US Pharm. 2015;40(10):HS22-HS25.
ABSTRACT: Sarcoidosis is a multisystem inflammatory disease of unknown etiology that causes noncaseating granulomas in one or more organs and tissues. It is more likely to develop in persons aged 20 to 40 years. The organs primarily affected include the lungs and the lymphatic system, but any organ can be involved. Some patients are asymptomatic, whereas others may present with dyspnea upon exertion and fatigue, malaise, night sweats, fever, anorexia, and arthralgias. Diagnosis is usually confirmed by chest x-ray, biopsy, and exclusion of other causes of granulomatous inflammation. There is currently no cure for sarcoidosis, and the selected treatment is typically individualized based upon the patient’s symptoms and the severity and degree of organ involvement. The use of corticosteroids is considered the mainstay of therapy.
Sarcoidosis, which is a multisystem inflammatory disease of unidentified etiology, manifests as noncaseating granulomas, predominantly in the lungs and the intrathoracic lymph nodes.1 Sarcoidosis can also affect other organs, including the heart, liver, skin, spleen, nervous system, and eyes.2 Although the cause of sarcoidosis is unknown, ongoing research has determined that genetic and environmental factors appear to play a role. Many clinicians believe that the etiology and diagnosis of sarcoidosis are inadequately understood.3-5 In most patients, sarcoidosis improves on its own, but in about one-third of cases, it ultimately becomes a chronic condition that negatively affects the organs and overall quality of life.2 In addition, while many people with sarcoidosis can live active lives, disease severity can range broadly from asymptomatic to severe.
According to the American Lung Association, sarcoidosis affects people from a variety of racial and ethnic backgrounds, but its incidence appears to be most prevalent among African Americans and Northern Europeans.4 Persons of German, Asian, and Puerto Rican descent are also more prone to developing sarcoidosis.4 Löfgren syndrome, a type of sarcoidosis, appears to be most prevalent in those of European descent.5 Studies suggest that females are at greater risk than males, and people with a familial history of sarcoidosis also have an elevated risk.
Sarcoidosis typically manifests before age 50 years, with an average age of incidence from 20 to 39 years.3,5 According to the American College of Chest Physicians (ACCP), approximately 70% of patients diagnosed with sarcoidosis are aged 20 to 40 years.3,6 An estimated 90% of patients with sarcoidosis have pulmonary sarcoidosis, which causes decreased diffusion capacity (the most common abnormality found on pulmonary-function testing).7 Pulmonary sarcoidosis is often accompanied by restrictive ventilatory dysfunction and the presence of obstructive airway disease, which occurs in approximately 30% of patients.8 It is estimated that, in the United States, cardiac sarcoidosis occurs in >10% of patients with sarcoidosis. Cardiac sarcoidosis can result in bradycardia, shortness of breath, and edema.9
Speculated Causes of Sarcoidosis
Since sarcoidosis can affect the lungs, eyes, and skin, ongoing research efforts are investigating the correlation between sarcoidosis and exposure to airborne antigens in the environment.6 Some of the earliest studies of sarcoidosis reported associations with exposure to irritants found in rural settings, such as tree pollen and emissions from wood-burning stoves.6 More recently, relationships between sarcoidosis and exposure to inorganic particles, insecticides, and moldy environments have been reported.6
Progress has been made in identifying the potential causes of sarcoidosis. The ACCESS trial collected data on 704 patients with newly diagnosed, biopsy specimen–proven sarcoidosis and controls matched by age, sex, race, and geographic area.8 Numerous environmental exposures that were moderately linked to sarcoidosis risks, such as agricultural employment, mold or mildew, musty odors at work, and pesticide-using industries, were identified.8 The risk of developing sarcoidosis increased with the extent of tobacco use, which validated results of previous studies.8 The ACCESS trial concluded that although no single cause of sarcoidosis was identified, multiple triggers likely exist.8
Sarcoidosis is also thought to be due to an inflammatory response to an environmental antigen in a genetically susceptible person.9 Possible triggers include Propionibacterium acnes, mycobacteria, mold or mildew, and certain unidentified substances present in work environments containing musty odors and pesticides.9 According to the Foundation for Sarcoidosis Research, certain bacteria, viruses, or chemicals may also be triggers.10
Signs and Symptoms
Patients with sarcoidosis may be asymptomatic or may present with a variety of symptoms, depending upon the extent and severity of the organ(s) involved. An estimated 5% of patients with sarcoidosis are asymptomatic, and the disease is detected incidentally by chest radiography performed to detect a different condition, such as pneumonia or another respiratory tract infection.11 Diagnosis is typically based upon medical history and physical examination (including diagnostic tests such as chest x-ray, lung-function tests, and biopsy) to detect granulomas in the organs.
In patients experiencing severe symptoms, multiple organ systems often are involved. Systemic complaints of fatigue, malaise, night sweats, fever, anorexia, and arthralgias occur in 45% of sarcoidosis cases, and pulmonary complaints such as dyspnea on exertion, cough, chest pain, and hemoptysis (rare) occur in 50% of cases.1,12 Other common symptoms include swelling or soreness of the lymph nodes, weight loss, and reddened, watery, or sore eyes.1,4,12 In some cases, lumps, ulcers, discolored skin, or skin sores on the back, arms, legs, scalp, and face may occur.4 Patients may also exhibit enlarged liver, spleen, or salivary glands.11
Sarcoidosis of the eyes may cause uveitis, which can result in significant vision loss if left untreated.2 According to the ACCP, other complications associated with sarcoidosis include hypercalcemia, hepatic disease, renal failure, peripheral neuropathy, and bone and joint damage.13 One study reported that 46% of patients with sarcoidosis may also have depression, since impaired lung function affects overall quality of life.3,14
Patients with Löfgren syndrome often have an acute presentation consisting of arthritis, erythema nodosum (a rash of red or reddish-purple bumps on the ankles and knees), and bilateral hilar lymphadenopathy (occurring in 9%-34% of patients).6,12,15 Those with brain involvement may experience alterations in memory or mental acuity, or strokelike symptoms.6,12,15
There is currently no cure for sarcoidosis, and treatment is typically individualized based upon the patient’s symptoms and the severity and degree of organ involvement. For many healthcare providers, the decision to treat sarcoidosis is often complex, since therapy is not standardized. In some cases, no treatment is warranted, and the disease may resolve on its own.3,13
In general, the goals of therapy include relieving symptoms, improving organ function, controlling inflammation, reducing the size of granulomas, and preventing pulmonary fibrosis (if pulmonary sarcoidosis is present) and other irreversible damage to organs.16-19 The treatment of sarcoidosis can be problematic for many reasons. First, treatment is often associated with significant adverse events, and treatment may cause more harm than the disease itself, especially since sarcoidosis may never cause significant symptoms.18 Second, although sarcoidosis is often well controlled with corticosteroids, patients often experience adverse effects from chronic use; therefore, even when sarcoidosis is well controlled with corticosteroids, corticosteroid-sparing medications may be required over time.18 Third, the treatment of sarcoidosis varies to some extent depending on which organ(s) may be involved.18 Finally, because sarcoidosis is not a common disease, there is a lack of clinical evidence-based data on which to establish treatment options.18
According to U.S. and updated British Thoracic Society guidelines on treatment options for pulmonary sarcoidosis, the decision to treat should include weighing the risks associated with corticosteroid use against the potential benefits, and treatment should be considered when organ function is affected.19-21 As a rule, experts recommend that treatment initiation be considered when organ function is threatened.19-21 The main points of the guidelines are as follows19-21:
• The majority of patients with sarcoidosis do not require treatment, and the disease may sometimes spontaneously regress
• Since episodes of erythema nodosum can be painful, short-term use of a nonsteroidal anti-inflammatory drug (NSAID) may be beneficial
• Typically, treatment is not indicated for asymptomatic stage 1 disease or for asymptomatic, stable stage 2 or 3 disease in patients with only mildly abnormal lung function
• Oral corticosteroids may be advantageous for patients with stage 2 or 3 disease who have moderate-to-severe or progressive symptoms or changes on chest x-rays
• Absolute indications for oral corticosteroids include hypercalcemia, neurologic involvement, cardiac involvement, or ocular involvement (if topical treatment for ocular problems has failed)
• Inhaled corticosteroids are not beneficial for initial treatment or maintenance treatment, although they are sometimes attempted in patients with an intractable cough.
While many patients with sarcoidosis do not require therapy, when treatment is warranted, patients in studies usually improved with individualized doses of corticosteroids, and this drug class is thought of as standard therapy.8 Oral prednisone is the most commonly prescribed corticosteroid. Generally, prednisone is given daily and then tapered over a 6-month period, which is adequate for pulmonary disease.12 Earlier treatment recommendations suggested an initial dose of prednisone 1 mg/kg/day; however, more recently it is recommended to use a lower dose (e.g., 40 mg/day) that is tapered to every-other-day long-term therapy over several weeks.1 Some patients requiring long-term corticosteroids may be treated with prednisone 10 to 15 mg every other day.1 While corticosteroids are often employed for symptom relief and remain the standard treatment, their efficacy in managing sarcoidosis is unclear.12 Patients receiving chronic corticosteroids need to be monitored for potential adverse effects, including routine monitoring of weight and nutrition, blood pressure, cortical bone density, the eyes (to detect development of cataracts or glaucoma), diabetes mellitus/hyperglycemia, and mood changes.18
Some clinicians seek an alternative therapy when a patient is unable to take prednisone because of contraindications such as other health conditions, intolerable adverse effects, or progression of sarcoidosis despite an adequate trial of prednisone.3 A method known as steroid sparing, in which a drug such as methotrexate or azathioprine is added to prednisone therapy in order to decrease the dosage of prednisone, is often employed.3 Adding a medication such as methotrexate and azathioprine may also be recommended when the disease progresses despite the use of prednisone.3
Other treatments are sometimes prescribed for sarcoidosis, such as immunosuppressive agents (e.g., methotrexate, azathioprine, cyclophosphamide, leflunomide, cyclosporine, chlorambucil), cytokine inhibitors (thalidomide and pentoxifylline), and immunomodulatory agents (tumor necrosis factor-alpha antagonists, infliximab, adalimumab, and antimalarial agents such as chloroquine).16,18,22,23 Currently, there is no clear evidence of the usefulness of these drugs, and these agents are indicated only in cases when the sarcoidosis does not respond to conventional treatment with oral corticosteroids; in patients with intolerance or contraindications to corticosteroids (i.e., poorly controlled diabetes, myopathy, osteoporosis); or when the dosage of corticosteroids must be reduced.20
Given the adverse-effect profile associated with long-term use of corticosteroids, methotrexate has recently received significant attention as either a corticosteroid alternative or a corticosteroid-sparing agent.19,20 Methotrexate is the most-studied alternative to corticosteroids for the treatment of sarcoidosis.18 In a recent Delphi study of sarcoidosis experts, methotrexate was determined to be the preferred corticosteroid-sparing agent for pulmonary sarcoidosis.18 Methotrexate has been found efficacious for most forms of sarcoidosis, including lung, eye, skin, and neurologic involvement.18
In some cases, specialized treatment may be warranted to treat and manage associated conditions in sarcoidosis patients, such as fatigue, depression, hypercalcemia, renal stones, and pulmonary hypertension.2 NSAIDs are often employed and indicated for arthralgias and other rheumatic complaints; they are not used for significant pulmonary disease.2 Patients with stage 1 sarcoidosis require only occasional treatment with NSAIDs.2
Clinical studies have also investigated the treatment of sarcoidosis with antimalarial agents used to treat rheumatoid arthritis; however, research supporting the use of antimalarials in sarcoidosis is limited to case studies.2 These agents are being investigated because they have a relatively benign adverse-effect profile and because immunosuppressants may be beneficial in patients who have not responded to corticosteroids or in those unable to tolerate prednisone.2 Additionally, it is important to note that individuals with severe or advanced pulmonary sarcoidosis may require oxygen therapy or lung transplantation when warranted.22
Researchers continue to look for emerging and better treatments for sarcoidosis. Since each case of sarcoidosis is different, it is imperative that clinicians ask many questions to ascertain the best approach to managing and treating each patient. Studies suggest that genetic, host immunologic, and environmental factors interact to cause sarcoidosis. Researchers are currently studying therapies aimed at the immune system and the use of antibiotics as a potential treatment for sarcoidosis that affects the skin.16,23 Several clinical trials are currently under way, and new treatments are being developed. See ClinicalTrials.gov for more information on clinical trials for sarcoidosis.
The CHEST Foundation and the Foundation for Sarcoidosis Research have collaborated to increase awareness about sarcoidosis. Their program, called “Seek Answers. Inspire Results,” is designed to encourage patients with sarcoidosis to take a proactive role in their overall health and management, as well as have an open dialogue with their primary healthcare provider. While ongoing research continues to gain a better understanding of the etiology of and best treatment options for sarcoidosis, there is still much more to learn. As healthcare professionals, pharmacists have the responsibility to continue to increase awareness about sarcoidosis and to be an educational resource for patients affected by it.
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5. National Heart, Lung, and Blood Institute (NHLBI). Who is at risk for sarcoidosis? www.nhlbi.nih.gov/health/health-topics/topics/sarc/atrisk. Accessed September 10, 2015.
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10. Foundation for Sarcoidosis Research (FSR). What is sarcoidosis? www.stopsarcoidosis.org/patient-resources/what-is-sarcoidosis. Accessed September 10, 2015.
11. NHLBI. What are the signs and symptoms of sarcoidosis? www.nhlbi.nih.gov/health/health-topics/topics/sarc/signs. Accessed September 10, 2015.
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13. ACCP. Sarcoidosis: complications. www.chestnet.org/Foundation/Patient-Education-Resources/Sarcoidosis/Complications. Accessed September 10, 2015.
14. Yeager H, Rossman MD, Baughman RP, et al. Pulmonary and psychosocial findings at enrollment in the ACCESS study. Sarcoidosis Vasc Diffuse Lung Dis. 2005;22:147-153.
15. Byun CW, Yang SN, Yoon JS, Kim SH. Lofgren’s syndrome-acute onset sarcoidosis and polyarthralgia: a case report. Ann Rehabil Med. 2013;37:295-299.
16. NHLBI. How is sarcoidosis treated? www.nhlbi.nih.gov/health/health-topics/topics/sarc/treatment. Accessed September 10, 2015.
17. Cleveland Clinic. Sarcoidosis. http://my.clevelandclinic.org/health/diseases_conditions/hic_Overview_of_Sarcoidosis. Accessed September 10, 2015.
18. Beegle SH, Barba K, Gobunsuy R, Judson MA. Current and emerging pharmacological treatments for sarcoidosis: a review. Drug Des Devel Ther. 2013;7:325-338.
19. FSR. Sarcoidosis treatment guidelines. www.stopsarcoidosis.org/wp-content/uploads/2013/03/FSR-Physicians-Protocol1.pdf. Accessed September 10, 2015.
20. Jara-Paromales L, Caballero-Eraso C, Díaz-Baquero A, Rodríguez-Portal JA. Updated guidelines for the treatment of pulmonary sarcoidosis. In: Motamedi MH, ed. Sarcoidosis Diagnosis and Management. Rijeka, Croatia: InTech; 2011.
21. Dempsey OJ, Paterson EW, Kerr KM, Denison AR. Sarcoidosis. BMJ. 2009;339:b3206.
22. ACCP. Sarcoidosis: treatment and drugs. www.chestnet.org/Foundation/Patient-Education-Resources/Sarcoidosis/Treatment-and-Drugs. Accessed September 10, 2015.
23. Chen ES, Moller DR. Etiologies of sarcoidosis. Clin Rev Allergy Immunol. 2015;49:6-18.
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