SARCOIDOSIS TREATMENT GUIDELINES

INTRODUCTION Goals of Sarcoidosis Management

Sarcoidosis is a chronic inflammatory granulomatous dis- The goals of sarcoidosis management are to prevent or con-
ease that primarily affects the lungs, although multi-organ trol organ damage, relieve symptoms and improve the
involvement is common. The etiology of sarcoidosis is not patient’s quality of life. An evaluation by a pulmonologist is
clear; however, genetic and environmental factors probably strongly recommended. For patients with extrapulmonary
play a role in the development and expression of the disease. involvement, a multidisciplinary approach may be required.
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 forth.
between the ages of 20 and 40 and in African Americans and
people 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.

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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
priately.
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.
months. Some clinicians measure thiopurine S-methyltransferase
(TPMT) levels prior to the first dose to determine if patients

2
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,
least every 1-3 three months. 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 cer, urinalysis is needed every month.

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 Infliximab. An infused TNF inhibitor, 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-
infection. ning therapy and that adalimumab be withheld in the event
of active infection.

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STANDARD THERAPIES
STANDARD THERAPIES
DRUG DOSAGE MAJOR TOXICITY MONITORING
Blood pressure, weight, glucose if
Diabetes, hypertension, weight gain,
Prednisone 5-40mg daily clinically indicated. Osteoporosis and
cataracts, glaucoma
bone density checks

Hydroxychloroquine 200-400mg daily Ocular, hepatic, cutaneous Eye examination every 6-12 months

CBC, hepatic and renal function

Methotrexate 5-20mg weekly Hematologic, hepatotoxic, pulmonary
every 1-3 months
CBC, hepatic and renal function
Azathioprine* 50-200mg daily Hematologic, gastrointestional
every 1-3 months
CBC, hepatic and renal function
Leflunomide* 10-20mg daily Hematologic, hepatotoxic
every 1-3 months
CBC, hepatic and renal function
Mycophenylate 500-1500mg twice daily Hematologic, gastrointestional
every 1-3 months

Allergic reactions, increased risk for

3-5mg/kg initially, two
infections, especially tuberculosis, PPD prior to initiating therapy, withhold
Infliximab weeks later, then every
worsening congestive heart failure, drug in face of active infection
4-8 weeks
possible increased risk for malignancy

Allergic reactions, increased risk for

40-80mg every 1-2 infections, especially tuberculosis, PPD prior to initiating therapy, withhold
Adalimumab
weeks worsening congestive heart failure, drug in face of active infection
possible increased risk for malignancy

Definitions: mg=milligrams; kg=kilogram; CBC=complete blood count; PPD=purified protein derivative, skin test to diagnose tuberculosis.
* See text for initial monitoring

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 Several other drugs have been used in selected cases. They Chloroquine. Another antimalarial agent, chloroquine is
include the following: 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
for treating sarcoidosis. drugs can cause nausea, and minocycline is associated with
hepatitis and vertigo.

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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), neously.
chest CT scan, and 6-minute walk, may be useful for individ- For patients with Stage 0 or I and dyspnea, an echocardio-
ual patients. 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-
functional impairment. 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 tapered at those visits.
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

7
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.
in combination with methotrexate. 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- 1.

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 Pulmonary Sarcoidosis

Minimal symptoms
Asymptomatic Moderate disease Severe disease
e.g. cough

Chest x-ray stage II or Evaluate for pulmonary

Follow with PFTs Inhaled corticosteroids
higher PFTs below normal hypertension
Dyspnea
No response, consider Begin prednisone*
oral steroids 20-40mg daily
Only one present Two or more present

Begin prednisone*
Consider steroids
20-40mg daily

Follow at least Taper dose over next

3 months 3-6 months

Prednisone* >10mg daily

*Where prednisone is indicated, an equivalent dose of Prednisone* <10mg daily
or toxicity
corticosteroids (i.e. methylprednisolone) could also be used.
+Cytotoxic drugs include: methotrexate, azathioprine,
mycophenolate and leflunomide.
++Anti-TNF therapy includes infliximab and adalimumab.
Continue prednisone* Add cytotoxic drug+

If no response consider
anti-TNF therapy++

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CARDIAC
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, mg/day for stable cardiac function.
the implications of a positive test in a patient with no symp- The role of TNF inhibitors remains undefined since these
toms or arrhythmias remain unclear. 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
mias/heart block. treatment of systemic sarcoidosis also benefits the cardiac
involvement.
There are no prospective clinical trials of medical regimens
for cardiac sarcoidosis, Current treatment recommendations Indications for prophylactic insertion of an implantable car-

10
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 block.
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

11
 Cardiac Sarcoidosis

Holter monitoring to
Echo to assess LVEF
evaluate for arrythmias

Negative Positive LVEF <50% LVEF >50%

Repeat Echo/Holter in Evaluate for ICD/pace- Maximize therapy for Repeat Echo/Holter in
6-12 months maker CHF 6-12 months

Evaluate for ICD

Treat prednisone*
<30mg daily

Taper slowly over next

*Where prednisone is indicated, an equivalent dose 6-12 months
of corticosteroids (i.e. methylprednisolone) could
also be used.
+Cytotoxic drugs include: methotrexate, Prednisone* >10mg daily
Prednisone* <10mg daily
azathioprine, mycophenolate and leflunomide. or toxicity

Continue prednisone*
Add cytotoxic drug+
alone

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OCULAR
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-
severity. 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-
corticosteroids and/or cytotoxic drugs. ed with a significantly higher rate of cataracts and glaucoma
and 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.

13
 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-
py. 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.

14
 Ocular Sarcoidosis

Dry eyes Anterior uveitis Posterior or pan uveitis

Wetting agents and Topical prednisone* Oral prednisone*

Evaluate for active cycloplegia Periocular or intravitreal
granulomatous disease steroid

Response: Continue No Response: Oral Consider adding

therapy prednisone* or cytotoxic drug+
periocular steroids
No response or side
Consider adding effects. Add/switch
cytotoxic drug+ cytotoxic drugs+.
Consider anti-TNF
therapy++

*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.

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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- associated aseptic meningitis.
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
peripheral neuropathies and myopathy. 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.
ion." 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,
treatment. 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

16
 Neurosarcoidosis

Peripheral Facial (7th) Mild to moderately

Severe disabling disease
cranial nerve weakness disabling disease

Prednisone* Prednisone* Anti-TNF therapy++ or

20-40mg daily 20-40mg daily IV methylprednisolone

Beneficial response: slow Poor clinical response or Selected patients:

Taper over 1-6 months
prednisone* taper deterioration prednisone* plus
cyclophosphamide, CSF
Weakness resolves: Successful prednisone* diversion, CNS radiation,
Relapse of disease or surgical debulking
discontinue prednisone* taper to <10mg daily

No relapse: continue slow Relapse: Increase

prednisone* taper prednisone* dose and
add/alter cytotoxic drug+
*Where prednisone is indicated, an
equivalent dose of corticosteroids (i.e.
Poor clinical response: Good clinical response: methylprednisolone) could also be used.
Consider anti-TNF slow prednisone* taper. +Cytotoxic drugs include: methotrexate,
therapy++ or Ultimately, slow cytotoxic azathioprine, mycophenolate and
IV methylprednisolone drug+ taper. leflunomide.
++Anti-TNF therapy includes infliximab
and adalimumab.

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SKIN
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
of life. 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, ered for longer-term treatment.
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
but are non-granulomatous. 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 thalidomide have been used.
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
the nose, around the eyes or mouth. 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

18
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
are required. toxicity and the risk/benefit ratio must be considered in
treating this chronic cutaneous condition.

19
 Cutaneous Sarcoidosis

Nonspecific (non
Specific lesions
granulomatous disease)

No treatment of skin
Cosmetically unimportant Cosmetically important
lesions required

Try topical therapy

No treatment of skin A few lesions (creams/injections);
lesions required systemic therapy if fails

Systemic therapy:
Several lesions prednisone*,
hydroxychloroquine,
cytotoxic drugs+,
tetraycycline derivatives
Lupus pernio
If the above therapy fails:
anti-TNF therapy++ *Where prednisone is indicated, an
Systemic therapy: equivalent dose of corticosteroids (i.e.
prednisone* methylprednisolone) could also be used.
+Cytotoxic drugs include: methotrexate,

If toxicity/failure of the If the above therapy is azathioprine, mycophenolate and

above therapy: add inadequate: anti-TNF leflunomide.
++Anti-TNF therapy includes infliximab
hydroxychloroquine therapy++, possibly with
and/or cytotoxic drug+ methotrexate and adalimumab.

20
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- disease).
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

21
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. plantation.
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.

22
 Hepatic Sarcoidosis

ASYMPTOMATIC
Abnormal CT scan, SYMPTOMATIC
abnormal liver
function test
Abnormal pain, fever, Jaundice, cholestasis,
Check liver function tests fatigue, constitutional pruritus
& synthetic function symptoms
• Alkaline phosphatase
• Transaminases Ursodeoxycholic acid
• Total bilirubin
• Albumin/protime
No response Response

Normal Bilirubin or Abnormal Bilirubin or Prednisone* 20-40mg

protime protime daily
Continue therapy

Disease worsening,
No treatment needed
unable to wean
prednisone*
Recheck LFTs every Taper off slowly over next
3-6 months 12 months Consider other
cytotoxic drugs+
*Where prednisone is indicated, an equivalent dose of corticosteroids
(i.e. methylprednisolone) could also be used. Liver failure
+Cytotoxic drugs include: azathioprine*, methotrexate, mycophenolate and
leflunomide.
*Azathioprine is the most commonly used cytotoxic drug for mild hepatic dis-
Consider liver transplant
ease. See text

23
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 IgA
nephropathy. While there is limited data upon which to base
therapeutic recommendations, corticosteroids are usually
used with evidence of renal insufficiency starting at 40 mg
daily, with a slow wean of therapy as used for other organ
involvement. Usually there is evidence of improvement in
renal 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
needed.
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 result
in 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 min D-1,25.
and/or hypercalcemia, and can cause renal insufficiency. As
in the other organs discussed above, data on which to base

24
 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. hypercalciuria.

25
 Hypercalciuria and
Hypercalcemia

NO YES

History of renal stones Calcium supplement

YES: 24 hour urine Yes: Stop supplement

NO No
calcium 24-hour urine calcium

Abnormal Check serum PTH Abnormal calcium

Follow and treat with Normal: treat for Normal calcium: continue
Normal Abnormal: treat PTH
calcium supplements Sarcoidosis to follow

Hydroxychloroquine

*Where prednisone is indicated, an

Elevated serum or urine
equivalent dose of corticosteroids Normal
calcium
(i.e. methylprednisolone) could also
be used.
+Cytotoxic drugs include:
Consider cytotoxic Prednisone* 20-40mg Consider taper over next
methotrexate, azathioprine, drugs+ daily 12 month
mycophenolate and leflunomide.

26
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 from
Fatigue
fatigue. 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 abdominal pain and headache.
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, fatigue.

27
 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 treatment strategy.

28
 Fatigue

No other signs of Sleep apnea, other sleep- Other signs of

disease activity related disorders, muscle disease activity
weakness

Lifestyle advice, Treat sarcoidosis if

Specific therapy
rehabilitation and/or necessary
sympathomimetic or
other agents
Prednisone* and/or
cytotoxic+ agents,
immunomodulators,
anti-TNF therapy++

*Where prednisone is indicated, an equivalent Effect on fatigue and Effect on sarcoidosis, no

dose of corticosteroids (i.e. methylprednisolone) sarcoidosis: follow effect on fatigue
could also be used.
+Cytotoxic drugs include: methotrexate,
azathioprine, mycophenolate and leflunomide.
++Anti-TNF therapy includes infliximab and
adalimumab.

29
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 ment
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.

30
 Pain

Neurosarcoidosis No neurosarcoidosis

Central or peripheral
Small fiber neuropathy Arthralgia Muscle/chest/bone pain Headache
neuropathy

See flow chart treatment Treat pain Treat pain and/or

Lofgren Non Lofgren
neurosarcoidosis Anti-inflammatory agents physical therapy
neuropathic pain
medications

Treat sarcoidosis
No effect NSAIDs
if necessary
No effect

No effect
Anti-TNF-α therapy++
Prednisone* and/or
cytotoxic+ agents,
*Where prednisone is indicated, an equivalent dose of immunomodulators,
corticosteroids (i.e. methylprednisolone) could also be anti-TNF-α++
used.
+Cytotoxic drugs include: methotrexate, azathioprine,
mycophenolate and leflunomide. Effect on sarcoidosis,
++Anti-TNF therapy includes infliximab and adalimumab. no effect on pain

31
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