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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

Sarcoidosis therapy

Rob Vassallo, MD

Mayo Clinic, Rochester, MN.

Pneumotrieste 2014

April 7-9, 2014.


Disclosures
Disclosures

  • I have no financial disclosures relevant to this presentation.


Sarcoidosis a granulomatous disease of unknown cause
SarcoidosisA granulomatous disease of unknown cause


Is it sarcoidosis not all granulomas sarcoidosis
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 sarcoidosis structure of today s presentation
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

Treatment of acute sarcoidosis

Observation vs NSAID vsbrief Corticosteroid therapy


Treatment of acute sarcoidosis1
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

Treatment of chronic sarcoidosis

Chronic sarcoidosis = >24 months duration

DG James Q J Med 1983;208:525–33.


Sarcoidosis i ndications for therapy topical or systemic g eneral principles
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
Do all patients with pulmonary sarcoidosis require treatment?Simple answer: NO!

63-year old with biopsy proven sarcoid

Asymptomatic


Cardiopulmonary exercise test
Cardiopulmonary exercise test treatment?

  • 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.


Recommendation
Recommendation treatment?

  • 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
Role of inhaled or topical steroids treatment?

  • 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 sarcoidosis often work really well at controlling disease activity but
Corticosteroids in sarcoidosis treatment?Often 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 therapy1
Sarcoidosis Therapy treatment?

Intolerance to corticosteroids – Methotrexate as a second-line agent


Methotrexate for sarcoidosis what s the evidence
Methotrexate for sarcoidosis treatment?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.


Methotrexate
Methotrexate treatment?

  • 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


Methotrexate toxicity concerns and monitoring
Methotrexate treatment?Toxicity 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 therapy2
Sarcoidosis Therapy treatment?

Clinical Case: Intolerance to corticosteroids – Azathioprine


Clinical case
Clinical Case treatment?

  • 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
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

*Before


Azathioprine
Azathioprine (<10mg/day)

  • 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.


Azathioprine toxicity concerns
Azathioprine (<10mg/day)Toxicity concerns

  • Liver toxicity

  • Bone marrow toxicity

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

  • Infection risk.

  • Pneumocystis prophylaxis.


Sarcoidosis therapy3
Sarcoidosis therapy (<10mg/day)

“Special situations”

Treatment of Neurologic Sarcoidosis


Neurologic involvement clinical case
Neurologic involvement: Clinical Case (<10mg/day)

  • 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.


Case (<10mg/day)

  • 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.


Neurosarcoidosis principles of treatment
Neurosarcoidosis (<10mg/day)Principles 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


Neurosarcoidosis treatment
Neurosarcoidosis (<10mg/day)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
TNF-alpha inhibitors in sarcoidosis (<10mg/day)

  • 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
TNF-alpha inhibitor therapy in (<10mg/day)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 therapy4
Sarcoidosis Therapy (<10mg/day)

Hypercalcemia


Treatment of hypercalcemia in sarcoidosis
Treatment of (<10mg/day)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 therapy5
Sarcoidosis therapy (<10mg/day)

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


Clinical case1
Clinical Case. (<10mg/day)

  • 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
Fatigue in sarcoidosis: clinical case (<10mg/day)

  • 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



Lymphadenopathy parenchymal involvement.


Laboratory studies and pulmonary function all normal
Laboratory parenchymal involvement.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
Surgical Pathology parenchymal involvement.

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


How would you manage
How would you manage? parenchymal involvement.

  • 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
Fatigue in Sarcoidosis parenchymal involvement.

  • 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.


Management
Management patients.

  • 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
Other general principles patients.

  • Pneumocystis prophylaxis

  • Prophylactic vaccinations

  • Age appropriate cancer screening

  • TB screening

  • Osteoporosis prophylaxis

  • Counselling regarding effect on pregnancy

  • Thiopurine methyl transferase (TPMT) level



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