©2013 mfmer | slide-1 sarcoidosis therapy rob vassallo, md mayo clinic, rochester, mn....
TRANSCRIPT
©2013 MFMER | slide-1
Sarcoidosis therapy
Rob Vassallo, MDMayo Clinic, Rochester, MN.
Pneumotrieste 2014 April 7-9, 2014.
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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).
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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.
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Treatment of acute sarcoidosis
Observation vs NSAID vs brief Corticosteroid therapy
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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.
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Treatment of chronic sarcoidosis
Chronic sarcoidosis = >24 months durationDG James Q J Med 1983;208:525–33.
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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.
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Do all patients with pulmonary sarcoidosis require treatment?Simple answer: NO!
63-year old with biopsy proven sarcoid Asymptomatic
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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.
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Recommendation
• Continue to stay active.
• Age appropriate vaccination.
• Follow up in 1 year with PFT and chest X ray – sooner if new symptoms develop.
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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).
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Corticosteroids in sarcoidosisOften work really well at controlling disease activity, but ...
1. Intolerable glucocorticoid side effects.
2. Progression of 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.
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Sarcoidosis TherapyIntolerance to corticosteroids – Methotrexate as a second-line agent
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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.
1. Curr Opin Pulm Med 2013, 19:545–5612. Thorax, 1999; 54: 742-6.
Methotrexate
• 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.
Curr Opin Pulm Med 2013, 19:545–561
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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
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Sarcoidosis TherapyClinical Case: Intolerance to corticosteroids – Azathioprine
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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 spine and lungs.
• The patient has been successfully treated with oral corticosteroid therapy and has developed many side effects.
• She is intolerant of steroids.
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9-months treatment with Azathioprine and low dose prednisone (<10mg/day)
FVC FEV1 DLCO0
20
40
60
80
100
120
3.83 L
4.07 L
2.06 L
2.89 L
% p
red
icte
d
* After Azathioprine* Before
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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.
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AzathioprineToxicity concerns
• Liver toxicity
• Bone marrow toxicity
• Check TPMT (thiopurine methyl transferase enzyme) level before starting.
• Infection risk.
• Pneumocystis prophylaxis.
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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.
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Case
• 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.
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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
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NeurosarcoidosisTreatment
• 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
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TNF-alpha inhibitors in sarcoidosis
• In the selected review, 232 patients (89.9%) were treated with Infliximab and 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.
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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.
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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.
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Sarcoidosis therapy
Clinical Case: Severe constitutional symptoms with Stage I pulmonary sarcoid.
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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.
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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 loss of about twenty to thirty pounds.
• Physical examination was normal
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Laboratory Studies and Pulmonary functionAll normal
• CBC – normal, ESR - 22, CRP - 2.37 (n<0.8)
• Calcium - 9.1, LFT’s, renal function - normal
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Surgical Pathology
• Left supraclavicular lymph node (1.3 x 0.8 x 0.4 cm) Epithelioid granulomas
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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?
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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”.
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• 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.
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Management
• 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.
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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