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Sarcoidosis therapy

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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  1. Sarcoidosis therapy Rob Vassallo, MD Mayo Clinic, Rochester, MN. Pneumotrieste 2014 April 7-9, 2014.

  2. Disclosures • I have no financial disclosures relevant to this presentation.

  3. SarcoidosisA granulomatous disease of unknown cause

  4. 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).

  5. 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.

  6. Treatment of acute sarcoidosis Observation vs NSAID vsbrief Corticosteroid therapy

  7. 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.

  8. Treatment of chronic sarcoidosis Chronic sarcoidosis = >24 months duration DG James Q J Med 1983;208:525–33.

  9. 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.

  10. Do all patients with pulmonary sarcoidosis require treatment?Simple answer: NO! 63-year old with biopsy proven sarcoid Asymptomatic

  11. 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.

  12. Recommendation • Continue to stay active. • Age appropriate vaccination. • Follow up in 1 year with PFT and chest X ray – sooner if new symptoms develop.

  13. 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).

  14. 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.

  15. Sarcoidosis Therapy Intolerance to corticosteroids – Methotrexate as a second-line agent

  16. 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.

  17. 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. CurrOpinPulm Med 2013, 19:545–561

  18. 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

  19. Sarcoidosis Therapy Clinical Case: Intolerance to corticosteroids – Azathioprine

  20. 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.

  21. 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

  22. 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.

  23. AzathioprineToxicity concerns • Liver toxicity • Bone marrow toxicity • Check TPMT (thiopurine methyl transferase enzyme) level before starting. • Infection risk. • Pneumocystis prophylaxis.

  24. Sarcoidosis therapy “Special situations” Treatment of Neurologic Sarcoidosis

  25. 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.

  26. 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.

  27. 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

  28. 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

  29. 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.

  30. 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.

  31. Sarcoidosis Therapy Hypercalcemia

  32. 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.

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

  34. 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.

  35. 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

  36. Representative chest CT images – no evidence of parenchymal involvement.

  37. Lymphadenopathy

  38. Laboratory Studies and Pulmonary functionAll normal • CBC – normal, ESR - 22, CRP - 2.37 (n<0.8) • Calcium - 9.1, LFT’s, renal function - normal

  39. Surgical Pathology • Left supraclavicular lymph node (1.3 x 0.8 x 0.4 cm) Epithelioid granulomas

  40. 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?

  41. 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”.

  42. 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.

  43. 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.

  44. 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

  45. Grazie

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