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SARCOIDOSIS TREATMENT GUIDELINES
INTRODUCTION
Sarcoidosis is a chronic inflammatory granulomatous dis-ease that primarily affects the lungs, although multi-organinvolvement is common. The etiology of sarcoidosis is notclear; however, genetic and environmental factors probablyplay a role in the development and expression of the disease.
Once thought to be rare, sarcoidosis affects peoplethroughout the world. It can affect people of any age, race,or gender; however, the prevalence is highest among adultsbetween the ages of 20 and 40 and in African Americans andpeople of European – particularly Scandinavian – descent.
Symptoms and severity can vary by race and gender, withAfrican Americans being more severely affected thanCaucasians. Extrapulmonary sarcoidosis is common in cer-tain populations, for example: chronic uveitis in AfricanAmericans, painful skin lesions in Northern Europeans andcardiac and ocular involvement in Japanese.
Goals of Sarcoidosis Management
The goals of sarcoidosis management are to prevent or con-trol organ damage, relieve symptoms and improve thepatient’s quality of life. An evaluation by a pulmonologist isstrongly recommended. For patients with extrapulmonaryinvolvement, a multidisciplinary approach may be required.A patient may need to see an ophthalmologist for ocular dis-ease, a cardiologist for cardiac disease, a neurologist for neu-rological disease, a nephrologist for renal disease, and soforth.
Pharmacologic Treatment
While a significant percentage of sarcoidosis patients neverneed therapy, there are several groups which require treat-ment. In this monograph, we will discuss several of the com-monly used drugs for sarcoidosis and their potential toxici-ties, and will provide algorithms for use of these drugs totreat the symptoms associated with specific organ involve-ment.
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Corticosteroids
Corticosteroid medications are considered the first line oftreatment for sarcoidosis that requires therapy. Oral corti-costeroids effectively reduce systemic inflammation in mostpeople, thereby slowing, stopping or even preventing organdamage. Corticosteroids may be prescribed alone or withother medications. Although there is no standard dosage orduration of corticosteroid therapy, the charts in this mono-graph will provide guidelines for individual organ involve-ment. It is recommended that patients on corticosteroidslong term be monitored for osteoporosis and treated appro-priately.
Topical corticosteroids or intralesional injections may beprescribed for cutaneous involvement, and eye drops may beprescribed for uveitis. Corticosteroid inhalers may be usefulin those with evidence of bronchial hyperactivity.
Hydroxychloroquine. As a treatment for sarcoidosis, theantimalarial drug hydroxychloroquine (Plaquenil®) is mostlikely to be effective in patients with dermatologic involve-ment, joint manifestations and hypercalcemia. Due to poten-tial macular toxicity, it is recommended that patients onhydroxychloroquine have an eye examination every 6-12months.
Methotrexate. Methotrexate is one of the most commonlyused corticosteroid-sparing therapies for sarcoidosis, due toits effectiveness, low cost and, at the dosages used to treatsarcoidosis, relatively low risk of side effects compared toother cytotoxic agents. The drug can be given orally or sub-cutaneously. Due to the potential for hepatic and hematolog-ic toxicity, regular monitoring is required. Since the drug iscleared by the kidneys, one should also monitor renal func-tion. Dosage adjustment may be needed or an alternativecorticosteroid-sparing drug may be considered in those withrenal insufficiency, e.g. serum creatinine > 1.5 (gfr < 50ml/min). It is recommended that patients have a CBC andhepatic and renal function every 1-3 months. Folic acid sup-plementation may be prescribed to reduce toxicity.
Azathioprine. What little research has been done on thesubject shows that azathioprine (Imuran®) is roughly aseffective as methotrexate in treating sarcoidosis. It is consid-ered when there is a contraindication to methothrexate, suchas renal or hepatic function impairment. The side effects ofazathioprine include dyspepsia, oral ulcers, myalgia, malaise,jaundice and blurred vision. Compared to methotrexate,there is also evidence of a higher frequency of opportunisticinfections and possibly malignancy with azathioprine use.Some clinicians measure thiopurine S-methyltransferase(TPMT) levels prior to the first dose to determine if patients
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have TPMT deficiency and therefore are at increased riskfor toxicity. Others measure the CBC 2-4 weeks after thefirst dosage. It is recommended that patients taking azathio-prine have a CBC and hepatic and renal function tests atleast every 1-3 three months.
Mycophenolate mofetil. First developed to prevent organtransplant rejection, mycophenolate mofetil (CellCept®) isprescribed for a number of autoimmune and inflammatorydiseases, including rheumatoid arthritis and lupus nephritis.Anecdotal reports have shown it to be effective in treatingsarcoidosis. The principal adverse reactions associated withthe administration of mycophenolate mofetil include diar-rhea, leukopenia, sepsis and vomiting. Compared to azathio-prine, there is also evidence of a higher frequency of oppor-tunistic infections and malignancy. It is recommended thatpatients taking mycophenolate have a CBC and hepatic andrenal function tests at least every 3 months.
Leflunomide. Leflunomide (Arava®) is a cytotoxic drugthat has been used as a single agent or in combination withmethotrexate for the treatment of rheumatoid arthritis. Insarcoidosis, the most common indications for therapy areocular and lung disease. Although experience is limited, it
should be considered as an alternative for patients who can-not tolerate methotrexate. It is recommended for the firstthree months of therapy patients have monthly CBCs. Forpatients who experience severe toxicity from leflunomide,cholestyramine therapy may be useful.
Cyclophosphamide. Due to its toxicity, cyclophosphamide(Cytoxan ®, Endoxan®) is usually reserved for severe dis-ease not controlled by methotrexate or azathioprine. Casestudies suggest that cyclophosphamide is effective for somepeople and is perhaps particularly useful in severe disablingneurosarcoidosis that has not responded to other therapies,including intravenous corticosteroids and anti-TNF therapy.Its side effects can include nausea, vomiting, anorexia,alopecia, acne, leukopenia, oral ulcers, skin hyperpigmenta-tion and fatigue. Less common but more severe side effectsinclude hemorrhagic cystitis and an increased risk for cancer.Overall, less toxicity has been reported with intermittentintravenous administration compared to daily oral use ofcyclophosphamide. As with other immunosuppressants,monitoring should include CBC and hepatic and renal func-tion tests every 1-3 months. Due to the risk of bladder can-cer, urinalysis is needed every month.
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Infliximab. An infused TNF inhibitor, infliximab(Remicade®) has been approved for several inflammatorydiseases including rheumatoid arthritis and Crohn’s disease.Small, short-term studies have shown infliximab to be effec-tive in reducing sarcoidosis symptoms in patients who didnot respond to other treatments. Infliximab can cause a vari-ety of side effects, including abdominal pain, nausea, diar-rhea, dyspepsia, headache, rash, pruritus, pharyngitis andsinusitis, and sore throat. Infusion reactions, includingsevere anaphylaxis, can occur. Infliximab also increases therisk of infection and certain types of cancer, autoimmune dis-ease and demyelinating disease. It is recommended thatpatients have a PPD for tuberculosis prior to beginning ther-apy and that infliximab be withheld in the event of activeinfection.
Adalimumab. The TNF inhibitor adalimumab (Humira®),given by subcutaneous injection, has been approved forrheumatoid arthritis and several other forms of arthritis.Anecdotal reports have shown adalimumab to be effective inreducing sarcoidosis symptoms. Adalimumab can cause avariety of side effects, including abdominal pain, nausea,diarrhea, dyspepsia, headache, rash, pruritus, pharyngitisand sinusitis, and sore throat. Local injection site reactionshave been reported. Adalimumab also increases the risk ofinfection and certain types of cancer, autoimmune diseaseand demyelinating disease. Adalimumab should be consid-ered for patients who have been treated successfully withinfliximab but have developed antibodies. It is recommend-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
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DRUG DOSAGE MAJOR TOXICITY MONITORING
Prednisone 5-40mg dailyDiabetes, hypertension, weight gain,
cataracts, glaucoma
Blood pressure, weight, glucose if
clinically indicated. Osteoporosis and
bone density checks
Hydroxychloroquine 200-400mg daily Ocular, hepatic, cutaneous Eye examination every 6-12 months
Methotrexate 5-20mg weekly Hematologic, hepatotoxic, pulmonaryCBC, hepatic and renal function
every 1-3 months
Azathioprine* 50-200mg daily Hematologic, gastrointestionalCBC, hepatic and renal function
every 1-3 months
Leflunomide* 10-20mg daily Hematologic, hepatotoxicCBC, hepatic and renal function
every 1-3 months
Mycophenylate 500-1500mg twice daily Hematologic, gastrointestionalCBC, hepatic and renal function
every 1-3 months
Infliximab
3-5mg/kg initially, two
weeks later, then every
4-8 weeks
Allergic reactions, increased risk for
infections, especially tuberculosis,
worsening congestive heart failure,
possible increased risk for malignancy
PPD prior to initiating therapy, withhold
drug in face of active infection
Adalimumab40-80mg every 1-2
weeks
Allergic reactions, increased risk for
infections, especially tuberculosis,
worsening congestive heart failure,
possible increased risk for malignancy
PPD prior to initiating therapy, withhold
drug in face of active infection
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. Theyinclude the following:
Pentoxifylline. A drug used to treat intermittent claudica-tion, pentoxifylline has been reported to be steroid sparingin some cases of pulmonary sarcoidosis. Its major toxicity isnausea, which is commonly encountered at the doses usedfor treating sarcoidosis.
Chloroquine. Another antimalarial agent, chloroquine isused for cutaneous and pulmonary sarcoidosis. It has a high-er rate of gastrointestinal and ocular toxicity than hydroxy-chloroquine, so it is used less frequently.
Tetracycline derivatives. Minocycline and doxycycline havebeen reported as useful for cutaneous sarcoidosis. Bothdrugs can cause nausea, and minocycline is associated withhepatitis and vertigo.
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PULMONARY
Pulmonary involvement, found in over 90 percent of sar-coidosis patients, is the most frequent manifestation of thedisease. The assessment of the degree of pulmonary involve-ment includes pulmonary function tests (PFTs), including atleast a forced vital capacity, chest imaging such as a chest x-ray, and ascertaining the level of dyspnea by questioning thepatient. Additional tests, such as diffusion capacity (DLCO),chest CT scan, and 6-minute walk, may be useful for individ-ual patients.
As shown in the figure, the treatment approach depends onwhether the disease is asymptomatic or has minimal symp-toms versus those with moderate or severe symptoms andfunctional impairment.
For asymptomatic patients with Stage 0 or I chest x-ray,therapy is not likely to offer benefits. For patients with mildsymptoms, such as a cough, treatment should begin withinhaled corticosteroids. If there is no response, oral corticos-teroids can be considered. While not specifically studied,asymptomatic patients with a significant drop in pulmonaryfunction should be considered for therapy.
For those with dyspnea, corticosteroid therapy has beenshown to improve lung function for both the short term and
up to five years after therapy has been discontinued. Lessclear is whether to recommend an 18-month course of corti-costeroids for patients with Stage II-IV disease and no dysp-nea. If pulmonary function tests are normal to mildly abnor-mal, the patient can be observed. About 70 percent of thesepatients will either remain the same or improve sponta-neously.
For patients with Stage 0 or I and dyspnea, an echocardio-gram may be useful to identify other causes of dyspnea, suchas cardiac. A high-resolution CT may also identify parenchy-mal lung disease not seen on a chest x-ray. If there is no evi-dence of congestive heart failure or pulmonary hyperten-sion, treatment with corticosteroids may be considered.
Corticosteroids remain the initial drug of choice for treat-ment of parenchymal lung diseases. A starting dosage is 20 -40 mg prednisone or its equivalent. Once corticosteroidshave been started, the patient is usually seen 1-3 months.Depending on the patient's condition, the dosage can betapered at those visits.
After 3-6 months, the dose should be tapered to physiolog-ic levels – for example, 10 mg of prednisone per day or less.If such a taper is not successful, or there is toxicity from the
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corticosteroids, one should consider the addition of asteroid-sparing agent, such as methotrexate or azathioprine.Both of these agents will take up to 6 months to demonstrateeffectiveness and are effective in only about two-thirds ofpatients. There is some evidence that combining two cyto-toxic agents may be useful. Leflunomide has also been usedin combination with methotrexate.
If a patient does not respond to the combination of pred-nisone and a cytotoxic agent, the clinician has to decidewhether or not the patient has a reversible disease process(granuloma versus fibrosis) in the lung. In addition, the cli-nician should rule out pulmonary hypertension as a cause ofdyspnea. There are also non-pulmonary causes of dypsnea,including anemia, heart failure, obesity, other systemic dis-
eases and fatigue that should be considered. A 6-minutewalk or a cardiopulmonary exercise test may help identifywhat is happening during exercise. It may identify patientswho require oxygen supplementation. It may also identifyother potential causes of dyspnea, such as cardiac causes,muscle strength impairment or deconditioning.
If no alternative cause of dyspnea is identified, an anti-TNFagent should be considered. Infliximab has been widely stud-ied, although adalimumab at higher doses may be effective.These agents have proved effective for treating inflammato-ry changes in the lung but will not reverse fibrosis. Benefitsare usually seen within 3-6 months of starting one of theseagents. For required monitoring for these agents, see Table1.
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Pulmonary Sarcoidosis
AsymptomaticMinimal symptoms
e.g. cough
Follow with PFTs Inhaled corticosteroids
Only one present Two or more present
Consider steroidsBegin prednisone*
20-40mg daily
Follow at least
3 months
Taper dose over next
3-6 months
Prednisone* <10mg dailyPrednisone* >10mg daily
or toxicity
Continue prednisone* Add cytotoxic drug+
If no response consider
anti-TNF therapy++
No response, consider
oral steroids
Evaluate for pulmonary
hypertensionChest x-ray stage II or
higher PFTs below normal
Dyspnea
Begin prednisone*
20-40mg daily
Moderate disease Severe disease
*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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Cardiac sarcoidosis is estimated to affect up to 20 percent ofsarcoidosis patients in the United States.
Common manifestations of cardiac sarcoidosis includearrhythmias, conduction abnormalities, and cardiomyopathydue to granulomatous inflammation of the myocardiumand/or conducting system. Rarer manifestations includevalvular dysfunction, ventricular or atrial mass lesions, peri-cardial disease, myocardial infarction or sudden death.
It is not clear how to best screen for cardiac sarcoidosis. AnEKG or echo may provide useful information.” If concernsabout possible cardiac involvement remain, advanced car-diac imaging such as cardiac scanning, cardiac MRI or car-diac PET scanning have greater sensitivity and specificitythan an echocardiogram and are recommended. However,the implications of a positive test in a patient with no symp-toms or arrhythmias remain unclear.
A diagnosis of cardiac sarcoidosis is usually established bya non-cardiac biopsy that confirms systemic sarcoidosistogether with consistent cardiac imaging and/or arrhyth-mias/heart block.
There are no prospective clinical trials of medical regimensfor cardiac sarcoidosis, Current treatment recommendations
are based on several retrospective studies from Japan(where cardiac manifestations may be present in approxi-mately 50 percent of sarcoidosis patients) and accumulatedexperience from referral centers in the U.S. and Europe.These studies suggest survival correlates with left ventricularfunction and severe ventricular arrhythmias with no differ-ence in 5-year survival rates for patients treated with pred-nisone >30 mg/day vs. <30 mg/day.
Many patients with significant cardiomyopathy and chronicsarcoidosis require long-term treatment to minimize pro-gressive cardiac dysfunction. Cytotoxic drugs are often usedas steroid-sparing agents in patients with left ventricularejection fraction (LVEF) <50%who require prednisone >10mg/day for stable cardiac function.
The role of TNF inhibitors remains undefined since thesetherapies have been shown to worsen congestive heart fail-ure (CHF) in non-sarcoidosis cardiomyopathy; however,small case series suggest these therapies may be beneficial insome patients with cardiac sarcoidosis, assuming that thetreatment of systemic sarcoidosis also benefits the cardiacinvolvement.
Indications for prophylactic insertion of an implantable car-
CARDIAC
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dioverter defibrillator (ICD) or pacemaker are evolving.Currently, common practice is to recommend prophylacticICD insertion for patients with LVEF<35% or for seriousarrhythmias and to recommend against prophylactic ICDinsertion when there is normal cardiac function, unless car-diac imaging studies show extensive inflammation. Theeffectiveness of radiofrequency ablation for prevention ofarrhythmias in cardiac sarcoidosis is uncertain, given limited
experience. Since cardiac sarcoidosis is often diffuse, it isunusual that a single focus can be identified for ablation.Permanent pacemakers are suggested for high-degree heartblock.
Cardiac transplantation is an option for patients withadvanced cardiac sarcoidosis with survival rates better thanthose with other causes of heart disease despite reports ofrecurrent granulomatous inflammation in the transplanted
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Cardiac Sarcoidosis
Holter monitoring to
evaluate for arrythmias
Negative Positive
Repeat Echo/Holter in
6-12 months
Evaluate for ICD/pace-
maker
LVEF <50% LVEF >50%
Maximize therapy for
CHF
Evaluate for ICD
Treat prednisone*
<30mg daily
Taper slowly over next
6-12 months
Prednisone* <10mg dailyPrednisone* >10mg daily
or toxicity
Continue prednisone*
aloneAdd cytotoxic drug+
Repeat Echo/Holter in
6-12 months
Echo to assess LVEF
*Where prednisone is indicated, an equivalent dose
of corticosteroids (i.e. methylprednisolone) could
also be used.+Cytotoxic drugs include: methotrexate,
azathioprine, mycophenolate and leflunomide.
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OCULAR
Ocular manifestations are frequent in sarcoidosis, affecting11 percent of patients in a recent U.S. study. Sarcoidosis canaffect virtually any part of the eye, including the lacrimalgland, ocular surface, and anterior and posterior segments.Treatment depends on the specific manifestation and itsseverity.
Lacrimal gland granulomas can lead to keratoconjunctivitissicca, which is best managed with artificial tears to keep theconjunctiva moist, lacrimal punctal plugs and/or topicalcyclosporine. Occasionally surgery or injection of thelacrimal glands with corticosteroids is used.
Involvement of the ocular surface can include conjunctivalgranulomas that may not require treatment. Symptomaticconjunctivitis, episcleritis or keratitis may be managed withcorticosteroid eye drops. Scleritis is typically managed withcorticosteroids and/or cytotoxic drugs.
The anterior segment is involved most frequently with achronic granulomatous uveitis that is characterized by "mut-ton fat" keratic precipitates and iris nodules. Posterior seg-ment disease occurs in the form of viritis and periphlebitisand can sometimes be the sole manifestation of ocular dis-
ease. Severe vasculitis can be associated with exudates thatgive the appearance of "candle wax drippings." Frequentlythere is involvement in the anterior segment when there isposterior segment disease. Although these are not the mostclassic presentations of sarcoidosis-related uveitis, sarcoido-sis is a potential cause of nearly any form of uveitis.
Management of uveitis is frequently carried out by an oph-thalmologist in collaboration with the pulmonologist orrheumatologist treating the systemic manifestations of sar-coidosis. Anterior uveitis usually can be managed with localtherapy using corticosteroid eye drops to suppress inflamma-tion and cycloplegic eye drops to suppress pain and avoidintraocular scarring. In some cases, periocular corticosteroidinjections and long-term intraocular corticosteroid implantsalso 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-tions such as sarcoidosis. For severe cases, infliximab hasbeen useful. Due to its flexibility, effectiveness and the abil-ity to provide ongoing therapy and treat extraocular aspectsof sarcoidosis simultaneously, cytotoxic therapy, usuallycytotoxic agents, has been the mainstay of therapy.
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For posterior uveitis or panuveitis, systemic therapy is usu-ally used. Systemic corticosteroids are usually effective incontrolling inflammation in both the short and long term.However, due the risks of systemic corticosteroids – especial-ly with long-term use – some physicians use periocular injec-tions of corticosteroids in the posterior or sub-Tenon'sspace, or in the orbital floor. Intravitreal corticosteroids,used since the 1990s, are useful for controlling acute exacer-bations but are probably not appropriate for chronic thera-py.
For severe disease, the typical initial dosage of prednisoneis 20-40 mg/day, while some use as much as 1 mg/kg/day. Ifimmediate therapy is needed, intravenous corticosteroids in1-gram pulses are given. If greater than 10 mg prednisone isneeded to control the disease, then corticosteroid-sparingdrugs should be used. Cytotoxic drugs such as methotrexate,azathioprine, and mycophenolate mofetil have been usedwith success. Recent experience suggests that the biologicagents 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.
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Ocular Sarcoidosis
Dry eyes
Wetting agents and
Evaluate for active
granulomatous disease
Posterior or pan uveitis
Oral prednisone*
Periocular or intravitreal
steroid
Consider adding
cytotoxic drug+
No response or side
effects. Add/switch
cytotoxic drugs+.
Consider anti-TNF
therapy++
Anterior uveitis
Topical prednisone*
cycloplegia
Response: Continue
therapy
Consider adding
cytotoxic drug+
No Response: Oral
prednisone* or
periocular steroids
*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 neurologicdisease. Neurologic manifestations of sarcoidosis includecranial neuropathies, meningeal disease [acute and chronicmeningitis, mass lesion(s)], hydrocephalus, CNS parenchy-mal disease [endocrinopathies, mass lesion(s), encephalopa-thy/vasculopathy, seizures, and spinal cord abnormalities],peripheral neuropathies and myopathy.
Treatment decisions depend, in part, on the certainty ofdiagnosis, the patient's clinical status, the anticipated clinicalcourse and contraindications to a particular intervention.Because of the rarity of neurosarcoidosis, there have beenno rigorous clinical trials to guide treatment; management ispredicated principally on clinical series and "expert opin-ion."
Corticosteroid treatment is recommended as the first line oftherapy for neurologic involvement. In order to avoid thelong-term complications of corticosteroid therapy, use ofadjuvant cytotoxic therapy is recommended early in the clin-ical course of patients who are likely require prolongedtreatment.
The most common neurologic manifestation of neurosar-coidosis is peripheral facial nerve palsy. A limited course ofprednisone 20-40 mg daily is recommended for these
patients. The dosage should be tapered over 1-6 months andcan be discontinued if weakness resolves. A similar coursemay be sufficient to treat patients with an acute sarcoidosis-associated aseptic meningitis.
It is suggested that patients with mild to moderately dis-abling disease (cranial nerves II and VIII, meningeal masslesions, hydrocephalus, CNS parenchymal disease, neu-ropathies and generalized myopathies) be treated with 20-30mg prednisone daily for at least one month. If the patientimproves, the dose can be decreased by 5 mg every twoweeks as the clinical course is monitored. Patients mayrequire a maintenance dose of 10 mg or lower daily even ifthey are treated with adjuvant drugs.
For patients who are acutely and severely ill, intravenousmethylprednisolone for three days or anti-TNF therapy isrecommended. Infliximab can also be used for chronic treat-ment or to "bridge" a patient until an immunosuppressivedrug's benefit becomes evident, typically in 2-3 months.Infusions of infliximab can be administered every 2-8 weeks,or at longer intervals, as clinically indicated.
Mycophenolate and cyclophosphamide have been reportedas useful for refractory neurosarcoidosis in selected cases.
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Neurosarcoidosis
Mild to moderately
disabling disease
Prednisone*
20-40mg daily
Beneficial response: slow
prednisone* taper
Peripheral Facial (7th)
cranial nerve weakness
Prednisone*
20-40mg daily
Taper over 1-6 months
Severe disabling disease
Anti-TNF therapy++ or
IV methylprednisolone
Selected patients:
prednisone* plus
cyclophosphamide, CSF
diversion, CNS radiation,
or surgical debulking
Poor clinical response or
deterioration
Weakness resolves:
discontinue prednisone*Relapse of disease
Poor clinical response:
Consider anti-TNF
therapy++ or
IV methylprednisolone
Good clinical response:
slow prednisone* taper.
Ultimately, slow cytotoxic
drug+ taper.
No relapse: continue slow
prednisone* taper
Successful prednisone*
taper to <10mg daily
Relapse: Increase
prednisone* dose and
add/alter cytotoxic drug+
*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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SKIN
One in four sarcoidosis patients will have cutaneousinvolvement. Although sarcoidosis of the skin is almostnever life-threatening, it can cause significant cosmetic prob-lems that may have a major impact on the patient's qualityof life.
Sarcoidosis skin lesions are classified in two groups: sar-coidosis-specific skin lesions and non-granulomatous lesions.The former represent true sarcoidosis of the skin. That is,the skin contains granulomas, the pathological lesions of sar-coidosis. The latter are inflammatory reactions of the skinbut are non-granulomatous.
Specific sarcoidosis skin lesions include thick, raised skinlesions that have an apple jelly color. They may be scaly, andoccasionally they are yellow to violet in color. Other specificskin lesions include skin nodules that develop on old scarsand tattoos; lesions that look like ulcers; lesions that may bemistaken for psoriasis; and lupus pernio, potentially disfigur-ing lesions that occur on the face, particularly on or aroundthe nose, around the eyes or mouth.
These specific lesions almost never cause pain or itchingand are not life-threatening. For that reason, they should betreated only if they are of cosmetic importance to the
patient. If the patient has very few localized lesions, theymay respond to application of a corticosteroid cream orintralesional injections. If lesions do not respond to localtherapy or if skin disease is more generalized, some type ofpharmacotherapy is required. Systemic corticosteroids areusually used at least for the short term, but because of theirmany potential side effects, other agents should be consid-ered for longer-term treatment.
Hydroxychloroquine is often the first steroid-sparing drugused. Among the cytotoxic drugs, methotrexate seems tohave a better response rate than other agents. In some cases,derivatives of tetracycline have been helpful in mild disease.For very severe cases, anti-TNF therapy, such as infliximabmay have a role. In selected patients chloroquine andthalidomide have been used.
Non-granulomatous lesions are very common with acuteinitial presentations of sarcoidosis. Also, they are associatedwith a good prognosis of sarcoidosis in that the disease oftengoes away within a few months when non-granulomatouslesions occur. The most common non-granulomatous sar-coidosis lesion is erythema nodosum. These lesions – whichare thick, slightly raised and often painful – are often seen
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with an acute presentation of sarcoidosis called Lofgren'ssyndrome. This syndrome, which is also associated with hilaradenopathy, fever and pain in the ankles and other joints,typically resolves completely in a few months. It can be usu-ally treated with only nonsteroidal drugs for painful skinlesions and joint pain; however, occasionally corticosteroidsare required.
We suggest an approach to the various forms of cutaneoussarcoidosis. For lupus pernio, a large retrospective studyreported that anti-TNF therapy was significantly better thancytotoxic or antimalarial therapy, and it could be consideredas second-line therapy for this particular form of skin sar-coidosis. However, anti-TNF therapy is associated with moretoxicity and the risk/benefit ratio must be considered intreating this chronic cutaneous condition.
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Cutaneous Sarcoidosis
Specific lesions
Cosmetically unimportant Cosmetically important
No treatment of skin
lesions required
A few lesions
Try topical therapy
(creams/injections);
systemic therapy if fails
Systemic therapy:
prednisone*,
hydroxychloroquine,
cytotoxic drugs+,
tetraycycline derivatives
If toxicity/failure of the
above therapy: add
hydroxychloroquine
and/or cytotoxic drug+
If the above therapy is
inadequate: anti-TNF
therapy++, possibly with
methotrexate
Several lesions
If the above therapy fails:
anti-TNF therapy++
No treatment of skin
lesions required
Lupus pernio
Systemic therapy:
prednisone*
Nonspecific (non
granulomatous disease)
*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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Estimates of liver involvement in sarcoidosis vary from 11-80 percent of cases, with lower rates based on symptomaticdisease and higher rates reported in studies performing ran-dom liver biopsies. Women and African Americans areaffected more frequently. Most individuals with liver diseasepresent asymptomatically with evidence of hepatomegaly,increased liver function test or CT scan abnormalities. Non-specific symptoms, including abdominal pain, fevers andweight loss are common in sarcoidosis liver disease, althoughpatients may present with pruritus, jaundice and chroniccholestasis. Cirrhosis, portal hypertension, Budd-Chiari syn-drome and variceal bleeding occur rarely. In cases of knownsarcoidosis a probable diagnosis of liver disease may beestablished based on increased alkaline phosphatase, ortransaminases, or CT findings of characteristic nodules, con-sisting of low attenuation lesions of varied but usually smallsize. Occasionally a liver biopsy may be obtained, althoughthis is not necessary to confirm liver sarcoidosis.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,a diagnosis of hepatic sarcoidosis must be confirmed andother causes of liver disease must be excluded.
There is limited data on which to base treatment recom-mendations for sarcoidosis liver disease. As there are nocontrolled trials, much of the following is based on clinicalexperience and retrospective case studies.
The majority of patients with sarcoidosis liver disease donot require therapy. This includes patients with asympto-matic disease and mildly elevated liver function tests, no evi-dence of cholestasis (normal bilirubin) and normal liver syn-thetic function (e.g., protime, PT), or with hepatomegalynoted on physical exam and/or radiographic abnormality.These individuals – including those with liver function testsmore than three times the upper limit of normal, even with-out symptoms – should be followed using liver-function teststo determine if they develop evidence of cholestasis orabnormal prothrombin time (PT), which would be consid-ered reasons for starting systemic therapy. Liver-functiontest abnormalities may resolve spontaneously over time orwith treatment aimed at other organ involvement (e.g., lungdisease).
Granulomatous hepatitis is usually treated in individualswith symptomatic liver disease, such as those with abdomi-nal pain or jaundice with evidence of cholestasis, or if there
LIVER DISEASE
22
are significant abnormalities in liver function, or even frankcirrhosis, demonstrated with increased PT. If liver-functiontests are more than 10 times normal, therapy may be consid-ered and these patients should be followed closely.
Corticosteroids are usually the first line therapy. When aninadequate response to corticosteroids is noted, cytotoxicagents are often used. Most experience has been with aza-thioprine for hepatic sarcoidosis. Methotrexate and lefluno-mide are more likely to be hepatotoxic; however, azathio-prine can also be hepatotoxic, so one would still have toclosely monitor LFTs. Ursodeoxycholic acid at 10 mg/kg/day
may be used to manage symptoms of cholestasis, includingjaundice and pruritus. Unfortunately, cirrhosis may occurdespite therapy, and even result in the need for liver trans-plantation.
Splenomegaly is common in sarcoidosis, more so thanhepatomegaly, but does not usually require treatment andmay resolve spontaneously. Although there are limited dataupon which to make recommendations for treatment, clini-cal indications for treatment include hypersplenism withcytopenia, or splenic infarction. Usually corticosteroids areeffective treatment. Splenectomy is not usually performed.
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Hepatic Sarcoidosis
ASYMPTOMATIC
Abnormal CT scan,
abnormal liver
function test
Abnormal pain, fever,
fatigue, constitutional
symptoms
Check liver function tests
& synthetic function
• Alkaline phosphatase
• Transaminases
• Total bilirubin
• Albumin/protime
Normal Bilirubin or
protime
No treatment needed
Recheck LFTs every
3-6 months
Abnormal Bilirubin or
protime
Prednisone* 20-40mg
daily
Jaundice, cholestasis,
pruritus
Ursodeoxycholic acid
No response
Disease worsening,
unable to wean
prednisone*
Consider other
cytotoxic drugs+
Liver failure
Consider liver transplant
Response
Continue therapy
Taper off slowly over next
12 months
SYMPTOMATIC
*Where prednisone is indicated, an equivalent dose of corticosteroids
(i.e. methylprednisolone) could also be used.+Cytotoxic drugs include: azathioprine*, methotrexate, mycophenolate and
leflunomide.
*Azathioprine is the most commonly used cytotoxic drug for mild hepatic dis-
ease. See text
24
Sarcoidosis nephropathy manifests as interstitial nephritismore commonly than glomerular disease, although renalfailure from either mechanism is uncommon.Granulomatous inflammation or other pathologic manifes-tations may be seen, including membranous nephropathy,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 ofcreatinine may not occur. Rarely renal transplantation isneeded.
An increase in 1,25-(OH)2- vitamin D3 production frompulmonary macrophages and granulomas may lead toincreased absorption of calcium. This can eventually resultin hypercalcemia, seen in up to 5 percent of patients with sar-coidosis, and more commonly hypercalciuria.Nephrocalcinosis may result from persistent hypercalciuriaand/or hypercalcemia, and can cause renal insufficiency. Asin the other organs discussed above, data on which to base
treatment recommendations are limited. However, in isolat-ed hypercalciuria, treatment may begin with a reduction incalcium intake, increased fluids and avoidance of sun.Occasionally, hydroxychloroquine may be effective at 200-400 mg daily for more significant hypercalciuria.
RENAL DISEASE AND ABNORMALITIES IN CALCIUM METABOLISM
In sarcoidosis patients, vitamin D-1,25 may
be elevated with normal or even low levels of
vitamin D- 25. In that setting, further supple-
mentation with vitamin D can lead to hyper-
calcemia and/or hypercalciuria. For sarcoido-
sis patients, screening for vitamin D deficien-
cy should be done by measurement of vita-
min D-1,25.
25
Mild hypercalcemia may also be treated with a reduction indietary calcium and increased fluid intake. For more signifi-cant hypercalcemia (e.g. Ca >11 mg/dl) or nephrolithiasis,corticosteroid therapy is usually implemented at 20-40 mgdaily. Reduction in hypercalcemia usually occurs fairlyquickly with steroid implementation, and some will attemptto taper the corticosteroids more quickly after 1-2 months.
Occasionally other agents, including hydroxychloroquine,are needed for more refractory disease. Vitamin D supple-mentation should be avoided in those with hypercalciuriaand hypercalcemia. Ketoconazole has no direct effect on sar-coidosis’ granulomas, but it inhibits vitamin D metabolismand can be used as an adjunct for treating hypercalcemia andhypercalciuria.
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NOYES: 24 hour urine
calcium
Follow and treat with
calcium supplements
Hypercalciuria and
Hypercalcemia
NO
History of renal stones
Yes: Stop supplement
24-hour urine calciumNo
Check serum PTH
Abnormal: treat PTH
YES
Calcium supplement
*Where prednisone is indicated, an
equivalent dose of corticosteroids
(i.e. methylprednisolone) could also
be used.+Cytotoxic drugs include:
methotrexate, azathioprine,
mycophenolate and leflunomide.
Abnormal
NormalNormal: treat for
Sarcoidosis
Abnormal calcium
Normal calcium: continue
to follow
Hydroxychloroquine
Prednisone* 20-40mg
daily
Elevated serum or urine
calcium
Consider taper over next
12 month
Normal
Consider cytotoxic
drugs+
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The clinical course of sarcoidosis is highly variable, and vir-tually every organ can be involved. In addition to organ-spe-cific symptoms such as coughing, dyspnea on exertion, chestpain, and wheezing, many patients experience non-specificsymptoms such as fatigue, psychologic distress, and painissues that are disabling, particularly when they becomechronic and have a great impact on the quality of life (QOL).
Fatigue
Despite adequate treatment for other manifestations of sar-coidosis, a substantial number of sarcoidosis patients sufferfrom persistent fatigue. Fatigue appears to be the most fre-quently reported symptom in sarcoidosis patients. Recentstudies suggest that fatigue may persist after all other mani-festations of sarcoidosis have resolved.
Fatigue may be debilitating, may become chronic and caus-es substantial reduction in professional, recreational, social,and/or educational activities and, as a consequence, reducesQOL. When features of disease activity – for example, radi-ological abnormalities and lung function impairment – areresolved during treatment, fatigue and pain may persist.Therefore, objective test results such as chest radiographs,
lung-function tests and laboratory parameters do not alwaysreflect the well-being of the patient. Other factors that needto be considered are small fiber neuropathy, autonomic dys-function, and steroid myopathy. Hypogonadism, hypothy-roidism and sleep apnea syndrome can also lead to fatigue.
Reduced respiratory muscle strength and endurance timewere demonstrated in sarcoidosis patients with normal lung-function test results at rest, especially in those suffering fromfatigue. Moreover, fatigue was related to dyspnea, sleepingdisorders and to the 6-minute walk distance during an exer-cise test. Fatigue appeared to be associated with specifictypes of pain, such as muscle pain, chest pain, arthralgia,abdominal pain and headache.
Little data are available regarding specific treatment forfatigue associated with sarcoidosis. In a recent small double-blinded, placebo-controlled crossover study, the stimulantdexmethylphenidate hydrochloride (d- MPH) was associat-ed with a significant reduction in sarcoidosis-associatedfatigue. Anti-TNF treatment for other sarcoidosis-relatedproblems also appeared beneficial for fatigue. Other studiessuggest that prednisone usage can be associated with patientfatigue.
QUALITY-OF-LIFE ISSUES
28
Unfortunately, these studies were not designed to ascertainif steroids represent cause or effect for fatigue. It is possiblethat corticosteroids represent a surrogate marker for moresevere or chronic disease or the development of co-morbid
conditions of weight gain, diabetes, depression, inactivity,sleep disturbance or altered mood states. Besides medica-tion, cognitive-behavioral therapy may also be considered astreatment strategy.
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Fatigue
No other signs of
disease activity
Lifestyle advice,
rehabilitation and/or
sympathomimetic or
other agents
Other signs of
disease activity
Treat sarcoidosis if
necessary
Effect on fatigue and
sarcoidosis: follow
Effect on sarcoidosis, no
effect on fatigue
Prednisone* and/or
cytotoxic+ agents,
immunomodulators,
anti-TNF therapy++
Sleep apnea, other sleep-
related disorders, muscle
weakness
Specific 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.
30
Pain, Small Fiber Neuropathy and Cognitive
Dysfunction
Chronic pain is a particular problem for sarcoidosispatients. A stepwise approach to management is shown.
A number of hitherto unexplained symptoms such asfatigue, pain and cognitive dysfunction may – at least partly– be attributable to small fiber neuropathy. It has beenobserved that sarcoidosis patients with symptoms displayedmore depressive symptoms and scored lower on health sta-tus compared with patients without current symptoms.Moreover, patients suffering from sarcoidosis often reportcognitive complaints, such as memory loss and concentrationproblems. Cognitive failures are a substantial problem insarcoidosis patients, even after adjustment for differences in
age and sex distribution. No substantial relationship hasbeen found with clinical characteristics, such as disease dura-tion, and severity. In some studies, fatigue, depression andsymptoms related to autonomic dysfunction were associatedwith the occurrence of cognitive dysfunction. These findingsemphasize the need for further research to integrate knowl-edge about coping, cognitive performance, fatigue anddepressive symptoms in sarcoidosis into clinical manage-ment
Standard anti-inflammatory therapies are usually ineffec-tive for this condition. Neuropathic drugs such as gabapentinmay be useful for symptomatic relief. For refractory cases,anecdotal reports suggest the effectiveness of standard anti-inflammatory therapies, intermittent immunoglobulin(IVIG) therapy and/or anti-TNF in selected cases.
Pain
Neurosarcoidosis
Small fiber neuropathyCentral or peripheral
neuropathyMuscle/chest/bone pain Headache
Treat pain and/or
physical therapy
Arthralgia
Treat pain
Anti-inflammatory agents
neuropathic pain
medications
Anti-TNF-α therapy++
No effect
No effect
No effect
See flow chart treatment
neurosarcoidosisNon LofgrenLofgren
Treat sarcoidosis
if necessary
Effect on sarcoidosis,
no effect on pain
Prednisone* and/or
cytotoxic+ agents,
immunomodulators,
anti-TNF-α++
NSAIDs
No neurosarcoidosis
*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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