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SARCOIDOSIS TREATMENT GUIDELINES
INTRODUCTION
Goals of Sarcoidosis Management
The goals of sarcoidosis management are to prevent or con- Sarcoidosis is a chronic inflammatory granulomatous dis- trol organ damage, relieve symptoms and improve the ease that primarily affects the lungs, although multi-organ patient’s quality of life. An evaluation by a pulmonologist is involvement is common. The etiology of sarcoidosis is not strongly recommended. For patients with extrapulmonary clear; however, genetic and environmental factors probably involvement, a multidisciplinary approach may be required.
play a role in the development and expression of the disease. A patient may need to see an ophthalmologist for ocular dis- Once thought to be rare, sarcoidosis affects people ease, a cardiologist for cardiac disease, a neurologist for neu- throughout the world. It can affect people of any age, race, rological disease, a nephrologist for renal disease, and so or gender; however, the prevalence is highest among adults between the ages of 20 and 40 and in African Americans andpeople of European – particularly Scandinavian – descent. Pharmacologic Treatment
Symptoms and severity can vary by race and gender, with While a significant percentage of sarcoidosis patients never African Americans being more severely affected than need therapy, there are several groups which require treat- Caucasians. Extrapulmonary sarcoidosis is common in cer- ment. In this monograph, we will discuss several of the com- tain populations, for example: chronic uveitis in African monly used drugs for sarcoidosis and their potential toxici- Americans, painful skin lesions in Northern Europeans and ties, and will provide algorithms for use of these drugs to cardiac and ocular involvement in Japanese. treat the symptoms associated with specific organ involve-ment.
Corticosteroids
Methotrexate. Methotrexate is one of the most commonly
used corticosteroid-sparing therapies for sarcoidosis, due to Corticosteroid medications are considered the first line of its effectiveness, low cost and, at the dosages used to treat treatment for sarcoidosis that requires therapy. Oral corti- sarcoidosis, relatively low risk of side effects compared to costeroids effectively reduce systemic inflammation in most other cytotoxic agents. The drug can be given orally or sub- people, thereby slowing, stopping or even preventing organ cutaneously. Due to the potential for hepatic and hematolog- damage. Corticosteroids may be prescribed alone or with ic toxicity, regular monitoring is required. Since the drug is other medications. Although there is no standard dosage or cleared by the kidneys, one should also monitor renal func- duration of corticosteroid therapy, the charts in this mono- tion. Dosage adjustment may be needed or an alternative graph will provide guidelines for individual organ involve- corticosteroid-sparing drug may be considered in those with ment. It is recommended that patients on corticosteroids renal insufficiency, e.g. serum creatinine > 1.5 (gfr < 50 long term be monitored for osteoporosis and treated appro- ml/min). It is recommended that patients have a CBC and hepatic and renal function every 1-3 months. Folic acid sup- Topical corticosteroids or intralesional injections may be plementation may be prescribed to reduce toxicity. prescribed for cutaneous involvement, and eye drops may be Azathioprine. What little research has been done on the
prescribed for uveitis. Corticosteroid inhalers may be useful subject shows that azathioprine (Imuran®) is roughly as in those with evidence of bronchial hyperactivity. effective as methotrexate in treating sarcoidosis. It is consid- Hydroxychloroquine. As a treatment for sarcoidosis, the
ered when there is a contraindication to methothrexate, such antimalarial drug hydroxychloroquine (Plaquenil®) is most as renal or hepatic function impairment. The side effects of likely to be effective in patients with dermatologic involve- azathioprine include dyspepsia, oral ulcers, myalgia, malaise, ment, joint manifestations and hypercalcemia. Due to poten- jaundice and blurred vision. Compared to methotrexate, tial macular toxicity, it is recommended that patients on there is also evidence of a higher frequency of opportunistic hydroxychloroquine have an eye examination every 6-12 infections and possibly malignancy with azathioprine use.
Some clinicians measure thiopurine S-methyltransferase(TPMT) levels prior to the first dose to determine if patients have TPMT deficiency and therefore are at increased risk should be considered as an alternative for patients who can- for toxicity. Others measure the CBC 2-4 weeks after the not tolerate methotrexate. It is recommended for the first first dosage. It is recommended that patients taking azathio- three months of therapy patients have monthly CBCs. For prine have a CBC and hepatic and renal function tests at patients who experience severe toxicity from leflunomide, cholestyramine therapy may be useful.
Mycophenolate mofetil. First developed to prevent organ
Cyclophosphamide. Due to its toxicity, cyclophosphamide
transplant rejection, mycophenolate mofetil (CellCept®) is (Cytoxan ®, Endoxan®) is usually reserved for severe dis- prescribed for a number of autoimmune and inflammatory ease not controlled by methotrexate or azathioprine. Case diseases, including rheumatoid arthritis and lupus nephritis.
studies suggest that cyclophosphamide is effective for some Anecdotal reports have shown it to be effective in treating people and is perhaps particularly useful in severe disabling sarcoidosis. The principal adverse reactions associated with neurosarcoidosis that has not responded to other therapies, the administration of mycophenolate mofetil include diar- including intravenous corticosteroids and anti-TNF therapy.
rhea, leukopenia, sepsis and vomiting. Compared to azathio- Its side effects can include nausea, vomiting, anorexia, prine, there is also evidence of a higher frequency of oppor- alopecia, acne, leukopenia, oral ulcers, skin hyperpigmenta- tunistic infections and malignancy. It is recommended that tion and fatigue. Less common but more severe side effects patients taking mycophenolate have a CBC and hepatic and include hemorrhagic cystitis and an increased risk for cancer.
renal function tests at least every 3 months. Overall, less toxicity has been reported with intermittent Leflunomide. Leflunomide (Arava®) is a cytotoxic drug
intravenous administration compared to daily oral use of that has been used as a single agent or in combination with cyclophosphamide. As with other immunosuppressants, methotrexate for the treatment of rheumatoid arthritis. In monitoring should include CBC and hepatic and renal func- sarcoidosis, the most common indications for therapy are tion tests every 1-3 months. Due to the risk of bladder can- ocular and lung disease. Although experience is limited, it Infliximab.
Adalimumab. The TNF inhibitor adalimumab (Humira®),
(Remicade®) has been approved for several inflammatory given by subcutaneous injection, has been approved for diseases including rheumatoid arthritis and Crohn’s disease.
rheumatoid arthritis and several other forms of arthritis.
Small, short-term studies have shown infliximab to be effec- Anecdotal reports have shown adalimumab to be effective in tive in reducing sarcoidosis symptoms in patients who did reducing sarcoidosis symptoms. Adalimumab can cause a not respond to other treatments. Infliximab can cause a vari- variety of side effects, including abdominal pain, nausea, ety of side effects, including abdominal pain, nausea, diar- diarrhea, dyspepsia, headache, rash, pruritus, pharyngitis rhea, dyspepsia, headache, rash, pruritus, pharyngitis and and sinusitis, and sore throat. Local injection site reactions sinusitis, and sore throat. Infusion reactions, including have been reported. Adalimumab also increases the risk of severe anaphylaxis, can occur. Infliximab also increases the infection and certain types of cancer, autoimmune disease risk of infection and certain types of cancer, autoimmune dis- and demyelinating disease. Adalimumab should be consid- ease and demyelinating disease. It is recommended that ered for patients who have been treated successfully with patients have a PPD for tuberculosis prior to beginning ther- infliximab but have developed antibodies. It is recommend- apy and that infliximab be withheld in the event of active ed that patients have a PPD for tuberculosis prior to begin- ning therapy and that adalimumab be withheld in the eventof active infection.
STANDARD THERAPIES
STANDARD THERAPIES
MAJOR TOXICITY
MONITORING
5-20mg weekly
PPD prior to initiating therapy, withhold PPD prior to initiating therapy, withhold Definitions: mg=milligrams; kg=kilogram; CBC=complete blood count; PPD=purified protein derivative, skin test to diagnose tuberculosis.
* See text for initial monitoring Several other drugs have been used in selected cases. They Chloroquine. Another antimalarial agent, chloroquine is
used for cutaneous and pulmonary sarcoidosis. It has a high- Pentoxifylline. A drug used to treat intermittent claudica-
er rate of gastrointestinal and ocular toxicity than hydroxy- tion, pentoxifylline has been reported to be steroid sparing chloroquine, so it is used less frequently. in some cases of pulmonary sarcoidosis. Its major toxicity is Tetracycline derivatives. Minocycline and doxycycline have
nausea, which is commonly encountered at the doses used been reported as useful for cutaneous sarcoidosis. Both drugs can cause nausea, and minocycline is associated withhepatitis and vertigo.
PULMONARY
Pulmonary involvement, found in over 90 percent of sar- up to five years after therapy has been discontinued. Less coidosis patients, is the most frequent manifestation of the clear is whether to recommend an 18-month course of corti- disease. The assessment of the degree of pulmonary involve- costeroids for patients with Stage II-IV disease and no dysp- ment includes pulmonary function tests (PFTs), including at nea. If pulmonary function tests are normal to mildly abnor- least a forced vital capacity, chest imaging such as a chest x- mal, the patient can be observed. About 70 percent of these ray, and ascertaining the level of dyspnea by questioning the patients will either remain the same or improve sponta- patient. Additional tests, such as diffusion capacity (DLCO), chest CT scan, and 6-minute walk, may be useful for individ- For patients with Stage 0 or I and dyspnea, an echocardio- gram may be useful to identify other causes of dyspnea, such As shown in the figure, the treatment approach depends on as cardiac. A high-resolution CT may also identify parenchy- whether the disease is asymptomatic or has minimal symp- mal lung disease not seen on a chest x-ray. If there is no evi- toms versus those with moderate or severe symptoms and dence of congestive heart failure or pulmonary hyperten- sion, treatment with corticosteroids may be considered.
For asymptomatic patients with Stage 0 or I chest x-ray, Corticosteroids remain the initial drug of choice for treat- therapy is not likely to offer benefits. For patients with mild ment of parenchymal lung diseases. A starting dosage is 20 - symptoms, such as a cough, treatment should begin with 40 mg prednisone or its equivalent. Once corticosteroids inhaled corticosteroids. If there is no response, oral corticos- have been started, the patient is usually seen 1-3 months.
teroids can be considered. While not specifically studied, Depending on the patient's condition, the dosage can be asymptomatic patients with a significant drop in pulmonary function should be considered for therapy. After 3-6 months, the dose should be tapered to physiolog- For those with dyspnea, corticosteroid therapy has been ic levels – for example, 10 mg of prednisone per day or less.
shown to improve lung function for both the short term and If such a taper is not successful, or there is toxicity from the corticosteroids, one should consider the addition of a eases and fatigue that should be considered. A 6-minute steroid-sparing agent, such as methotrexate or azathioprine.
walk or a cardiopulmonary exercise test may help identify Both of these agents will take up to 6 months to demonstrate what is happening during exercise. It may identify patients effectiveness and are effective in only about two-thirds of who require oxygen supplementation. It may also identify patients. There is some evidence that combining two cyto- other potential causes of dyspnea, such as cardiac causes, toxic agents may be useful. Leflunomide has also been used muscle strength impairment or deconditioning.
If no alternative cause of dyspnea is identified, an anti-TNF If a patient does not respond to the combination of pred- agent should be considered. Infliximab has been widely stud- nisone and a cytotoxic agent, the clinician has to decide ied, although adalimumab at higher doses may be effective.
whether or not the patient has a reversible disease process These agents have proved effective for treating inflammato- (granuloma versus fibrosis) in the lung. In addition, the cli- ry changes in the lung but will not reverse fibrosis. Benefits nician should rule out pulmonary hypertension as a cause of are usually seen within 3-6 months of starting one of these dyspnea. There are also non-pulmonary causes of dypsnea, agents. For required monitoring for these agents, see Table including anemia, heart failure, obesity, other systemic dis- *Where prednisone is indicated, an equivalent dose of corticosteroids (i.e. methylprednisolone) could also be used.
+Cytotoxic drugs include: methotrexate, azathioprine,mycophenolate and leflunomide.
++Anti-TNF therapy includes infliximab and adalimumab.
Cardiac sarcoidosis is estimated to affect up to 20 percent of are based on several retrospective studies from Japan sarcoidosis patients in the United States. (where cardiac manifestations may be present in approxi- Common manifestations of cardiac sarcoidosis include mately 50 percent of sarcoidosis patients) and accumulated arrhythmias, conduction abnormalities, and cardiomyopathy experience from referral centers in the U.S. and Europe.
due to granulomatous inflammation of the myocardium These studies suggest survival correlates with left ventricular and/or conducting system. Rarer manifestations include function and severe ventricular arrhythmias with no differ- valvular dysfunction, ventricular or atrial mass lesions, peri- ence in 5-year survival rates for patients treated with pred- cardial disease, myocardial infarction or sudden death. nisone >30 mg/day vs. <30 mg/day.
It is not clear how to best screen for cardiac sarcoidosis. An Many patients with significant cardiomyopathy and chronic EKG or echo may provide useful information.” If concerns sarcoidosis require long-term treatment to minimize pro- about possible cardiac involvement remain, advanced car- gressive cardiac dysfunction. Cytotoxic drugs are often used diac imaging such as cardiac scanning, cardiac MRI or car- as steroid-sparing agents in patients with left ventricular diac PET scanning have greater sensitivity and specificity ejection fraction (LVEF) <50%who require prednisone >10 than an echocardiogram and are recommended. However, the implications of a positive test in a patient with no symp- The role of TNF inhibitors remains undefined since these therapies have been shown to worsen congestive heart fail- A diagnosis of cardiac sarcoidosis is usually established by ure (CHF) in non-sarcoidosis cardiomyopathy; however, a non-cardiac biopsy that confirms systemic sarcoidosis small case series suggest these therapies may be beneficial in together with consistent cardiac imaging and/or arrhyth- some patients with cardiac sarcoidosis, assuming that the treatment of systemic sarcoidosis also benefits the cardiacinvolvement. There are no prospective clinical trials of medical regimens for cardiac sarcoidosis, Current treatment recommendations Indications for prophylactic insertion of an implantable car- dioverter defibrillator (ICD) or pacemaker are evolving.
experience. Since cardiac sarcoidosis is often diffuse, it is Currently, common practice is to recommend prophylactic unusual that a single focus can be identified for ablation.
ICD insertion for patients with LVEF<35% or for serious Permanent pacemakers are suggested for high-degree heart arrhythmias and to recommend against prophylactic ICD insertion when there is normal cardiac function, unless car- Cardiac transplantation is an option for patients with diac imaging studies show extensive inflammation. The advanced cardiac sarcoidosis with survival rates better than effectiveness of radiofrequency ablation for prevention of those with other causes of heart disease despite reports of arrhythmias in cardiac sarcoidosis is uncertain, given limited recurrent granulomatous inflammation in the transplanted *Where prednisone is indicated, an equivalent dose of corticosteroids (i.e. methylprednisolone) couldalso be used.
+Cytotoxic drugs include: methotrexate, azathioprine, mycophenolate and leflunomide.
Ocular manifestations are frequent in sarcoidosis, affecting ease. Severe vasculitis can be associated with exudates that 11 percent of patients in a recent U.S. study. Sarcoidosis can give the appearance of "candle wax drippings." Frequently affect virtually any part of the eye, including the lacrimal there is involvement in the anterior segment when there is gland, ocular surface, and anterior and posterior segments.
posterior segment disease. Although these are not the most Treatment depends on the specific manifestation and its classic presentations of sarcoidosis-related uveitis, sarcoido- sis is a potential cause of nearly any form of uveitis. Lacrimal gland granulomas can lead to keratoconjunctivitis Management of uveitis is frequently carried out by an oph- sicca, which is best managed with artificial tears to keep the thalmologist in collaboration with the pulmonologist or conjunctiva moist, lacrimal punctal plugs and/or topical rheumatologist treating the systemic manifestations of sar- cyclosporine. Occasionally surgery or injection of the coidosis. Anterior uveitis usually can be managed with local lacrimal glands with corticosteroids is used. therapy using corticosteroid eye drops to suppress inflamma- Involvement of the ocular surface can include conjunctival tion and cycloplegic eye drops to suppress pain and avoid granulomas that may not require treatment. Symptomatic intraocular scarring. In some cases, periocular corticosteroid conjunctivitis, episcleritis or keratitis may be managed with injections and long-term intraocular corticosteroid implants corticosteroid eye drops. Scleritis is typically managed with also have been used; however, implants have been associat- ed with a significantly higher rate of cataracts and glaucomaand are still being studied in chronic inflammatory condi- The anterior segment is involved most frequently with a tions such as sarcoidosis. For severe cases, infliximab has chronic granulomatous uveitis that is characterized by "mut- been useful. Due to its flexibility, effectiveness and the abil- ton fat" keratic precipitates and iris nodules. Posterior seg- ity to provide ongoing therapy and treat extraocular aspects ment disease occurs in the form of viritis and periphlebitis of sarcoidosis simultaneously, cytotoxic therapy, usually and can sometimes be the sole manifestation of ocular dis- cytotoxic agents, has been the mainstay of therapy. For posterior uveitis or panuveitis, systemic therapy is usu- For severe disease, the typical initial dosage of prednisone ally used. Systemic corticosteroids are usually effective in is 20-40 mg/day, while some use as much as 1 mg/kg/day. If controlling inflammation in both the short and long term.
immediate therapy is needed, intravenous corticosteroids in However, due the risks of systemic corticosteroids – especial- 1-gram pulses are given. If greater than 10 mg prednisone is ly with long-term use – some physicians use periocular injec- needed to control the disease, then corticosteroid-sparing tions of corticosteroids in the posterior or sub-Tenon's drugs should be used. Cytotoxic drugs such as methotrexate, space, or in the orbital floor. Intravitreal corticosteroids, azathioprine, and mycophenolate mofetil have been used used since the 1990s, are useful for controlling acute exacer- with success. Recent experience suggests that the biologic bations but are probably not appropriate for chronic thera- agents infliximab or adalimumab, both anti-TNF monoclon- al antibodies, are also effective. In uveitis in general – includ-ing uveitis related to sarcoidosis – either infliximab or adali-mumab has been useful in refractory cases.
*Where prednisone is indicated, an equivalent dose of corticosteroids (i.e. methylprednisolone) could also be used.
+Cytotoxic drugs include: methotrexate, azathioprine,mycophenolate and leflunomide.
++Anti-TNF therapy includes infliximab and adalimumab.
NEUROSARCOIDOSIS
Approximately 5-15 percent of patients have neurologic patients. The dosage should be tapered over 1-6 months and disease. Neurologic manifestations of sarcoidosis include can be discontinued if weakness resolves. A similar course cranial neuropathies, meningeal disease [acute and chronic may be sufficient to treat patients with an acute sarcoidosis- meningitis, mass lesion(s)], hydrocephalus, CNS parenchy- mal disease [endocrinopathies, mass lesion(s), encephalopa- It is suggested that patients with mild to moderately dis- thy/vasculopathy, seizures, and spinal cord abnormalities], abling disease (cranial nerves II and VIII, meningeal mass lesions, hydrocephalus, CNS parenchymal disease, neu- Treatment decisions depend, in part, on the certainty of ropathies and generalized myopathies) be treated with 20-30 diagnosis, the patient's clinical status, the anticipated clinical mg prednisone daily for at least one month. If the patient course and contraindications to a particular intervention.
improves, the dose can be decreased by 5 mg every two Because of the rarity of neurosarcoidosis, there have been weeks as the clinical course is monitored. Patients may no rigorous clinical trials to guide treatment; management is require a maintenance dose of 10 mg or lower daily even if predicated principally on clinical series and "expert opin- they are treated with adjuvant drugs.
For patients who are acutely and severely ill, intravenous Corticosteroid treatment is recommended as the first line of methylprednisolone for three days or anti-TNF therapy is therapy for neurologic involvement. In order to avoid the recommended. Infliximab can also be used for chronic treat- long-term complications of corticosteroid therapy, use of ment or to "bridge" a patient until an immunosuppressive adjuvant cytotoxic therapy is recommended early in the clin- drug's benefit becomes evident, typically in 2-3 months.
ical course of patients who are likely require prolonged Infusions of infliximab can be administered every 2-8 weeks, or at longer intervals, as clinically indicated. The most common neurologic manifestation of neurosar- Mycophenolate and cyclophosphamide have been reported coidosis is peripheral facial nerve palsy. A limited course of as useful for refractory neurosarcoidosis in selected cases.
prednisone 20-40 mg daily is recommended for these *Where prednisone is indicated, anequivalent dose of corticosteroids (i.e.
methylprednisolone) could also be used.
leflunomide.
++Anti-TNF therapy includes infliximaband adalimumab.
One in four sarcoidosis patients will have cutaneous patient. If the patient has very few localized lesions, they involvement. Although sarcoidosis of the skin is almost may respond to application of a corticosteroid cream or never life-threatening, it can cause significant cosmetic prob- intralesional injections. If lesions do not respond to local lems that may have a major impact on the patient's quality therapy or if skin disease is more generalized, some type of pharmacotherapy is required. Systemic corticosteroids are Sarcoidosis skin lesions are classified in two groups: sar- usually used at least for the short term, but because of their coidosis-specific skin lesions and non-granulomatous lesions.
many potential side effects, other agents should be consid- The former represent true sarcoidosis of the skin. That is, the skin contains granulomas, the pathological lesions of sar- Hydroxychloroquine is often the first steroid-sparing drug coidosis. The latter are inflammatory reactions of the skin used. Among the cytotoxic drugs, methotrexate seems to have a better response rate than other agents. In some cases, Specific sarcoidosis skin lesions include thick, raised skin derivatives of tetracycline have been helpful in mild disease.
lesions that have an apple jelly color. They may be scaly, and For very severe cases, anti-TNF therapy, such as infliximab occasionally they are yellow to violet in color. Other specific may have a role. In selected patients chloroquine and skin lesions include skin nodules that develop on old scars and tattoos; lesions that look like ulcers; lesions that may be Non-granulomatous lesions are very common with acute mistaken for psoriasis; and lupus pernio, potentially disfigur- initial presentations of sarcoidosis. Also, they are associated ing lesions that occur on the face, particularly on or around with a good prognosis of sarcoidosis in that the disease often goes away within a few months when non-granulomatous These specific lesions almost never cause pain or itching lesions occur. The most common non-granulomatous sar- and are not life-threatening. For that reason, they should be coidosis lesion is erythema nodosum. These lesions – which treated only if they are of cosmetic importance to the are thick, slightly raised and often painful – are often seen with an acute presentation of sarcoidosis called Lofgren's We suggest an approach to the various forms of cutaneous syndrome. This syndrome, which is also associated with hilar sarcoidosis. For lupus pernio, a large retrospective study adenopathy, fever and pain in the ankles and other joints, reported that anti-TNF therapy was significantly better than typically resolves completely in a few months. It can be usu- cytotoxic or antimalarial therapy, and it could be considered ally treated with only nonsteroidal drugs for painful skin as second-line therapy for this particular form of skin sar- lesions and joint pain; however, occasionally corticosteroids coidosis. However, anti-TNF therapy is associated with more toxicity and the risk/benefit ratio must be considered intreating this chronic cutaneous condition. equivalent dose of corticosteroids (i.e.
methylprednisolone) could also be used.
+Cytotoxic drugs include: methotrexate, LIVER DISEASE
Estimates of liver involvement in sarcoidosis vary from 11- There is limited data on which to base treatment recom- 80 percent of cases, with lower rates based on symptomatic mendations for sarcoidosis liver disease. As there are no disease and higher rates reported in studies performing ran- controlled trials, much of the following is based on clinical dom liver biopsies. Women and African Americans are experience and retrospective case studies. affected more frequently. Most individuals with liver disease The majority of patients with sarcoidosis liver disease do present asymptomatically with evidence of hepatomegaly, not require therapy. This includes patients with asympto- increased liver function test or CT scan abnormalities. Non- matic disease and mildly elevated liver function tests, no evi- specific symptoms, including abdominal pain, fevers and dence of cholestasis (normal bilirubin) and normal liver syn- weight loss are common in sarcoidosis liver disease, although thetic function (e.g., protime, PT), or with hepatomegaly patients may present with pruritus, jaundice and chronic noted on physical exam and/or radiographic abnormality.
cholestasis. Cirrhosis, portal hypertension, Budd-Chiari syn- These individuals – including those with liver function tests drome and variceal bleeding occur rarely. In cases of known more than three times the upper limit of normal, even with- sarcoidosis a probable diagnosis of liver disease may be out symptoms – should be followed using liver-function tests established based on increased alkaline phosphatase, or to determine if they develop evidence of cholestasis or transaminases, or CT findings of characteristic nodules, con- abnormal prothrombin time (PT), which would be consid- sisting of low attenuation lesions of varied but usually small ered reasons for starting systemic therapy. Liver-function size. Occasionally a liver biopsy may be obtained, although test abnormalities may resolve spontaneously over time or this is not necessary to confirm liver sarcoidosis.
with treatment aimed at other organ involvement (e.g., lung Radiographic findings are not specific for hepatic sarcoido- sis; ultrasound may be obtained to assess portal hyperten-sion and to exclude other causes of liver disease. In general, Granulomatous hepatitis is usually treated in individuals a diagnosis of hepatic sarcoidosis must be confirmed and with symptomatic liver disease, such as those with abdomi- other causes of liver disease must be excluded.
nal pain or jaundice with evidence of cholestasis, or if there are significant abnormalities in liver function, or even frank may be used to manage symptoms of cholestasis, including cirrhosis, demonstrated with increased PT. If liver-function jaundice and pruritus. Unfortunately, cirrhosis may occur tests are more than 10 times normal, therapy may be consid- despite therapy, and even result in the need for liver trans- ered and these patients should be followed closely. Corticosteroids are usually the first line therapy. When an Splenomegaly is common in sarcoidosis, more so than inadequate response to corticosteroids is noted, cytotoxic hepatomegaly, but does not usually require treatment and agents are often used. Most experience has been with aza- may resolve spontaneously. Although there are limited data thioprine for hepatic sarcoidosis. Methotrexate and lefluno- upon which to make recommendations for treatment, clini- mide are more likely to be hepatotoxic; however, azathio- cal indications for treatment include hypersplenism with prine can also be hepatotoxic, so one would still have to cytopenia, or splenic infarction. Usually corticosteroids are closely monitor LFTs. Ursodeoxycholic acid at 10 mg/kg/day effective treatment. Splenectomy is not usually performed. • Alkaline phosphatase• Transaminases *Where prednisone is indicated, an equivalent dose of corticosteroids (i.e. methylprednisolone) could also be used.
+Cytotoxic drugs include: azathioprine*, methotrexate, mycophenolate andleflunomide.
*Azathioprine is the most commonly used cytotoxic drug for mild hepatic dis- RENAL DISEASE AND ABNORMALITIES IN CALCIUM METABOLISM
Sarcoidosis nephropathy manifests as interstitial nephritis treatment recommendations are limited. However, in isolat- more commonly than glomerular disease, although renal ed hypercalciuria, treatment may begin with a reduction in failure from either mechanism is uncommon.
calcium intake, increased fluids and avoidance of sun.
Granulomatous inflammation or other pathologic manifes- Occasionally, hydroxychloroquine may be effective at 200- tations may be seen, including membranous nephropathy, 400 mg daily for more significant hypercalciuria. minimal change disease, proliferative or crescentic glomeru-lonephritis, focal glomerulosclerosis and even IgAnephropathy. While there is limited data upon which to basetherapeutic recommendations, corticosteroids are usuallyused with evidence of renal insufficiency starting at 40 mgdaily, with a slow wean of therapy as used for other organinvolvement. Usually there is evidence of improvement inrenal function with treatment, although normalization of In sarcoidosis patients, vitamin D-1,25 may creatinine may not occur. Rarely renal transplantation is be elevated with normal or even low levels of vitamin D- 25. In that setting, further supple- An increase in 1,25-(OH)2- vitamin D3 production from mentation with vitamin D can lead to hyper- pulmonary macrophages and granulomas may lead to calcemia and/or hypercalciuria. For sarcoido- increased absorption of calcium. This can eventually resultin hypercalcemia, seen in up to 5 percent of patients with sar- sis patients, screening for vitamin D deficien- coidosis, and more commonly hypercalciuria.
cy should be done by measurement of vita- Nephrocalcinosis may result from persistent hypercalciuria and/or hypercalcemia, and can cause renal insufficiency. Asin the other organs discussed above, data on which to base Mild hypercalcemia may also be treated with a reduction in Occasionally other agents, including hydroxychloroquine, dietary calcium and increased fluid intake. For more signifi- are needed for more refractory disease. Vitamin D supple- cant hypercalcemia (e.g. Ca >11 mg/dl) or nephrolithiasis, mentation should be avoided in those with hypercalciuria corticosteroid therapy is usually implemented at 20-40 mg and hypercalcemia. Ketoconazole has no direct effect on sar- daily. Reduction in hypercalcemia usually occurs fairly coidosis’ granulomas, but it inhibits vitamin D metabolism quickly with steroid implementation, and some will attempt and can be used as an adjunct for treating hypercalcemia and to taper the corticosteroids more quickly after 1-2 months.
(i.e. methylprednisolone) could alsobe used.
+Cytotoxic drugs include: QUALITY-OF-LIFE ISSUES
The clinical course of sarcoidosis is highly variable, and vir- lung-function tests and laboratory parameters do not always tually every organ can be involved. In addition to organ-spe- reflect the well-being of the patient. Other factors that need cific symptoms such as coughing, dyspnea on exertion, chest to be considered are small fiber neuropathy, autonomic dys- pain, and wheezing, many patients experience non-specific function, and steroid myopathy. Hypogonadism, hypothy- symptoms such as fatigue, psychologic distress, and pain roidism and sleep apnea syndrome can also lead to fatigue.
issues that are disabling, particularly when they become Reduced respiratory muscle strength and endurance time chronic and have a great impact on the quality of life (QOL). were demonstrated in sarcoidosis patients with normal lung- function test results at rest, especially in those suffering fromfatigue. Moreover, fatigue was related to dyspnea, sleeping Despite adequate treatment for other manifestations of sar- disorders and to the 6-minute walk distance during an exer- coidosis, a substantial number of sarcoidosis patients suffer cise test. Fatigue appeared to be associated with specific from persistent fatigue. Fatigue appears to be the most fre- types of pain, such as muscle pain, chest pain, arthralgia, quently reported symptom in sarcoidosis patients. Recent studies suggest that fatigue may persist after all other mani- Little data are available regarding specific treatment for festations of sarcoidosis have resolved. fatigue associated with sarcoidosis. In a recent small double- Fatigue may be debilitating, may become chronic and caus- blinded, placebo-controlled crossover study, the stimulant es substantial reduction in professional, recreational, social, dexmethylphenidate hydrochloride (d- MPH) was associat- and/or educational activities and, as a consequence, reduces ed with a significant reduction in sarcoidosis-associated QOL. When features of disease activity – for example, radi- fatigue. Anti-TNF treatment for other sarcoidosis-related ological abnormalities and lung function impairment – are problems also appeared beneficial for fatigue. Other studies resolved during treatment, fatigue and pain may persist.
suggest that prednisone usage can be associated with patient Therefore, objective test results such as chest radiographs, Unfortunately, these studies were not designed to ascertain conditions of weight gain, diabetes, depression, inactivity, if steroids represent cause or effect for fatigue. It is possible sleep disturbance or altered mood states. Besides medica- that corticosteroids represent a surrogate marker for more tion, cognitive-behavioral therapy may also be considered as severe or chronic disease or the development of co-morbid *Where prednisone is indicated, an equivalent dose of corticosteroids (i.e. methylprednisolone)could also be used.
+Cytotoxic drugs include: methotrexate, azathioprine, mycophenolate and leflunomide.
++Anti-TNF therapy includes infliximab and adalimumab.
Pain, Small Fiber Neuropathy and Cognitive
age and sex distribution. No substantial relationship has Dysfunction
been found with clinical characteristics, such as disease dura-tion, and severity. In some studies, fatigue, depression and Chronic pain is a particular problem for sarcoidosis symptoms related to autonomic dysfunction were associated patients. A stepwise approach to management is shown. with the occurrence of cognitive dysfunction. These findings A number of hitherto unexplained symptoms such as emphasize the need for further research to integrate knowl- fatigue, pain and cognitive dysfunction may – at least partly edge about coping, cognitive performance, fatigue and – be attributable to small fiber neuropathy. It has been depressive symptoms in sarcoidosis into clinical manage- observed that sarcoidosis patients with symptoms displayed more depressive symptoms and scored lower on health sta- Standard anti-inflammatory therapies are usually ineffec- tus compared with patients without current symptoms.
tive for this condition. Neuropathic drugs such as gabapentin Moreover, patients suffering from sarcoidosis often report may be useful for symptomatic relief. For refractory cases, cognitive complaints, such as memory loss and concentration anecdotal reports suggest the effectiveness of standard anti- problems. Cognitive failures are a substantial problem in inflammatory therapies, intermittent immunoglobulin sarcoidosis patients, even after adjustment for differences in (IVIG) therapy and/or anti-TNF in selected cases.
*Where prednisone is indicated, an equivalent dose of corticosteroids (i.e. methylprednisolone) could also be used.
+Cytotoxic drugs include: methotrexate, azathioprine, Anti-TNF therapy includes infliximab and adalimumab.

Source: http://sa.sbmu.ac.ir/uploads/FSR-Physicians-Protocol1.pdf