Sarcoidosis therapy
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Sarcoidosis therapy. Rob Vassallo, MD Mayo Clinic, Rochester, MN. Pneumotrieste 2014 April 7-9, 2014. Disclosures. I have no financial disclosures relevant to this presentation. Sarcoidosis A granulomatous disease of unknown cause . Is it sarcoidosis? Not all granulomas = sarcoidosis.

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Sarcoidosis therapy

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Sarcoidosis therapy

Rob Vassallo, MD

Mayo Clinic, Rochester, MN.

Pneumotrieste 2014

April 7-9, 2014.


  • I have no financial disclosures relevant to this presentation.

SarcoidosisA granulomatous disease of unknown cause

Is it sarcoidosis?Not all granulomas = sarcoidosis

  • Must rule out infection including mycobacterial or fungal.

  • If there is a prior history of recurrent infections (bronchitis, pneumonia, sinusitis etc) must think of common variable immune deficiency (rule out with IgG, IgA and IgM determination).

  • Consider other causes of granulomatous diseases (example Crohn’s disease).

Pharmacologic therapy for SarcoidosisStructure of today’s presentation

  • 1. First option of management is observation.

  • 2. Mainstay of pharmacologic therapy are corticosteroids

  • 3. Many so-called second line agents:

    • Methotrexate

    • Azathioprine

    • Hydroxychloroquine

    • Pentoxifylline

  • 4. Other agents: ? 3rd line or for use in selected or difficult situations including TNFa inhibitors, cyclophosphamide, cyclosporine etc.

  • 5. Discuss difficult situations at end.

Treatment of acute sarcoidosis

Observation vs NSAID vsbrief Corticosteroid therapy

Treatment of acute sarcoidosis

  • Observation alone is sufficient in many cases.

  • NSAIDs for arthritic symptoms.

  • Prednisone 0.5-1mg/kg/day once daily or every other day in some instances:

    • Hypercalcemia

    • Marked arthritic symptoms

    • Acute neurologic involvement (Facial nerve)

    • If treat with steroids, plan for rapid taper and close follow-up.

Löfgren S. Acta Med Scand 1953 145 (6): 424–431.

Treatment of chronic sarcoidosis

Chronic sarcoidosis = >24 months duration

DG James Q J Med 1983;208:525–33.

SarcoidosisIndications for therapy (topical or systemic)General principles

  • 1. Hypercalcemia

  • 2. Organ involvement with the potential of impaired organ function if left untreated – example:

    • Pulmonary parenchymal involvement

    • Ocular involvement

    • Cardiac disease (conduction disease or myocardial)

    • Neurologic (central or peripheral)

    • Cutaneous disease.

    • Muscle, liver etc.

Do all patients with pulmonary sarcoidosis require treatment?Simple answer: NO!

63-year old with biopsy proven sarcoid


Cardiopulmonary exercise test

  • The patient exercised for ten minutes and achieved a peak workload of 200 watts. This was a maximal study with oxygen consumption at 80% of the predicted max.

  • The cardiac response to activity was normal. The HR increased appropriately with activity. The blood pressure response appeared appropriate. The cardiac output increased from 4.7 L/min at rest to 12.1 L/min at mid activity.

  • The ventilatory response to exercise was normal increasing to a peak of 80% of maximal predicted. Oxygen saturation was maintained throughout. No evidence of ventilatory limitation noted.


  • Continue to stay active.

  • Age appropriate vaccination.

  • Follow up in 1 year with PFT and chest X ray – sooner if new symptoms develop.

Role of inhaled or topical steroids

  • Relatively limited role, generally for management of mild disease (airway of mild ocular involvement).

  • Consider trial of inhaled corticosteroid in patients with airway involvement (mild).

Corticosteroids in sarcoidosisOften work really well at controlling disease activity, but ...

  • 1. Intolerable glucocorticoid side effects.

  • 2. Progressionof disease despite adequate glucocorticoid therapy (0.5mg/kg/day).

  • 3. Need for a glucocorticoid-sparing agent in a patient who requires long-term glucocorticoid therapy and is concerned re long-term side effects.

  • 4. Patient refusal to take glucocorticoids.

Sarcoidosis Therapy

Intolerance to corticosteroids – Methotrexate as a second-line agent

Methotrexate for sarcoidosis What’s the evidence?

  • Methotrexate is an immunosuppressive and anti-inflammatory agent.

  • Can be administered orally or intramuscularly.

  • The initial dosage = 7.5mg once per week, with progressive increases until reaching 10-20mg per week.

  • Folic acid must also be administered, and CBC and liver function must be periodically checked.

CurrOpinPulm Med 2013, 19:545–561

Thorax, 1999; 54: 742-6.


  • Effective in approximately two thirds of patients.

  • MTX should not be used by men or women for at least 3 months before planned pregnancy, and should not be used during pregnancy or breast feeding.

CurrOpinPulm Med 2013, 19:545–561

MethotrexateToxicity concerns and monitoring

  • 1. Lung toxicity – hypersensitivity

  • 2. Liver toxicity – much more significant concern. See recent review. Would stop after every 1gram total of methotrexate therapy and assess need to continue.

  • 3. Bone marrow toxicity – uncommon with folic acid supplementation.

  • 4. Teratogenicity

Sarcoidosis Therapy

Clinical Case: Intolerance to corticosteroids – Azathioprine

Clinical Case

  • 41-year-old nonsmoker with a solitary kidney who has a diagnosis of histopathologically proven non-necrotizing granulomatous inflammation affecting the skull, the spineand lungs.

  • The patient has been successfully treated with oral corticosteroid therapy and has developed many side effects.

  • She is intolerant of steroids.

9-months treatment with Azathioprine and low dose prednisone (<10mg/day)

4.07 L

2.89 L

3.83 L

% predicted

2.06 L

* After Azathioprine



  • No randomized studies – case reports and case series.

  • Consider in patients intolerant of methotrexate or unable to take methotrexate due to contra-indications.

  • Limited data suggests similar efficacy profile as methotrexate.

AzathioprineToxicity concerns

  • Liver toxicity

  • Bone marrow toxicity

  • Check TPMT (thiopurine methyl transferase enzyme) level before starting.

  • Infection risk.

  • Pneumocystis prophylaxis.

Sarcoidosis therapy

“Special situations”

Treatment of Neurologic Sarcoidosis

Neurologic involvement: Clinical Case

  • 44-year-old lady with progressive imbalance and unsteadiness, episodic vomiting, and weight loss.

  • The neurologic examination showed ataxia of gait, without limb ataxia or extraocular movement abnormalities or nystagmus.

  • Spinal fluid exam showed elevated protein, low glucose; total nucleated cell count was 92 /μl with predominantly lymphocytes. There was positive oligoclonal banding.


  • Conjunctiva, right, biopsy: Non-necrotizing granulomatous inflammation.

  • Brain, right frontal, biopsy: Non-necrotizing granulomatous inflammation with giant cells extensively involving the leptomeninges. GMS stain for fungi and auramine-rhodamine stain for mycobacteria were negative.

NeurosarcoidosisPrinciples of Treatment

  • Always establish the diagnosis by tissue before beginning treatment

  • Corticosteroids are the cornerstone for treatment

  • Plan for a minimum of six months of therapy

  • Steroid-sparing agents have less experience based success then corticosteroids.

  • MRI GAD enhancing lesions take months to improve on successful treatment


  • TNF- blockers

    • inflixamib (Remicade)

      • 5 mg/kg IV at initiation, 2 weeks, 4 weeks, then q 4 weeks IV

      • continue 3-6 months depending on response

      • follow a target parameter at 3 months

TNF-alpha inhibitors in sarcoidosis

  • In the selected review, 232 patients (89.9%) were treated with Infliximaband 26 (10.0%) were treated with Etanercept.

  • In 2 RCTs, favorable response of the lung disease was reported with Infliximab.

  • In the cases series, results were diverse.

Maneiro et al. Semin Arthritis Rheum. 2012 Aug;42(1):89-103.

TNF-alpha inhibitor therapy in sarcoidosis

  • Mean weighted rates of events per 100 patient years

    • Adverse events: 39.9

    • Infections: 22.1

    • Serious infections: 5.9

    • Malignancy: 1.0

  • At this point in time, there is insufficient evidence to routinely support the use of TNF-alpha inhibitor therapy, except in selected cases.

Sarcoidosis Therapy


Treatment of Hypercalcemia in Sarcoidosis

  • Adequate hydration

  • Avoidance of exposure to sunlight, calcium/Vitamin D supplementation, adherence to low calcium diet

  • Prednisone 40mg/day for 1 week, reduction to 20mg/day within 1-2 weeks, maintenance of 10 mg/day or every other day with attempts to discontinue prednisone if chronic renal dysfunction is not present.

  • Hydroxychloroquine in steroid resistant or steroid intolerant patients.

Sarcoidosis therapy

Clinical Case: Severe constitutional symptoms with Stage I pulmonary sarcoid.

Clinical Case.

  • 59-year-old non-smoker complained of low grade fevers x 7 days, joint aches, and mild shortness of breath.

  • Otherwise feels fine.

  • Physical exam if totally unremarkable. Eyes normal. Joints normal. Lung exam is normal. No skin findings.

  • Normal lung function on PFTs.

  • Calcium level normal.

Fatigue in sarcoidosis: clinical case

  • 51yr-old non-smoker. Well until 8 weeks prior to presentation: felt fatigue, discomfort in the hips and subjective fever. About 2 weeks prior to referral, he developed fevers [102 to 104 range] and dry cough.

  • Main symptoms include fatigue and lethargy, anorexia and weight lossof about twenty to thirty pounds.

  • Physical examination was normal

Representative chest CT images – no evidence of parenchymal involvement.


Laboratory Studies and Pulmonary functionAll normal

  • CBC – normal, ESR - 22, CRP - 2.37 (n<0.8)

  • Calcium - 9.1, LFT’s, renal function - normal

Surgical Pathology

  • Left supraclavicular lymph node (1.3 x 0.8 x 0.4 cm) Epithelioid granulomas

How would you manage?

  • 1. Patient has normal lung function and Stage 1 pulmonary sarcoidosis.

  • 2. Absence of hypercalcemia, ocular involvement, cardiac, neurologic, cutaneous or hepatic involvement.

  • 3. Although organ function is normal, he is debilitated by fatigue.

  • Observe or treat? What would you treat with?

Fatigue in Sarcoidosis

  • Common complaint for patients with sarcoid: incidence reported 30-70%.

  • Cause is unclear, ?role for TNF-a, IL-1b, IL-6.

  • Not always related to disease extent (pts. with Stage 1 disease may have more fatigue than patients with more advanced disease).

  • May last for a significant period of time (>6months) - one report quotes 5% of patients with sarcoid develop a “post-sarcoidosis chronic fatigue syndrome”.

  • A cross-sectional study performed in 38 sarcoidosis patients.

  • Patients with fatigue (n=25) suffered more frequently from other symptoms, compared to those without fatigue (n=13).

  • No relationship was found between fatigue and ACE or lung function impairment.

  • Patients with fatigue had higher levels of CRP and REE compared to those without fatigue.


  • First need to make sure nothing else is going on – rule out other medical conditions like thyroid disease, sleep disorders, adrenal insufficiency, depression, occult malignancy etc.

  • No good data on drugs!

  • Low dose prednisone, hydroxychloroquine, and tricylic antidepressants have all been suggested as useful for management.

  • My patient – treated with low dose prednisone for 6 months.

Other general principles

  • Pneumocystis prophylaxis

  • Prophylactic vaccinations

  • Age appropriate cancer screening

  • TB screening

  • Osteoporosis prophylaxis

  • Counselling regarding effect on pregnancy

  • Thiopurine methyl transferase (TPMT) level

  • Grazie

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