Presentation on Sarcoidosis by S.K Jindal | Jindal Chest Clinic, Chandigarh

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.

1. Sarcoidosis
SurinderK. Jindal
(Former Professor & Head, PulmMed, PGIMER, Chandigarh)
Medical Director, Jindal Clinics, Sec 20 D, Chandigarh

2. Sarcoidosis
•Multisystem
•Unknown cause(s)
•Granulomatousdisease
•Young adults
? children

3. Immunopathogenesis -basic scenario
Beagle SH 2013

5. Diagnosis
•Clinico-radiological
•TuberculinAnergy
•SACElevels
•KveimSiltzbachtest
•Histopathology
•Miscellaneous:Haematological
Biochemical
PFT/BAL/Galliumscan

6. Radiology
•Hilarand/or mediastinalLN
•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.Endobronchialbiopsy
3.Transbronchialbiopsy
4.Bronchoalveolarlavage
5.Endoscopic FNAC (EBUS guided)

10. Granulomas: Causes
•Infections:TB,Fungi,Others
•Sarcoidosis
•Foreignbodies
•Miscellaneous

11. Serum ACE levels
•Modulator of granulomaformation (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
Bronchoalveolarlavage (BAL)
Calcium metabolism
Abnormality
Raised
Raised
Raised
Uptake in granulomas
Increased CD4:CD8
RANTES
Increased TGF-ß
Imbalance IL-Ira:ILIß
Hypercalcaemia
Hypercalciuria
Reflecting
Epithelioidgranulomas
Macrophage activity
Activated lymphocytes
Activated macrophages
Sarcoidalveolitisactivity
Calcitriolsensitivity by
alveolar macrophages

13. Technique
Kappa & lambda IGs
Tuberculin skin test
Kveim-Siltzbachtest
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
Mediastinalnodes
Neurosarcoidosis
Markers of activity of sarcoidosis

14. Predictors of Relapse
1.Historyofconstitutionalsymptoms–malaise
2.Physicalsigns–crepts/wheezes
3.Bloodeosinophilia
4.Pretmt.FEV
1/FVC<65%(Predicted)
5.Nocorrelationofage,sex,labfeatures

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
CyclosporinA
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, hemorrhagiccystitis,
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
CutaneousCorticosteroids 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
•Chloroquinand 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 sarcoidosispatients
who started methotrexateor azathioprineuntil 2 years after initiation or
discontinuation.
•145 received methotrexateand 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 azathioprinegroup (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 sarcoidosisreported during treatment

28. Refractory Sarcoid Mononeuritis Multiplex
Inês Brás Marques2014

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
•Pulmfibrosis & hypoxaemia
•Pulmhypertension & cor
pulmonale
•Aspergilloma
•Anti-depressants
•Antibiotics, Surgery
•Balloon dilatation with
mitomycinC
•LTOT
•Pulmvasodilators, 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
Diarrhoeaor 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
•Biologicalagents:Monoclonalantibodies-Adalimumab,Ustekinumab
andgolimumab
•Anti-oxidants:Dietary
Exogenous
•Sarcoidosis-associatedfatigue:
Neurostimulants,including
methylphenidate
Psychologicalinterventions
•Nicotine

36. Role of Anti-oxidants
Increasedoxidativestressinsarcoidosis:
•IncreasedTNF-alpha,IL-8,MDAetc
•Anti-oxidantsshowntodecreaseoxidativestress
•N-Acetylcysteine(Homma2012)
•Quercetin:Dietaryanti-oxidantfoundinflowerbedsofCapparis
spinosa,buckwheat,blueberryandcranberry.
•Accumulateinthelungs
•ReduceTNF-alpha,IL-8,MDA;

37. Nutritional Supplements
Boots AW 2011
•Oxidative stress and low antioxidant levels are implicated in the
aetiology
•Quercetinis a potent dietary antioxidant
•A double-blind intervention study; two groups of non-smoking, un-
treated sarcoidosis. One group was given 4x500mg quercetin(n=12)
orally within 24h, the other group placebo
•Quercetinsupplementation improved the antioxidant defence
•Sarcoidosispatients 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
•Sarcoidosisis diagnosed from the presence of consistent clinical findings
and presence of non-caseatinggranulomas 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 2
nd
or 3
rd
line treatment is as effective as the 1
st
line treatment
with steroids

41. THANK YOU