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 Rob Vassallo, MD Mayo Clinic, Rochester, MN. Pneumotrieste 2014 April 7-9, 2014. Disclosures
  • 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 Asymptomatic 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 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 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 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 Therapy treatment? Intolerance to corticosteroids – Methotrexate as a second-line agent 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 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 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 Therapy treatment? Clinical Case: Intolerance to corticosteroids – Azathioprine 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) 4.07 L 2.89 L 3.83 L % predicted 2.06 L * After Azathioprine *Before 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 (<10mg/day)Toxicity concerns
  • Liver toxicity
  • Bone marrow toxicity
  • Check TPMT (thiopurine methyl transferase enzyme) level before starting.
  • Infection risk.
  • Pneumocystis prophylaxis.
  • Sarcoidosis therapy (<10mg/day) “Special situations” Treatment of Neurologic Sarcoidosis 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 (<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 (<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 (<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 (<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 Therapy (<10mg/day) Hypercalcemia 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 therapy (<10mg/day) Clinical Case: Severe constitutional symptoms with Stage I pulmonary sarcoid. 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 (<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
  • Representative chest CT images – no evidence of parenchymal involvement. Lymphadenopathy parenchymal involvement. 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 parenchymal involvement.
  • Left supraclavicular lymph node (1.3 x 0.8 x 0.4 cm) Epithelioid granulomas
  • 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 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 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 patients.
  • Pneumocystis prophylaxis
  • Prophylactic vaccinations
  • Age appropriate cancer screening
  • TB screening
  • Osteoporosis prophylaxis
  • Counselling regarding effect on pregnancy
  • Thiopurine methyl transferase (TPMT) level
  • Grazie patients.
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