Presentation on Sarcoidosis by S.K Jindal | Jindal Chest Clinic, Chandigarh
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When the immune system overreacts, granulomas are formed, leading to a condition known as sarcoidosis. This disorder can cause mild to severe symptoms, or no symptoms at all. This Presentation describes sarcoidosis and gives an overview on Sarcoidosis including causes, symptoms, diagnosis, complications, supplements for sacrcoidosis, and treatment strategies. For more information, please contact us: 9779030507.
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Presentation on Sarcoidosis by S.K Jindal | Jindal Chest Clinic, Chandigarh
- 1. Sarcoidosis Surinder K. Jindal (Former Professor & Head, Pulm Med, PGIMER, Chandigarh) Medical Director, Jindal Clinics, Sec 20 D, Chandigarh
- 2. Sarcoidosis • Multisystem • Unknown cause(s) • Granulomatous disease • Young adults ? children
- 3. Immunopathogenesis - basic scenario Beagle SH 2013
- 5. Diagnosis • Clinico-radiological • Tuberculin Anergy • SACE levels • Kveim Siltzbach test • Histopathology • Miscellaneous: Haematological Biochemical PFT/BAL/Gallium scan
- 6. Radiology • Hilar and/or mediastinal LN • Disseminated miliary/nodular • Linear reticular shadows • Diffuse/confluent patchy • Diffuse fibrosis • Fibrosis with cavitation • Diffuse ground glass • Confluent, massive opacities • Atelectasis • Pleural effusion: Rare
- 9. Bronchoscopic Investigations 1. Endoscopic examination 2. Endobronchial biopsy 3. Transbronchial biopsy 4. Bronchoalveolar lavage 5. Endoscopic FNAC (EBUS guided)
- 10. Granulomas: Causes • Infections: TB, Fungi, Others • Sarcoidosis • Foreign bodies • Miscellaneous
- 11. Serum ACE levels • Modulator of granuloma formation (local production of angiotensin II) • Elevated 40-90% • ? Marker of activity • Non-specific elevation in other diseases
- 12. Markers of activity of sarcoidosis Technique SACE enzyme Monocyte chemo-attractant protein Interferon inducible protein Radioactive Ga+ and octreotide Bronchoalveolar lavage (BAL) Calcium metabolism Abnormality Raised Raised Raised Uptake in granulomas Increased CD4:CD8 RANTES Increased TGF-ß Imbalance IL-Ira:ILIß Hypercalcaemia Hypercalciuria Reflecting Epithelioid granulomas Macrophage activity Activated lymphocytes Activated macrophages Sarcoid alveolitis activity Calcitriol sensitivity by alveolar macrophages
- 13. Technique Kappa & lambda IGs Tuberculin skin test Kveim-Siltzbach test Spirometry Tc-DTPA lung scan Fluorescein angiography ECG and 24 hr. tape Magnetic resonance Abnormality Raised Negative Positive Impairment Impaired clearance Retinal vasculitis Cardiac arrhythmia Abnormal Reflecting B cell overactivity Cutaneous anergy IL-12 neutralized Specific for sarcoidosis Interaction of CD4 cells Granuloma load Inflammation – fibrosis Epithelial permeability Indication for steroid therapy and/or laser to overcome leakage Myocardial sarcoidosis Mediastinal nodes Neurosarcoidosis Markers of activity of sarcoidosis
- 14. Predictors of Relapse 1. History of constitutional symptoms – malaise 2. Physical signs – crepts/ wheezes 3. Blood eosinophilia 4. Pretmt. FEV1/FVC < 65% (Predicted) 5. No correlation of age, sex, lab features
- 15. Poor Prognosis Markers • Onset > 40 yrs age • Symptoms < 6 months • Absence of E.N. • Splenomegaly • > 3 organ involvement
- 16. Treatment Indications Stage I: Asymptomatic Observe with/without EN Symptomatic NSAID or Short course CS Stage II: Asymptomatic Observe PFT (Mild) Observe PFT (severe) CS Stage III & IV: Treatment (CS/others) Extrapulmonary: -do-
- 17. Pulmonary sarcoidosis- general approach Beagle SH, 2013
- 18. Corticosteroid Therapy 1. Standard dosages: 0.5 – 1 mg/kg . Taper to 10-15 mg/day after 3-6 mths 2. Higher dosages: 60-80 mg/day . Severe ocular . Neurological, myocardial . Malignant hypercalcaemia 3. Relapses (20-50%) 4. Complications
- 19. Potential End-points for Treatment Judson MA, 2014
- 20. When do steroids fail? • Some forms of extra-pulmonary disease • Advanced disease • Presence of co-morbidities • Steroid resistant/ non-responsive disease • Recurrences
- 21. Steroid Sparing Drugs 1. Cytotoxic: 2. Non-cytotoxic: 3. Anticytokine: Methotrexate Azathioprine Cyclophosphamide NSAIDs Antimalarials Cyclosporin A Ketoconazole Thalidomide Pentoxifylline Infliximab
- 22. Adverse effects of non-steroidal drugs Methotrexate Hepatitis, hepatic fibrosis, interstitial pneumonia, pulmonary fibrosis, leucopenia, gastrointestinal intolerance, teratogenicity Azathioprine Myelosuppression, opportunistic infections, hepatitis, teratogenicity Leflunomide Rash, alopecia, peripheral neuropathy, interstitial pneumonia, gastrointestinal intolerance, teratogenicity Mycophenolate mofetil Hyperglycemia, hypercholesterolemia, gastrointestinal intolerance, bone marrow suppression, hepatitis, teratogenicity Cyclophosphamide Myelosuppression, opportunistic infections, hemorrhagic cystitis, bladder malignancy, cardiomyopathy, infertility, teratogenicity Chloroquine, hydroxychloroquine Retinopathy, corneal changes, muscle weakness, gastrointestinal intolerance TNF- antagonists Infections (especially reactivation of tuberculosis), infusion reactions, gastrointestinal intolerance, headache Rituximab Infusion reactions, lymphopenia, opportunistic infections, asthenia
- 23. Treatment recommendations Korsten et al 2013 First line Second line Third line Pulmonary Corticosteroids MTX TNFi AZA RTX VIP? Antioxidants? Extrapulmonary Ocular Corticosteroids MTX, AZA? LEF TNFi Cutaneous Corticosteroids HCQ, LEF MTX? AZA? Apremilast? Lymph node Corticosteroids MTX, LEF? AZA? TNFi?
- 24. Methotrexate • Preferred second line drug • Also used as a steroid-sparing drug • Dosage: 10-15 mg once a week • Response: Slower Clinical - 2-4 weeks Functional & Radiological- 6-8 weeks Monitoring of liver, renal and hematological functions Concomitant administration of Folic Acid
- 25. Anti-malarial Drugs • Chloroquin and Hydroxychloroquin • Indications: Cutaneous sarcoidosis Upper respiratory tract sarcoidosis Hypercalcemia Neurosarcoidosis Side-effects: Irreversible retinopathy (HCQS is safer for the eyes) Agranulocytosis Myopathy
- 26. Methotrexate vs. Azathioprine Vorselaars AD 2013 • An international retrospective cohort study, reviewing all sarcoidosis patients who started methotrexate or azathioprine until 2 years after initiation or discontinuation. • 145 received methotrexate and 55 azathioprine. • A similar steroid-sparing capacity for both: Prednisone daily dose decreased a mean of 6.32 mg/y (P < .0001); FEV1 showed a mean increase of 52 mL/y (P = .006) and VC of 95 mL/y (P = .001) in both treatment groups. • DLCO % predicted increased, (mean of 1.23%/y,P = 018). • More patients suffered from infections in the azathioprine group (34.6% vs 18.1%, P = .01)
- 27. Tumour Necrosis Factor-alpha Antagonists • Infliximab, Adalimumab, Etanercept • TNF-alpha plays central role in granuloma formation, therefore TNF antagonists are useful. • Indications: Refractory neuro-sarcoidosis Cardiac, cutaneous and upper- airway sarcoidosis Long term efficacy and safety, unclear Infliximab given as intravenous infusion of 3-5 mg/ kg on weeks 2 and 2, repeated every 4-8 weeks thereafter. Increased risk of TB, lymphomas; Occurrence of sarcoidosis reported during treatment
- 28. Refractory Sarcoid Mononeuritis Multiplex Inês Brás Marques 2014
- 29. Adalimumab for Refractory Pulmonary Sarcoidosis (52 wk trial) Sweiss NJ 2014 Physician Global Patient Global Assessment Score
- 30. Treatment of Complications • Depression • Bronchiectasis • Bronchostenosis • Pulm fibrosis & hypoxaemia • Pulm hypertension & cor pulmonale • Aspergilloma • Anti-depressants • Antibiotics, Surgery • Balloon dilatation with mitomycin C • LTOT • Pulm vasodilators, oxygen • Antifungal agents, Surgery
- 31. Sarcoidosis SFN Granulomas Intra-epidermal nerve fibers
- 32. Symptoms of small fiber neuropathy Sensory symptoms Pain* Paraesthesias Sheet intolerance Restless legs syndrome** Symptoms of autonomic dysfunction Hypo- or hyperhidrosis Diarrhoea or constipation Urinary incontinence or -retention Gastroparesis Sicca syndrome Blurry vision Facial flushes Orthostatic intolerance Sexual dysfunction
- 33. Sarcoidosis-related Small Fibre Neuropathy (SFN) • Prednisone and methotrexate do not appear beneficial • Other agents: Intravenous immunoglobulin Anti-TNF-alpha Antidepressants Anticonvulsants Prolonged-release opioids Provide limited pain relief, Considerable side effects
- 34. Multiple aspergillomas in sarcoidosis
- 35. Experimental/ Supplementary Treatments • Biological agents: Monoclonal antibodies- Adalimumab, Ustekinumab and golimumab • Anti-oxidants: Dietary Exogenous • Sarcoidosis-associated fatigue: Neurostimulants, including methylphenidate Psychological interventions • Nicotine
- 36. Role of Anti-oxidants Increased oxidative stress in sarcoidosis: •Increased TNF-alpha, IL-8, MDA etc •Anti-oxidants shown to decrease oxidative stress •N-Acetyl cysteine (Homma 2012) •Quercetin: Dietary anti-oxidant found in flower beds of Capparis spinosa, buckwheat, blueberry and cranberry. •Accumulate in the lungs •Reduce TNF-alpha, IL-8, MDA;
- 37. Nutritional Supplements Boots AW 2011 • Oxidative stress and low antioxidant levels are implicated in the aetiology • Quercetin is a potent dietary antioxidant • A double-blind intervention study; two groups of non-smoking, un- treated sarcoidosis. One group was given 4x500 mg quercetin (n = 12) orally within 24 h, the other group placebo • Quercetin supplementation improved the antioxidant defence • Sarcoidosis patients might benefit from the use of antioxidants
- 38. ARA 290 -an erythropoietin derivative van Velzen M 2014 • Painful peripheral neuropathy is a common, difficult-to-treat complication • Two Phase II clinical trials on ARA290, an erythropoietin derivative with tissue protective and healing properties that does not stimulate erythropoiesis. • ARA 290 treatment resulted in significant improvement of neuropathic pain, significant increases in corneal nerve fibers, improved sensory pain thresholds, improved quality of life and physical functioning
- 39. Nicotine treatment Julian MW 2013 • Nicotine is linked to the regulation of T cell-mediated inflammation • 12 weeks of nicotine treatment plus conventional therapy or conventional therapy alone • Treatment was well tolerated and restored peripheral immune responsiveness • Nicotine improved TLR 2 and TLR 9 responsiveness in active pulmonary sarcoidosis • The immune phenotype of patients with symptomatic sarcoidosis treated with nicotine closely resembled that of asymptomatic patients
- 40. SUMMARY • Sarcoidosis is diagnosed from the presence of consistent clinical findings and presence of non-caseating granulomas on cyto-histopathology • Steroids constitute the first line of treatment • Non-steroidal treatment is frequently required for Refractory disease - Severe extra-pulmonary - Recurrences - Complications - Co-morbidities - Steroid induced side-effects • None of the 2nd or 3rd line treatment is as effective as the 1st line treatment with steroids
- 41. THANK YOU