although sarcoidosis has been identified as a specific disease entity for more than one century , the specific cause of sarcoidosis is unknown . in addition , the diagnostic criteria , treatment algorithms , method of follow - up and natural course of the disease have not been clearly elucidated .
these concepts reflect our deeper understanding of this enigmatic disease . in terms of the diagnosis of sarcoidosis ,
presently , this is a clinical diagnosis as there is no reliable diagnostic test . in lieu of a diagnostic test
these criteria will be outlined in this manuscript . although these diagnostic criteria are based on clinical data and have been vetted by world experts in the field , they are arbitrary and inexact .
there is a general consensus that corticosteroids are the drug of choice when treatment is required .
several alternative agents may be used , usually as corticosteroid sparing agents , because of the development of significant corticosteroid toxicity .
the assessment of the efficacy of alternative anti - sarcoidosis medications is complex for many reasons , including distinguishing the effects of corticosteroids from the study drug and reliably assessing disease activity .
the diagnosis of sarcoidosis is never secure but is arbitrarily made when the statistical likelihood of alternative diagnoses becomes too small to warrant further investigation .
a patient may present with a constellation of clinical findings that is so specific for sarcoidosis that the diagnosis may be made empirically without the need for a confirmatory biopsy ( left side of figure 1 ) .
if these rare presentations are not observed , the diagnosis requires a tissue biopsy revealing granulomatous inflammation ( usually noncaseating ) , exclusion of alternative causes of granulomatous inflammation , and documentation of systemic disease ( right side of figure 1 ) .
the diagnosis of sarcoidosis may be established without performing a tissue biopsy ( left side of figure ) .
this requires the presence of specific clinical findings that are highly specific for the diagnosis ( one of the conditions in the box on the left side of the figure ) .
if none of these specific clinical presentations occurs , then the diagnosis requires tissue biopsy confirmation of granulomatous inflammation , exclusion of alternative causes for the granulomatous inflammation , and documentation that the disease is systemic and is , therefore , not confined to a single organ ( pathway on the right side of the figure ) .
abbreviations : cxr , chest radiograph ; ncg , noncaseating granulomas ; , controversial criterion .
first , granulomatous inflammation is , by itself , inadequate to establish a diagnosis of sarcoidosis .
in one recent study of 131 lung biopsy specimens revealing necrotic granulomatous lesions without an obvious etiology , 52 ( 40% ) remained unknown , and only 4/79 ( 5% ) of those where the etiology was determined were found to have sarcoidosis .
second , the diagnosis of sarcoidosis requires that alternative causes of granulomatous inflammation are excluded .
although biopsy specimens are usually examined for the presence of mycobacteria and fungi , other alternative granulomatous diseases are more problematic to exclude .
in one german sarcoidosis clinic , patients diagnosed with sarcoidosis completed a detailed questionnaire concerning occupations where exposure to beryllium was possible . over 7 years
, 84 patients had positive responses to this questionnaire , and 34/84 ( 40% ) of these patients were confirmed to have chronic beryllium disease , rather than sarcoidosis , on the basis of beryllium lymphocyte proliferation testing .
atypical mycobacteriosis hypersensitivity pneumonitis pneumoconiosis : beryllium ( chronic beryllium disease ) , titanium , aluminum aspiration of foreign materials wegener s granulomatosis ( sarcoid - type granulomas are rare ) necrotizing sarcoid granulomatosis ( nsg ) atypical mycobacteriosis granulomatous histiocytic necrotizing lymphademitis ( kikuchi s disease ) sarcoid reaction in regional lymph nodes to carcinoma non - hodgkin s lymphomas granulomatous lesions of unknown significance ( the glus syndrome ) atypical mycobacteriosis reaction to foreign bodies : beryllium , zirconium , tattooing , paraffin , etc .
primary biliary cirrhosis non - hodgkin s lymphomas infectious mononucleosis non - hodgkin s lymphomas giant cell myocarditis adapted from reference   and reprinted with permission of the american thoracic society .
third , sarcoidosis is a systemic disease that is not confined to the lung or any organ in isolation .
some features that show sarcoidosis is a systemic illness are that the disease is associated with anergy , non - granulomatous inflammatory conditions such as erythema nodosum , systemic symptoms such as fatigue   and small fiber neuropathy , and that the disease may recur in transplanted allografts . usually , confirmation that the disease is systemic involves identifying granulomatous inflammation in at least two organs .
indeed , idiopathic granulomatous diseases of some isolated organs are thought to be distinct from sarcoidosis , such as idiopathic granulomatous hepatitis .
more than one decade ago , the national institute of health sponsored a case control etiologic study of sarcoidosis ( access ) that developed an organ assessment instrument to document a second organ being involved with sarcoidosis , short of performing a biopsy .
the instrument classified the likelihood of several specific clinical scenarios being caused by sarcoidosis in an organ as  definite  , 
possible  provided that a ) granulomatous inflammation had already been identified in another organ , and b ) alternative causes for the clinical scenario could reliably be excluded .
for example , if histologic evidence of granulomatous inflammation was found on skin biopsy , then eye sarcoidosis was considered 
for the purposes of access , definite or probable involvement was considered as sarcoidosis involvement in that organ .
therefore , the access instrument allowed for the diagnosis of sarcoidosis to be established by confirming the presence of sarcoidosis in a second organ , without the need to biopsy that second organ .
more recently , the world association of sarcoidosis and other granulomatous disorders ( wasog ) has updated the access assessment instrument to take into account new advances in diagnostic technology . however , an issue that has recently surfaced is whether the requirement of documenting involvement of a second organ / systemic disease is universally required for the diagnosis of sarcoidosis . despite the aforementioned idiopathic granulomatous diseases in single organs that appear to be distinct from sarcoidosis , there may be specific presentations in single organs that are highly specific for sarcoidosis . two such examples would be lupus pernio ( disfiguring facial sarcoidosis ) and chest imaging , revealing mediastinal adenopathy plus parenchymal lung nodules in a perilymphatic distribution .
if granulomatous inflammation was identified in such clinical situations and no other evidence of granulomatous inflammation was identified in other organs , most would consider the diagnosis of sarcoidosis secure .
indeed , most large sarcoidosis series reported by sarcoidosis experts , including the multicenter access trial investigators , have reported a large proportion of patients as having sarcoidosis with only a single organ involved ( 366/736 , 49.7% ) . as a counter - argument to this viewpoint ,
a recent retrospective analysis of patients with concomitant sarcoidosis and connective tissue diseases ( ctds ) suggested that a significant proportion of them may have had solely a ctd , and that the granulomatous inflammation may have been a result of the ctd .
since ctds are not recognized as a cause of granulomatous inflammation , several of these patients may have been misdiagnosed as having sarcoidosis .
summing up these data , we believe that sarcoidosis can be diagnosed when a single organ is involved , provided that alternative causes have been excluded and the presentation is highly specific for the diagnosis .
we do believe that confirming granulomatous inflammation in a second organ does raise the specificity of the diagnosis , albeit with a potential drop in sensitivity .
the entire diagnosis discussion to this point has focused on a set of criteria that are arbitrary .
these criteria require that the patient has a clinical presentation suggestive of sarcoidosis and that alternative causes of granulomatous inflammation are reasonably excluded . these are not objective , rigorous conditions .
obviously , sarcoidosis must have a specific cause or causes associated with specific immune mechanisms .
recently , chen and colleagues demonstrated intense expression and wide distribution of serum amyloid a ( saa ) within the sarcoidosis granuloma that exceeded that found in all other granulomatous diseases that were examined .
saa appeared to have been produced by macrophages and giant cells within the sarcoid granuloma .
these authors postulated that saa could consolidate a poorly soluble protein aggregate to form a nidus for granuloma formation .
saa may disrupt the clearance of an antigen within the granuloma that allows for its persistence .
the granulomatous inflammation in sarcoidosis may result from a prolonged immunogenic response to a persistent antigen , resulting in immune system exhaustion . as the identification of saa may be a specific marker for sarcoidosis - related granulomatous inflammation
hopefully , saa or another specific biomarker to be developed in the future will make the previous discussion of diagnosis obsolete .
furthermore , such a biomarker may answer the question as to whether several other granulomatous diseases of unknown cause such as blau s syndrome , granulomatous lesions of unknown significance ( glus syndrome ) , granulomatous - lymphocytic interstitial lung disease , and necrotizing sarcoid granulomatosis , are truly distinct entities from sarcoidosis or whether they fall under the  sarcoidoses umbrella  .
sarcoidosis does not mandate treatment because the disease may never cause symptoms or organ dysfunction , may remit spontaneously , and therapy ( particularly corticosteroids ) is associated with a myriad of significant side effects .
sarcoid granulomas are thought to result from the interaction of an antigen with the immune system .
it has been conjectured that granulomatous inflammation in sarcoidosis is necessary to clear the antigen .
if this theory is correct , it is plausible that effective anti - sarcoidosis therapy may resolve granulomatous inflammation that may result in failure of clearance of the putative sarcoidosis antigen(s ) . in this scenario , when treatment is withdrawn , the antigen may still be present and could lead to recurrent granulomatous inflammation and , therefore , relapse .
this schema is supported by data that suggest that a relapse of sarcoidosis is more common in patients previously treated for sarcoidosis , or with higher doses of corticosteroids .
in addition , this concept is consistent with the premise that anti - sarcoidosis treatment improves granulomatous inflammation but does not alter the natural course of the disease [ 21,3136 ] .
therefore , the granulomatous inflammation of sarcoidosis may be beneficial and should probably be left unsuppressed , provided that it does not result in significant patient symptoms or organ dysfunction . when treatment is indicated for sarcoidosis , corticosteroids are considered the drug of choice because they appear to have the greatest likelihood of efficacy and work most rapidly .
although a consensus statement of the american thoracic society , european respiratory society , and wasog have recommended 20 to 40 mg of daily prednisone equivalent for the initial treatment of pulmonary sarcoidosis , the lower end of that dosage range appears to be adequately effective .
a recent review of acute pulmonary exacerbations of sarcoidosis found that 20 mg of daily prednisone for a median of 3 weeks returned spirometry and pulmonary symptoms back to baseline .
indeed , a regimen of 15 mg / day of prednisone was shown to be effective for sarcoidosis more than 40 years ago .
little is known concerning the optimal algorithm for tapering corticosteroids , although relapses with such tapers occur in a significant percent of cases .
although corticosteroids are currently entrenched as the drug of choice for most forms of sarcoidosis , alternative agents are often used because of the frequency of the development of corticosteroid side effects .
usually , these drugs are corticosteroid - sparing as often a small amount of corticosteroid must be continued for adequate efficacy .
these corticosteroid - sparing drugs should be considered for patients deemed at risk of developing corticosteroid side effects and most patients who require long - term corticosteroid therapy . a recent delphi study of 36 sarcoidosis experts reached a consensus that methotrexate be considered the second - line agent for pulmonary sarcoidosis . in an unusual study design ,
two european medical centers were compared where one used methotrexate as a second - line anti - sarcoidosis agent and the other used azathioprine .
the reduction in corticosteroid dose and improvement of pulmonary function was not statistically different between these two groups .
however , the rate of drug side effects , particularly the rate of infection , was significantly greater in the patients receiving azathioprine as a second - line agent .
leflunomide has also been shown to be an effective anti - sarcoidosis medication in a large number of sarcoidosis patients in the united states .
we believe that the use of second - line agents should be individualized based on the patient s potential for toxicity and the organ that is being treated . in regards to this latter point ,
antimalarial agents are particularly effective for skin sarcoidosis as well as for sarcoidosis - induced derangement of vitamin d metabolism causing hypercalcemia , hypercalciuria , nephrolithiasis and renal insufficiency .
as these drugs have been shown to be better tolerated than other treatments in rheumatoid arthritis , they may be preferred for the aforementioned forms of sarcoidosis . over the past decade ,
several studies have shown a benefit of tumor necrosis factor alpha ( tnf- ) antagonists for the treatment of sarcoidosis .
these studies have included case series [ 4750 ] and a randomized double - blind placebo - controlled trial .
there is a sound rationale for this therapy because tnf- is released by macrophages recovered from sarcoidosis patients   and tnf- is thought to be integrally involved in the development of the granulomatous inflammation .
infliximab appears to be a particularly effective for lupus pernio ( disfiguring facial sarcoidosis ) , neurosarcoidosis , and pulmonary sarcoidosis .
adalimumab may be effective for sarcoidosis   although , extrapolating from clinical reports , the optimal dose may need to be higher than that routinely used in rheumatoid arthritis .
a recently completed placebo - controlled trial of golimumab failed to show a benefit over placebo for the treatment of pulmonary and cutaneous sarcoidosis .
furthermore , all tnf- antagonist agents have been occasionally associated with relapse , worsening , or development of sarcoidosis [ 5963 ] .
these occurrences are most commonly reported with etanercept and are postulated to be the result of tnf- antagonist - induced stimulation of interferon - gamma production leading to granulomatous inflammation .
personalized  or  precision  medical care where therapy is individualized based on the patient s specific clinical features or genetics .
one example of such care is the observation that the presence of the tnf- g-308a polymorphism in rheumatoid arthritis patients is associated with a more favorable response to tnf- antagonist therapy than those who do not possess this polymorphism .
recently , these results have been duplicated in a sarcoidosis cohort who received infliximab or adalimumab .
rituximab is a monoclonal antibody directed at the c20 cell surface antigen of b - lymphocytes .
although the granulomatous inflammation of sarcoidosis is thought to primarily develop through an interaction with t - lymphocytes , there is often abnormal b - lymphocyte activity , as demonstrated by the frequent development of a polyclonal gammopathy in active sarcoidosis .
several case reports and open - label case series have shown the potential efficacy of rituximab in the treatment of sarcoidosis [ 6972 ] .
the results of recent sarcoidosis drugs trials have uncovered several issues that may be of critical importance in designing future studies .
first , subjects with severe forms of sarcoidosis may have a greater potential to respond to therapeutic agents than those with mild disease . a post - hoc analysis of a randomized placebo - controlled trial of infliximab versus placebo for pulmonary sarcoidosis demonstrated the greatest improvement in percent predicted forced vital capacity ( fvc ) at 24 weeks in those with lower baseline fvc , st .
although this finding could be explained by a  ceiling effect  where those with mild disease have less room to show significant improvement , it is also possible that those with more severe disease have more severe active granulomatous inflammation .
although it has previously been thought that pulmonary sarcoidosis patients with fibrocystic disease may have  burnt - out  inactive disease , a recent study demonstrated that 85% of such patients have significant lung uptake on positron emission tomography ( pet ) , suggesting that they have active disease . because sarcoidosis may result in both treatable granulomatous inflammation and irreversible fibrosis , it is imperative to identify subjects with active disease in clinical sarcoidosis trials
. this will require the establishment of reliable biomarkers of active granulomatous inflammation that can be used to select appropriate patients .
a second issue of importance in many sarcoidosis trials is distinguishing study drug effects from corticosteroid effects .
alternative agents are still in great demand because of the numerous significant toxicities of corticosteroids .
most clinical trials of potential sarcoidosis patients enroll subjects who are corticosteroid - dependent , as these are the patients who would be potential candidates for these drugs and it would be problematic to taper them off corticosteroids and risk disease exacerbation . because of the efficacy of corticosteroids , it is problematic to detect additional benefits of the study drug in such patients . as an example of this issue , in a randomized placebo - controlled trial of infliximab versus placebo for pulmonary sarcoidosis , although the trial was positive , those receiving more than 15 mg / day of daily prednisone equivalent did not demonstrate an appreciable additional benefit from infliximab .
potential trial designs to circumvent this issue include a ) non - inferiority comparison trials versus corticosteroids in de novo sarcoidosis patients with corticosteroid rescue for study drug failure ; b ) including a corticosteroid withdrawal phase in the trial ; and c ) initiating a corticosteroid taper prior to trial enrollment and only enrolling subjects who deteriorate .
probably the single most challenging issue in the design of a clinical sarcoidosis trial is the establishment of an appropriate endpoint .
the presence of disease activity would be an adequate endpoint for a uniformly progressive disease such as lung cancer or tuberculosis .
as previously mentioned , the presence of disease activity should probably be an entry criterion for sarcoidosis clinical trials .
in addition , measurement of disease activity may be an appropriate endpoint to detect anti - sarcoidosis activity of a drug .
however , reduction of disease activity is an unreliable endpoint to determine if a drug is useful for the treatment of sarcoidosis .
however , such impairment is usually mild in sarcoidosis   and poorly correlates with impaired quality of life , which is what patients usually care about most , so this is an appropriate clinical endpoint for most sarcoidosis trials .
however , pulmonary symptoms and impaired quality of life are often not directly related to sarcoidosis , so this endpoint is not uniformly reliable . because this issue is complex and unresolved ,
the granulomatous inflammation of sarcoidosis can be measured by various methods ( left box).the endpoint of granulomatous inflammation would be appropriate to detect the anti - sarcoidosis activity of a drug . however , granulomatous inflammation from sarcoidosis may not result in physiologic impairment ( middle box ) .
when physiologic impairment occurs , it may be mild and not lead to the development of symptoms .
therefore , the presence of active sarcoidosis ( left box ) or physiologic impairment ( middle box ) may be inadequate clinical endpoints to base decisions on whether sarcoidosis patients require therapy . if physiologic impairment leads to significant functional impairment and/or worsening quality of life ( right box ) , then therapy for sarcoidosis is required .
therefore , a rational clinical endpoint would need to incorporate the patients functional status and health - related quality of life .
abbreviations : ace , angiotensin converting enzyme ; bal , bronchoalveolar lavage ; ef , ejection fraction ; hrqol , health - related quality of life ; mri , magnetic resonance imaging ; pet , positron emission tomography ; pft , pulmonary function test ; pro , patient reported outcome measure . adapted from .
the diagnosis of sarcoidosis remains a challenging issue principally because there is no specific reliable diagnostic test available .
various algorithms and criteria have been established as diagnostic guidelines that may be useful while we remain hopeful for the development of a gold standard diagnostic test .
such trials involve overcoming several problematic issues , but this can be accomplished with prudent thought and planning .
marc a. judson is a consultant for janssen , celgene , novartis , mitsubishi - tanabe , and questcor .
 this manuscript outlines recent advances in the diagnosis and treatment of sarcoidosis . 
 the diagnosis of sarcoidosis can occasionally be made on clinical grounds without a confirmatory biopsy when very specific clinical findings are present . 
 otherwise , the diagnosis requires histologic evidence of granulomatous inflammation , exclusion of alternative causes , and evidence of systemic disease . because there is no available diagnostic test for sarcoidosis , the diagnosis is never completely secure . 
 instruments have been developed to establish the presence of sarcoidosis in a second organ and hence establish the systemic nature of the disease . 
 corticosteroids remain the drug of choice for the treatment of sarcoidosis . 
 additional sarcoidosis medications are most commonly used as corticosteroid - sparing agents . 
 recent clinical sarcoidosis drug trials have exposed important issues that may confound trial results , including selecting patients with active disease , identifying study drug effects in patients receiving concomitant corticosteroids , and establishing proper study endpoints . 
Introduction
Advances in the diagnosis of sarcoidosis
Advances in the treatment of sarcoidosis
Conclusion
Disclosures