation to treatment options and prognosis , is influenced by patient sex . men are diagnosed at a younger age than women , and the onset of sarcoidosis in women follows a bimodal distribution with a second peak of onset occurring after age of 50 . in this older cohort of patients , chest x - ray may not be sensitive enough to identify pulmonary changes and computed tomography is recommended . women are more likely to have cutaneous involvement than men , and the mortality rate is higher in women . several medications used to treat sarcoidosis are contraindicated in pregnancy ; therefore , discussions regarding birth control should be thorough and repeated at every visit .
sarcoidosis is an inflammatory disease with a wide range of clinical presentations . 
 the manifestations and prognosis in sarcoidosis are dependent upon not only organ involvement but also age and sex . 
 the purpose of this review is to describe the systemic and ocular manifestations of sarcoidosis with a specific focus on sex - dependent difference in presentation and management . 
 sarcoidosis is more common in women , particularly in patients who present after age of 50 years . 
 women with sarcoidosis are more likely to develop cystoid macular edema and the mortality rate is higher than that of men .