Some studies required histopathologic confirmation of noncaseating granuloma in the liver, while an unexplained liver chemistry abnormality in known cases of systemic sarcoidosis was sufficient for assumed hepatic involvement in others. Among those who are symptomatic, symptoms are usually of a general nature, such as nonspecific abdominal pain, nausea, and fatigue.
By contrast, elevated alanine aminotransferase and aspartate aminotransferase levels are less common and are usually of less magnitude less than times the upper limit of normal. Computed tomography and ultrasonography are of slightly lower sensitivity but are usually more available in clinical practice. Definite diagnosis of hepatic sarcoidosis requires demonstration of noncaseating granuloma in the liver and exclusion of other diseases, such as infection, that can give rise to similar histopathologic changes and drug-induced liver injury that can cause transaminitis.
These granulomas are commonly found in the portal and periportal areas although can be found throughout the lobules. Any part of the nervous system can be affected, and multiple parts can be affected in a single patient. Involvement of the pituitary gland, spinal cord, and peripheral nerves is far less common. Involvement can be either unilateral or bilateral. Cerebrospinal fluid analysis usually reveals monocyte pleocytosis and a high protein level.
The glucose level in cerebrospinal fluid is usually normal, but low levels are measured in about one-fifth of cases. Intraparenchymal granulomatous lesions are less common. Lesions could be either a solitary mass or multiple nodules and may cause focal neurologic deficits, seizures, or increased intracranial pressure.
The majority of these patients also have evidence of active sarcoidosis in other organs. Up to half of renal biopsies reveal only evidence of interstitial nephritis without granuloma, which may reflect the nature of the inflammation or sampling error of the biopsy.
Several diseases, such as tuberculosis, fungal infection, foreign body reaction, autoimmune diseases granulomatosis with polyangiitis and Crohn disease , and drug allergy can give rise to the same histopathologic picture. Other renal diseases associated with sarcoidosis are nephrocalcinosis and nephrolithiasis secondary to hypercalcemia and hypercalciuria.
Clinical manifestations are similar to those of nephrocalcinosis and nephrolithiasis from other causes. In one study, isolated cardiac sarcoidosis accounted for two-thirds of all cases of cardiac sarcoidosis, 55 although the number is generally lower in other reports. The crucial pathology of cardiac sarcoidosis is granulomatous inflammation of the myocardium, leading to arrhythmia and cardiomyopathy.
It should be noted that this recommendation is based on clinical experience without data from prospective studies. Further studies are still required to prove the benefit of this screening strategy.
Any part of the gastrointestinal tract GI , from oral cavity to colon, can be affected by sarcoidosis. The stomach is the most frequently affected hollow organ, with approximately 60 biopsy-proven cases reported in the literature. Over half of patients with gastric sarcoidosis present with epigastric pain. Other common manifestations include nausea, vomiting, diarrhea, and weight loss.
Definitive diagnosis of sarcoidosis cannot be made on the basis of clinical and radiologic findings alone. The presence of noncaseating granuloma on biopsy is not pathognomonic of sarcoidosis because several other diseases can cause similar histopathologic changes. Histopathologic confirmation is required to establish the diagnosis of sarcoidosis in most patients. However, tissue biopsy of every affected organ is not required because the presence of noncaseating granuloma in at least one organ is generally considered sufficient for diagnosis.
Sarcoidal involvement of the other organs is generally assumed if signs and symptoms are compatible. The need for surgical lung biopsy and mediastinoscopy to obtain intrathoracic tissue has been decreasing with the availability of flexible bronchoscopy. The characteristic histopathologic feature of sarcoidosis is the presence of multiple well-formed, noncaseating granulomas, which are compact clusters of epithelioid cells and multinucleated giant cells with minimal to no central necrosis.
The granulomas are often surrounded by lymphocytes. Several types of inclusions may be seen in the granulomas, such as Schaumann bodies, asteroid bodies, Hamazaki-Wesenberg bodies, and calcium oxalate crystals. This process includes special staining and culture for mycobacteria and fungi. Diagnosis of sarcoidosis in some organs can be particularly challenging because of the inaccessibility for histopathologic confirmation.
This issue includes the central nervous system, the heart, and the eyes. Biopsy of nervous system tissue is frequently not possible because of the potential damage to the biopsied tissue itself such as cranial nerve or nearby structures such as lesions in the brain stem.
Therefore, the diagnosis of neurosarcoidosis often relies on histopathologic examination of tissue from an extraneural organ and indirect evidence of inflammation in the central nervous system. Proposed criteria for diagnosis of neurosarcoidosis based on this information are summarized in Table 2. Data from QJM. Similarly, endomyocardial biopsy is an invasive procedure associated with high risk of complications. It also has low sensitivity for detection of noncaseating granulomas because of the patchy nature of cardiac sarcoidosis.
Both cardiovascular magnetic resonance imaging CMRI with gadolinium and 18 F-fluorodeoxyglucose—positron emission tomography FDG-PET are useful tools to detect the presence of cardiac involvement by sarcoidosis. The characteristic CMRI pattern is multifocal areas of subepicardial and midmyocardial late gadolinium enhancement, which is an indicator of fibrosis.
Late gadolinium enhancement is typically seen in the basal segments of the septum and lateral wall, although more extensive involvement, including the right ventricle, can be seen. Proper preparation is essential to enhance the accuracy of cardiac FDG-PET and may include prolonged fasting, dietary manipulation, and intravenous heparin administration to reduce the normal physiologic glucose uptake of the myocardium.
In , the Heart Rhythm Society published a guideline recommending 2 pathways to a diagnosis of cardiac sarcoidosis based on histopathology and the aforementioned imaging studies. Both pathways require exclusion of other explanations of the cardiac abnormalities. Diagnosis of intraocular sarcoidosis sarcoid uveitis is also complicated by the inaccessibility of intraocular tissue.
Therefore, diagnosis of sarcoid uveitis is generally accepted in patients with unexplained uveitis who have a confirmed diagnosis of sarcoidosis in extraocular organs. In , the International Workshop on Ocular Sarcoidosis proposed its first diagnostic criteria for intraocular sarcoidosis based on this principle.
All of these diagnoses are made after other causes of uveitis are excluded. It should be noted that the definition of definite ocular sarcoidosis and presumed ocular sarcoidosis does not require the presence of intraocular signs listed in Table 3 because those signs are essentially the signs of granulomatous uveitis, which are not universally seen on slit-lamp examination. The criteria are intended to allow diagnosis of sarcoid uveitis in the absence of those signs if evidence for sarcoidosis in extraocular tissue is strong.
Abnormalities on chest computed tomography compatible with pulmonary sarcoidosis for patients with negative findings on chest x-ray. Data from Ocul Immunol Inflamm. Serum markers have only a limited role in the diagnosis of sarcoidosis. Elevation of serum angiotensin-converting enzyme level was thought to be specific for sarcoidosis and correlate well with disease activity when it was first reported in The test is not currently used in clinical practice because of the concern about possible transmission of contagious disease and the lack of approval by the US Food and Drug Administration.
There are 2 fundamental facts that exert heavy influence on the management of sarcoidosis. First, sarcoidosis frequently undergoes spontaneous regression without causing any permanent damage to the affected organs. Most patients with pulmonary sarcoidosis do not require treatment. A study from the Mayo Clinic in Rochester, Minnesota, found that oral glucocorticoids were required in only about one-third of patients with pulmonary sarcoidosis.
Systemic glucocorticoids are the first-line therapy for pulmonary sarcoidosis. In addition, with relapse, most experts will also recommend disease-modifying antirheumatic drugs DMARDs for their corticosteroid-sparing effect because these patients tend to be corticosteroid dependent and are at a higher risk for development of glucocorticoid toxicity.
Methotrexate has a slow onset of action, and maximal efficacy will not be observed until at least 2 to 3 months after initiation of the therapy. Biologic agents are considered third-line therapy for patients with refractory disease that does not respond to glucocorticoids and DMARDs or for those who cannot tolerate these agents. This difference was statistically significant, although its clinical importance remained unclear.
The use of H. Acthar Gel Mallinckrodt Pharmaceuticals , a purified form of porcine or bovine corticotropin, has been reported in the literature.
Some investigators believe that Acthar Gel can suppress the immune system through the stimulation of multiple melanocortin receptors, in addition to stimulation of endogenous glucocorticoid secretion by adrenal glands. For instance, a retrospective study found that only approximately one-third of patients had objective improvement with this therapy and another one-third could not tolerate its adverse effects beyond 3 months. The investigators do not recommend use of this medication for management of sarcoidosis.
Extrathoracic sarcoidosis tends to undergo spontaneous remission less frequently than pulmonary sarcoidosis. In addition, inflammation in some vital organs, such as the central nervous system, eyes, and heart, can lead to permanent damage and disability.
Treatment for involvement of these organs with immunosuppression is required more often than for pulmonary sarcoidosis. Erythema nodosum, the common nonspecific cutaneous lesion, is usually self-limited and often does not require any specific therapy. Short-course nonsteroidal anti-inflammatory drugs NSAIDs or glucocorticoids may be prescribed to alleviate pain and discomfort. Sarcoidosis-specific cutaneous lesions can also regress spontaneously and generally do not cause significant morbidity.
Treatment is not always indicated unless the lesions are disfiguring or cosmetically distressing. Ultrapotent formulations, such as clobetasol and halobetasol propionate, are generally required for topical therapy.
Oral glucocorticoids are the next line of therapy after failure of local treatment but could be considered as the first option for patients with extensive or rapidly progressive cutaneous disease.
In patients with more refractory skin disease that does not respond to systemic glucocorticoids or patients who are corticosteroid dependent, addition of DMARDs is generally considered, although data on their efficacy are quite limited.
The most commonly used DMARDs for skin sarcoidosis include hydroxychloroquine, chloroquine, and methotrexate. Infliximab is the most commonly used biologic agent with the most robust data, from both a case series and a randomized placebo-controlled trial. The presence of uveitis almost always necessitates treatment because the consequences of untreated intraocular inflammation, such as posterior synechiae, glaucoma, and neovascularization, are sight-threatening.
Cycloplegic eye drops are often prescribed concomitantly for anterior chamber inflammation to relieve ciliary spasm, reduce pain, and prevent posterior synechiae.
Disease-modifying antirheumatic drugs are the next step for patients in whom glucocorticoids fail or are not tolerated, with methotrexate being the most widely used agent with the most comprehensive data.
Infliximab and adalimumab are the most widely used of these drugs, although data supporting their efficacy are primarily derived from studies of nonspecific noninfectious uveitis. External eye diseases, including scleritis, episcleritis, and conjunctivitis, generally do not cause visual impairment. Aggressive treatment of these ocular manifestations of sarcoidosis is typically not necessary.
Sarcoid arthropathy is usually self-limited, and treatment beyond short-course NSAIDs is generally not required. However, only infliximab has been evaluated by a randomized controlled study that found a greater percentage of resolution of joint inflammation compared with placebo, although the sample size was too small to demonstrate statistical significance.
Data on the treatment of hepatic sarcoidosis are limited to observational studies and case reports.
Most experts do not recommend treatment for patients with asymptomatic liver biochemical test abnormalities because spontaneous improvement is often seen. Methotrexate, despite its potential hepatotoxicity, has been commonly used based on data from case series that reported its ability to reduce liver test abnormalities and to reduce glucocorticoid dose requirements.
Neurosarcoidosis almost always requires treatment with glucocorticoids because spontaneous remission is uncommon, with the exception of facial nerve palsy, and damage associated with the inflammatory lesion can cause permanent neurologic deficit.
Unfortunately, neurosarcoidosis-related symptoms recur quite frequently, especially after the dose of prednisone is reduced to 20 to 25 mg daily. Some experts suggest combination therapy of glucocorticoids and DMARDs as initial management of neurosarcoidosis. That study suggested a trend toward improvement with infliximab compared with placebo, although the sample size was too small to detect statistical significance.
Data on treatment of sarcoidosis-associated small fiber neuropathy are very scarce. Most experts agree that treatment for renal sarcoidosis is indicated to prevent permanent damage that would ultimately lead to chronic kidney disease.
This regimen is largely derived from experience with treatment of sarcoidosis of other organs because the data on use of these agents for renal sarcoidosis are scarce. Normalization of calcium levels is expected within a week after treatment with prednisone, 20 to 40 mg daily or equivalent. A relatively quick tapering weeks can be attempted with frequent monitoring. The management of cardiac sarcoidosis consists of immunosuppression and general cardiological care for arrhythmia and heart failure.
Immunosuppression is prescribed to suppress ongoing myocardial inflammation with the aims of reducing damage and scarring to myocardium and preventing or reversing ventricular dysfunction. Treatment is also indicated for management of conduction tissue involvement to prevent or reverse conductive abnormalities, especially heart block. A Delphi study surveying experts in the management of cardiac sarcoidosis recommends treatment with immunosuppression for patients who have hypermetabolic activity on cardiac FDG-PET, delayed enhancement on CMRI, conduction defect, ventricular arrhythmia, left ventricular dysfunction, or right ventricular dysfunction in the absence of pulmonary hypertension.
The evidence for efficacy of glucocorticoids is more robust for conduction defects because a systematic review of 10 published studies found that among 57 patients with AV block who were treated with glucocorticoids, 27 improved whereas none of the 16 patients with AV block who were not treated got better. The same systematic review also evaluated the efficacy of glucocorticoids for left ventricular function and arrhythmia, but the results were more difficult to interpret because only a few controls who did not receive glucocorticoids were available.
The same diagnostic modalities used to diagnose cardiac sarcoidosis can be used to assess for response to treatment. As with other organ involvement, infliximab is the preferred biologic agent if adequate response is not achieved with the use of glucocorticoids and DMARDS. For those without obvious indications, electrophysiologic study may be considered to further stratify the risk of sudden cardiac death and the need for prevention with an implantable cardioverter-defibrillator.
Because of the rarity of cases of GI sarcoidosis, the optimal treatment for GI involvement is virtually unknown. Case reports have described both cases with spontaneous remission and cases that required glucocorticoid therapy. The most important recent innovation in the field of sarcoidosis is the development of biologic agents that has changed the landscape of treatment of refractory disease. Infliximab is the biologic agent with the most comprehensive data.
More agents, such as canakinumab, roflumilast, and the nicotine patch, are currently being investigated by ongoing clinical trials. Clinical presentations of sarcoidosis are diverse and may mimic several other diseases, posing diagnostic and management challenges for clinicians.
The presence of noncaseating granuloma alone is not sufficient to make a definite diagnosis of sarcoidosis, and other possible causes of granuloma formation first must be excluded.
Once the diagnosis is established, a systematic evaluation for the extent of disease should be conducted. This should, at minimum, include history, physical examination, measurement of calcium, liver enzyme, and creatinine levels, urinalysis, ECG, and ophthalmologic examination. Treatment is indicated for patients with disabling symptoms or with progressive organ failure. Glucocorticoids are the mainstay of therapy even though the ideal dose and duration are not known with certainty because of the lack of data from randomized controlled studies.
Methotrexate is the most commonly used corticosteroid-sparing agent for corticosteroid-resistant disease or corticosteroid-intolerant patients. Potential Competing Interests: The authors report no competing interests. National Center for Biotechnology Information , U. Published online Aug 2.
Ryu , MD, b and Eric L. Jay H. Eric L. Author information Article notes Copyright and License information Disclaimer. Patompong Ungprasert: moc. Received Feb 21; Accepted Apr Published by Elsevier Inc. This article has been cited by other articles in PMC.
Abstract The focus of this review is current knowledge about the epidemiology, clinical manifestations, diagnosis, and treatment of both pulmonary sarcoidosis and extrapulmonary sarcoidosis.
Article Highlights. Epidemiology of Sarcoidosis The annual incidence of sarcoidosis among adults varies considerably across ethnic groups. No adenopathy Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Extrapulmonary Sarcoidosis Skin Involvement of the skin is the most common extrathoracic manifestation of sarcoidosis, present in up to one-third of patients. Figure 5. Figure 6. Eyes Ocular sarcoidosis is the second most common extrathoracic manifestation of this disease. Gastrointestinal Tract Any part of the gastrointestinal tract GI , from oral cavity to colon, can be affected by sarcoidosis.
Diagnosis Definitive diagnosis of sarcoidosis cannot be made on the basis of clinical and radiologic findings alone. Histopathology The characteristic histopathologic feature of sarcoidosis is the presence of multiple well-formed, noncaseating granulomas, which are compact clusters of epithelioid cells and multinucleated giant cells with minimal to no central necrosis.
Diagnosis of Neurosarcoidosis, Cardiac Sarcoidosis, and Intraocular Sarcoidosis Diagnosis of sarcoidosis in some organs can be particularly challenging because of the inaccessibility for histopathologic confirmation. Suggestive ocular signs 1. Additional Tests Serum markers have only a limited role in the diagnosis of sarcoidosis. Treatment There are 2 fundamental facts that exert heavy influence on the management of sarcoidosis. Treatment of Extrapulmonary Sarcoidosis Extrathoracic sarcoidosis tends to undergo spontaneous remission less frequently than pulmonary sarcoidosis.
The evidence that currently used treatments achieve these aims is weak, and the risk of adverse effects is concerning for patients and may outweigh perceived benefits. Treatment with corticosteroids is suppressive rather than curative, and guidelines recommend at least 1 years' therapy for patients with progressive disease.
In the BTS sarcoidosis study, long term corticosteroids given to patients with non-resolving pulmonary disease after six months' initial observation improved lung function and chest x-ray appearances by a small amount.
Importantly, of patients who were given early steroids for troublesome symptoms, almost half were still taking steroids 5 years later. Yet whether steroids prevent fibrosis or improve clinically meaningful outcomes that are important to patients in the longer term is unknown.
Worryingly, there is evidence that early steroid therapy may promote more aggressive disease later on. Side effects of steroid therapy are often distressing and disfiguring, and sometimes serious or fatal. When sarcoidosis is refractory to steroid treatment, second line immunomodulators such as methotrexate, azathioprine, or mycophenolate are commonly prescribed based on their efficacy in treating rheumatic diseases, and are recommended in guidelines.
In sarcoidosis, the best evidence is that they are steroid sparing i. As with steroids, long term benefits have not been demonstrated and liver and bone marrow toxicity is a concern, requiring regular blood testing. Whilst a unifying cause of sarcoidosis remains elusive, it has been established that inflammatory cells including T lymphocytes, monocytes, and macrophages become hyper-activated in the lungs and peripheral blood.
Recently, using mouse models it has been shown that chronic signalling through the mTOR complex 1 mTORC1 in macrophages pathway drives the formation of sarcoid-like granulomas that closely mimic non-resolving sarcoidosis in humans.
These datasets indicate a key role for mTOR pathways and the metabolic status of tissue macrophages in triggering and driving disease pathology. The macrolide antibiotic azithromycin is immunomodulatory and anti-bacterial, both of which are plausible beneficial properties in sarcoidosis. Many studies have implicated bacteria as triggers for sarcoidosis, and although convincing evidence implicating a specific organism is lacking, improvements in sarcoidosis have been described in antibiotic combination studies that included azithromycin.
Beneficial immunomodulatory properties of macrolides became apparent in the treatment of Asian diffuse panbronchiolitis, where reduced inflammatory cytokine production in several cell types was demonstrated. Patients with pulmonary sarcoidosis need treatment options that effectively modulate disease activity, reduce risk of disease progression, and improve symptoms and quality of life, with an acceptable side effect profile.
Azithromycin is a cheap, readily available generic drug. Long term treatment with azithromycin has been shown to be safe in other chronic lung diseases.
Azithromycin is preferable to other macrolide antibiotics because of its safety data for long term use, once daily administration, and lack of inhibition of liver CYP3A isoenzymes. The safety profile of azithromycin makes it preferable to non-antibiotic macrolide mTOR inhibitors such as rapamycin sirolimus, used to treat transplant rejection and everolimus an anti-cancer drug.
Whether azithromycin will benefit patients with sarcoidosis can only be answered definitively by a large multicenter clinical trial. The Investigators proposed exploratory study aims to facilitate this aim by exploring mechanisms and evaluating potential blood biomarkers, and assessing feasibility of a subsequent large clinical trial.
Mean Change in Kings sarcoidosis questionnaire total score from baseline [ Time Frame: 3 months ] Kings sarcoidosis questionniare will be completed at baseline and compared with that at 1 month and 3 months post azithromycin Eligibility Criteria Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.
Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Try the modernized ClinicalTrials. Learn more about the modernization effort. Your Email. Share this article: Share article via email Copy article link. Recommended Reading. Print This Page. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases.
Tags autoimmune disorder , Bellerophon Therapeutics , granulomas , inhaled nitric oxide , INOpulse , Phase 2 trial , pulmonary blood pressure , sarcoidosis , top-line results.
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