2. SARCOIDOSIS
• The term Sarcoid was introduced by Boeck (in 1899)
because of superficial resemblance of a skin lesion to
sarcoma.
• But in 1940, the term Sarcoidosis was universally accepted
as defined by Lofgren.
• Multisystem granulomatous disorder of unknown origin
characterized by activation of T-Lymphocytes and
mononuclear phagocytes at sites of disease.
3. • Most commonly affects young adults & presents frequently
with Lungs, skin & Eye manifestations. Other – Parotid, CNS,
Bones, RES and CVS.
•Diagnosis is securely established from compatible history,
histology → Non caseating granulomas in more than one
organ or positive Kveim-Siltzbach skin test & absence of
competing Dx like TB/Fungal Disease/Malignancy.
• Immunologically there is impaired CMI Depression of
DTH ; with raised or abnormal immunoglobulin.
4. EPIDEMIOLOGY
Incidence and Prevalence- Varies much 28.2/100000 in
Finland to 3.7/100000 in Japan
More common in 3rd to 4th decade with variable female
predominance, more common in black than white. Black
people tend to have more extrathoracic and severe disease,
but rare erythema nodosum.
Genetic influence – more in monozygotic twins than dizygotic,
more in like sex over unlike sex, more in mother-child than
father-child relation.
Human leucocyte antigens associated are HLA-B8, -DR3, -Cw7,
-DRw52, -DR5J.
5. ETIOLOGY
•Sarcoid granulomas are formed in response to a
persistent, poorly degradable antigenic stimulus.
• Non-infective agents : Pine Pollen, Clay soil, talc,
beryllium, ziroconium. None of these theories have
endured.
• Infective : • Communicable agent was likely the major
causative factor in the disease. Individuals in close proximity
to sarcoidosis cases may be at a higher risk of disease,
possibly due to a transmissible agent.
6. MICROBIAL CANDIDATE ORGANISM :
i) Mycobacteria :
Experiments in mice (inoculated Sarcoid homogenates) by Mitchall et al
proved that there was a transmissible agent for Sarcoidosis and this was
mycobacteria
•Possible therefore in Sarcoidosis, mycobacterial lysis might result in
modified form of organisms persisting and driving a granulomatous
response.
b) Anti-Mycobacterial Ab. Study :
Chapman et al → ppt. Ab. To atypical mycobacteria in
78% of sarcoid pts.
7. c) Molecular Studies :
PCR based studies : MTB found in <10%.
Reasons :
• Sensitivity : AFB –ve, culture –ve samples PCR + ve is 10-30%. By
analogy, if sarcoidosis is mycobacterialtriggered then positivity rates no
greater than this can be expected.
• However, mycobacterial DNA fingerprint are seen in some
pts. with sarcoidosis but not seen in all.
d) Other Reasons
• Over the years, there has been ↓ in incidence of TB, this is not
paralleled by new cases of sarcoidosis
• Involvement of heart and salivary glands is peculiar to sarcoidosis and
is not commonly described with mycobacterial infection.
8. Summary :
Pointers of mycobacterial inf.
i) Histopathological appearance of granuloma.
ii) Presence of mycobacterial disease existing co-incidentally,
succeeding or antedating sarcoidosis.
iii) Finding of organisms in occasional granuloma together with
occasional caseation.
iv) Transmissibility in animal experiments
v) Nucleic acid detection studies.
vi) Comparison with leprosy in which tuberculoid (paucibacillary) and
lepromatous (multi-bacillary) are found.
Inference can be drawn that sarcoidosis might represent tuberculoid
form of pathological response to mycobacteria.
9. Against :
1) Absence of Caseation
2) Organisms are demonstrated rarely.
3) Absence of response to ATT.
4) Tuberculin anergy.
ii)Propionibacteria P.acnes : Normal skin and intestinal commensal.
In 1999, Ishige et al demonstrated P. acnes in 12 of 15 pts. with
sarcoidosis but in only 3 of 15 pts in control group, using PCR technique.
.
iii)Other organisms :
Rickettsia, Chlamydia pneumoniae, Borrelia burgdoferri, Viruses(Human
herpes virus 8).
10. PATHOGENESIS
Granulomatous inflammation is the central feature in the
pathogenesis of sarcoidosis. Granulomatous reaction is a
protective response to an inciting agent.
Essentially there are four stages -
1. The presence of the inciting agent and its contact APCs
(mostly alveolar macrophages).
2. The interaction between APCs and CD4+ T lymphocytes to
initiate the formation of simple granuloma.
3. It includes further recruitment of CD4+ and elicitation of
type 1 and 2 helper responses.
4. Stage of formation and maintenance of complex
granuloma.
11. IMMUNOLOGY
Altered balance of Th1 or Th2 responses with dominant
expression of Th1 cytokines (IFN gamma) and IL-2 with low
levels of expression of Th2 cytokines ( IL-4 , 5).
Depression of DTH esp. in active sarcoidosis. A subgroup of
CD4 cells may account for this anergy by abolishing IL-2
production and inhibiting T cell proliferation.
Anergic state may be related to diminished dendritic cell
functions.
Earliest is accumulation of CD4+ cells and release of IL-2 in
alveoli and interstitium.
12. LUNG LYMPHOCYTES
1. T helper cells > T suppressor cells appx. 10:1
2. Lymphokines – IL-2, some other Lymphokines cause
polyclonal activation of B-cells, increased
immunoglobulins.
3. Activated T cells – MCF (monocyte chemotactic factor),
MIF (migration inhibiting factor) helps in attract,
immobilize and activate monocytes Granuloma
formation.
13. ALVEOLAR MACROPHAGES
↑ in no. of activated alveolar macrophages.
Release cytokines : IL-1, IL- 6, IL-8, IL-15, TNF−α, INF-Ƴ, GM-
CSF.
Release chemokines : RANTES(regulated on activation, T cell
expressed and secreted), MIP-1α, IL-16.
1. IL-1 – increase expression of adhesion factors thus helps
in migration of phagocytes, lymphocytes to site of need.
2. IL-8 (potent neutrophil chemotactic factor) ---
Neutrophilic alveolitis reflects ongoing inflammation a/w
disease progression.
14. 3. IL-12 contributes to proliferation.
4. IL-12, IL-18 ---- stimulates IFN production.
5. IL-18 induces release of IFN- γ from T-Cells results in further
stimulation of macrophages and cytotoxic T-cells.
6. IL-15 – proliferation of T-cells and B-cells.
7. MIP-1α, MCP-1 a/w ongoing inflammation.
8. TGF-β a/w spontaneous resolution.
9. IL-6 , IL-8 are elevated in BAL fluid in active sarcoidosis.
10. Release ACE, 1α hydoxylase, PTHrp( PTH realted peptide).
15. Chemo attractant cytokines like IL-8,IL-15,IL-16, RANTES
recruit CD4 cells to site of inflammation from blood.
IL-2 induces an in situ proliferation of these cells.
TGF-β is inhibitor of IL-12 and IFN. Increased during
remission of sarcoidosis.
Increased level of activation markers(HLA-DR, HLA-DQ,
CD71) and adhesion molecules (CD49a, CD54, CD102).
16. • TNFα : Higher in active disease.
• ↑TNFα → in asymptomatic disease, higher in BAL fluid
↑risk of disease progression.
• Symptomatic disease : Higher rate of relapse.
• Chronic Sarcoid pts. with ↑TNF-α do not respond to
steroids.
Reasons : TNF-α -- ↓sensitivity of monocytes to
dexamethasone.
↓
Corticosteroid resistance
17.
18.
19. PATHOLOGY
• Active sarcoidosis - Granulomas which are at same stage of
development in early stages.
• Granuloma contains macrophages, epitheloid cells, Giant cells,
lymphocytes(T-cells and B-cells).
• Cytoplasm may contain inclusion bodies like Schaumann
bodies/conchoid bodies, Doubly refractile crystalline inclusion
bodies, Asteroid bodies.
• Necrosis do not occur or minimal.
• Reticulin between histiocytes and around the nodule remain intact.
• No AFB are found or cultured.
20. Fate of Granuloma : May resolve spontaneously and
completely, may form an avascular fibrous tissue,
eosinophilic mass of hyaline material.
21. Histological features of sarcoid lesion are not specific – TB,
Leprosy, T. Syphilis, Brucellosis, PBC, Fungal inf., berylliosis,
hypogammaglobulinemia.
Localized Sarcoid like – L/N in Carcinoma, Lymphoma, Fungal
inf., Trauma, Chemicals (Zirconium).
28. Skin may show specific and non specific lesions – EN,
Subcutaneous nodules, plaques, lupus pernio,
maculopapular eruptions.
LOFGREN’S SYNDROME
Erythema nodosum with hilar
lymphadenopathy, also often
with polyarthropathy and
nongranulomatous uveitis.
29. DIAGNOSIS
1. Based on History + Radiological (80%) + Histology (except
in Lofgren’s syndrome).
2. Histology : Conventional TBNA – 60% EBUS TBNA – 80%,
TBLB – 80%.
3. Tuberculin Test – usually negative.
4. BAL – A sample containing 15% lymphocytes if shows
CD4/CD8 >3.5 --- specificity of 93-96%, sensitivity – 53-
59%.
30. 5. Kveim-Siltzbach test - An intradermal inj. of sarcoid tissue
is injected & papule formation seen after 4 wks. – Positive
upto 98%.
6. Serum ACE levels- neither specific nor sensitive.
Sensitivity - 55%, Specificity - 90%.
7. Gallium Scan – Hilar L/N + Rt. Paratracheal nodes –
Lambda sign, Lacrimal and salivary gland – Panda sign. This
is outdated now.
8. 18-FDG PET scan.
9. FMT(F-methyltyrosine) PET : -ve in Sarcoidosis bt +ve in
tumors.
33. TREATMENT OF SARCODOSIS:
A) General Principles From Clinical Observations :
1. Suppression of granuloma formation results in
preservation of organ function and minimize long term
fibrotic outcomes.
2. Corticosteroids : Effective in suppressing granuloma
formation over both short term and long term. Non
corticosteroid therapy variably effective.
3. Threshold level of drug effect for most pts.
→ Below which : Progression of granuloma
→ Above which : Suppression of granuloma
4. Different tissues respond differently to drugs.
34. STRATEGIES FOR TREATMENT OF SARCOIDOSIS
BASED ON STAGES OF INFLAMMATION IN DISEASE
Step 1 : Inhibit Ag Presentation
(Anti-Malarial Drugs)
Step 2 : Suppress Granuloma Formation
(Corticosteroids, Immunosuppressive, Anti TNF agents)
Step 3 : Enhance Ag Clearance
? Peptide based therapy (future)
Step 4 : Inhibit Fibrosis
(Corticosteroids, Immunosuppressive, Anti TNF agents)
35. 1. Treatment to suppress initiation of granuloma
formation :
Strategies :
1. Reduce Ag deposition
2. Enhance Ag clearance
3. (-) Ag processing and presentation
Reduce Ag deposition :
Antibiotic therapy :
a. Doxycycline, Minocycline → Effective against propinobacteria.
b. Dapsone, Clofazimine → Anti mycobacterial effects.
• Beneficial in subset of sarcoidosis pts.
• However, these agents have anti-inflammatory effects.
• Effective in only few anecdotal cases
36. 2. Anti-Malarial Drugs Choroquin/Hydroxy Chloroquin :
MoA : (-) Degradation of proteins by acid hydrolases within
lysosomes.
(-) MHC – peptide complexes.
Net effect :(-) Ag presentation to T-cells.
II. Treatment of Progressive granulomatous inflammation :
1. Corticosteroids :
A. Broad spectrum anti-inflammatory effects on multiple cells –> T-
cells/macrophages/granulocytes.
b. (-) Expression of pro-inflammatory cytokines such as IL-1, IL-2, IL-3,
IL-4, IL-5, IL-6, IL-8, IL-11, IL-12, IL-19, IFN-α & TNF.
c. (-) Arachadonic acid metabolism : overall - ↓ cell activation
d. - Enhanced apoptosis of activated T-cells.
37. 2) Azathioprine :
MoA : (a) Azathioprine
Thiopurine –S-methyltransferase
6-Mercaptopurine.
Accumulation of 6 –thioguanine nucleotides in target
organs → Imp. Mediator of immuno suppression. b) (-) T-cell and B-cell
proliferation and cytotoxic T-cell function.
Toxicities :
:BM suppression
: GI S/E
: Hepatitis
: Oncogenic effects
Use : Reserved for progressive organ threatening disease not
responding to safer alternatives.
38. 3) Methotrexate :
MoA : Folic acid analogue that (–) dihydrofolate reductase and
transmethylation reactions.
Net effect : Interfere with purine metabolism and polyamine synthesis.
High doses : Anti-Proliferative.
Low doses : Anti-Inflammatory (due to ↑ release of Adenosine)
(-) TNF, IL-6, IL-8, (-) Release of ROI, (-) Lymphocyte proliferation
Toxicity : Hepatic, BM, Pulmonary.
Use : Maintenance treatment of serious organ threatening
disease.
39. 4. Cyclosporin :
T-cell (-) T-cell activation → 2 signals → TCR complex
↓
Costimulatory molecules CD 28, CD40 on T cell surface.
These drugs block signal 1.
↓
IL-2 (-)
• However, cyclosporin not very effective.
• Toxicity : Renal, malignancy.
• Use : Serious cases failing more standard therapies.
• Efficacy : 0-80%
40. d) Infliximab :
- Humanized monoclonal ab. formed of human IgG1 Ab +
protein segments from mouse monoclonal Ab against
human TNF.
MoA : Block TNF.
Limitation : Development of Anti-murine Ab. Which ↓ its
actions.
Requires concomitant therapy with methotrexate to
suppress this humoral response.
↑ risk of recrudescent TB.
Allergic reaction to chimeric Ab.
Use : Steroid resistant disease (Anecdotal reports)
• None of these drugs classified as TNF (-) have been
shown to be effective in sarcoidosis by rigorous study.
• All these have high cost.
• Notable toxicities.
41. 5. TNF Inhibition :
TNF plays critical role in granuloma formation.
a) Pentoxifylline : Methylxanthine derivative :
- Non-selective phosphodiesterase (-)
- (-) TNF production by mononuclear cells including alveolar macrophages.
- May have a limited role because it is difficult to achieve therapeutic doses due to
frequent GI S/E.
- Dose : 400 mg TDS
- Efficacy : 50-70%
b) Thalidomide :
(-) TNF production by mononuclear cells.
- Use : Skin/Mucosal sarcoidosis.
- Toxicity : Teratogenic
- Peripharal Neuropathy
- Sedation
c) Etanercept : Biologic dimeric fusion protein which binds to TNF and related
protein lymphotoxin α
- Toxicities : 1. Infections risk ↑
2. Lupus syndr.
3. Demyelinating disease.
42. DIFFERENT STRATEGIES FOR DIFFERENT STAGES OF SARCOIDOSIS
ROLE OF TH-1 RESPONSE :
Early Stages : Th-1 driven granulomatous response effective in clearing
granuloma inducing Ag.
Chronic Sarcoidosis : Ongoing Th-1 immune response results in
impaired organ function.
Therefore,
1. Minimize immuno suppression early in disease.
2. In chronic stages focus should be on minimizing granulomatous
inflammation.
43. When to treat Pulmonary Sarcoidosis
• It depends upon radiological stage, symptoms and Lung function
impairment.
• Stage 0 or 1: usually pt. are asymptomatic and requires no
treatment. If Fever/joint pains – NSAIDs or 15-20mg/day pred if
no respond.
• Stage 2: asymptomatic or mild functional impairment – no Rx
but if decrease in FVC is 10% or DLCO 20% over 3-6 mths ->
needs immunosuppressive drugs. Symptomatic patients or
significant functional impairment -> Rx needed.
• Stage 3: Usually symptomatic and need Rx.
• Stage 4: Poor response to drugs.
44. TREATMENT OF PROGRESSIVE PULMONARY FIBROSIS
1. Persistent granulomatous inflammation
↓
Fibrosis
2. Probably, there is a switch to Th-2 response in late stages
resulting in elaboration of pro-fibrotic cytokines like IL-4.
3. No data to support Anti-fibrotic agents such as
colchicine/perfenidone in fibrocystic sarcoidosis.
4. Anti-fibrotic biologic agents : IFN - a/w relapse of sarcoidosis
5. For now, anti-inflammatory drug therapy that (-) granuloma
formation → retard/prevent progressive fibrosis
45. FUTURE DIRECTIONS :
1. Identify tissue Ag so that effective action can be taken
against them.
2. Suppress granuloma : Less toxic more targeted
approach.
3. Regulating T-cell response by targeting MHC/Ag/TCR
complex and downstream pathways. Drug blocking
T-cell costimulatory pathway may induce T-cell anergy
or tolerance. (Rapamycin, mycophenolate mofetil).
4. (-) Pro inflammatory cytokines like TNF
↓
Limits immunopathology esp. In chr. Sarcoidosis.
5. Enhance anti-inflammatory cytokines like IL-10.
Overall Goal : Suppress granuloma
↓
Limit tissue injury and fibrosis in pts.
demonstrating progressive organ dysfunction.
46. DIFFICULT TREATMENT ISSUES IN SARCOIDOSIS
Management Issues
When to start therapy :
Specific conditions requiring therapy
1. Cardiac involvement
2. Neurologic involvement
3. Hypercalcemia
4. Ocular disease not controlled by topical therapy
Pulmonary involvement per se does not require therapy.
So, for Pulmonary disease
1. Symptomatic
2. Worsening lung functions
47. Corticosteroid therapy in pulmonary sarcoidosis.
• Treatment of pulmonary sarcoidosis with oral steroids for a period of
6-24 mths. Showed improvement in CXR findings.
• Pts. not Treatment with steroids had more chances of deterioration
compared with those receiving prednisolone.
• In one study, Israel HL et al (Am Rev Respir. Dis 1973 ; 107 : 609-614)
showed improvement in
CXR/symptoms/Lung functions in steroid group esp. in stage 2 & 3 but
not in 1.
• Results from these RCT confirm that stage I do not require Treatment
with OCS but those with ILD (stageII/III) may show radiologic
improvement.
48. APPROACH TO TREAT PULMONARY SARCOIDOSIS WITH CORTICOSTEROIDS
AC. PULMONARY SARCOIDOSIS :
• Present early.
• Symptoms of short duration.
CHRONIC PULMONARY SARCOIDOSIS :
• Symptoms persist > 2 yrs.
DECISION TO TREAT WITH CORTICOSTEROIDS : Patient Subgroup Decision
1. Asymptomatic Pts. -- No treatment
2. Mild Pulmonary Dysfunction -- Observation
3. Pts. With excellent prognosis --- Observation, Palliative therapy.
4. Mild-Mod. Pul. Dysfunction ----- Observation → Treat if Mild-Mod. & Functional Limitation
deteriorate, Treatment if no improvement after 6 mths.
5. Severe Pul. Dysfunction – Treatment if Severe Functional Limitation
• No long term benefit from corticosteroid therapy in asymptomatic
pts., regardless of CXR stage.
• Asymptomatic pts. with (n) PFT should not be treated because
of radiographic abnormality alone.
49. • Decision to taper based on stabilization or
improvement in symptoms/PFT.
• Sarcoidosis pts. with stable PFT should not have
their treatment plan adjusted on the basis of Lab.
evidence (S.ACE level, BAL cell count differentials, Ga
Scans) of ‘active disease’.
• Maintenance period : 6 mths. – 1 yr. → a/w few
relapses.
• Pulmonary symptoms and spirometry are most
useful parameters to monitor when deciding if
corticosteroid therapy should be reinstituted.
50. • > 20% relapse occur after > 1 yr. of steroid cessation while
10% relapse occur after 2 yrs.
• Observation period- post steroid cessation should be at
least 2 yrs.
• Relapse occur 20-50% of pts. in whom steroids are
stopped.
• Relapse : Re-institution of high dose steroids for 2-6 wks.
followed by tapering scheme.
• Some authors : ↑ Maintenance dose or ↑ Maintenance
period After Relapse
51. CHRONIC PULMONARY SARCOIDOSIS
• 3/4 of these pts. who require >5yrs. of steroids and relapse
when steroids are withdrawn.
• Almost all relapses occur within 1-2 mths. of withdrawal.
• Therefore OCS should be weaned very slowly with close
monitoring of symptoms, spirometry, CXR.
• Asymptomatic radiographic infiltrates, pul. Dysfunction
↓
Smaller steroid “bursts” may be used rather than higher
doses used for initial treatment.
52. • If pt. cannot be completely weaned off
↓
continue lowest maintenance dose.
• Corticosteroid dependence should not be considered
corticosteroid failure.
• Low dose steroids may be superior to alternative
therapies, or to no therapy.
53. Alternatives to corticosteriods and when should they be used :
1. Methotrexate :
Used in chronic sarcoidosis
Appears to take 6 mths. to become effective.
Initial dose – 10 mg/wk then 15 mg/wk (max dose) dose adjusted
based on neutropenia or nausea
CBC, Renal parameters monitored every 8 wks.
Folic acid 1 mg/day used for GI toxicity.
Toxicity : GI, stomatitis, Hepatotoxicity, Pulmonary, BM.
Efficacy : 60-80%.
54. 2. Anti-Malarial Agents :
Steroid sparing in RCT of Chr. Pul. Sarcoidosis
Chloroquin 500mg/day (~300 mg base drug), Hydroxychloroquin : 200-400 mg/day.
S/E: GI, Ocular toxicity (Eye exam. yearly)
Efficacy : 30-50%.
3. Azathioprine :
Efficacy : 50-80% (similar to methotrexate)
Usual dose : 50-200 mg/day.
Monitoring : CBC, LFT -- every 2 mths.
Toxicity : Nausea, Abd. Pain, Pancytopenia
Helps in improvement of Pul./extra-Pul. Disease.
Relapsed on drug withdrawal may be seen but may respond to re-institution therapy.
55. 4. Cyclophosphamide :
Used for refractory disease esp. neurological disease.
Dose : 50-150mg/day PO
S/E : BM depression, Nausea, Haemorrhagic cystitis, Bladder Cancer.
Efficacy : 80%.
5. Thalidomide :
Dose 100-200mg/day
S/E : sedation, constipation, Painless peripheral neuropathy
Precaution : Review monthly adherence to contraceptive programme.
6. Infliximab :
Anti-TNF Ab.
Dose : 5mg/kg
Frequency : Every 4-6 wks.
Toxicity : ↑ risk of infection.
Chronic/Refractory sarcoidosis - Use combination therapy (Monitor for ↑ toxicity)
56. EXTRA PULMONARY SARCOIDOSIS
CNS : 2-7% of sarcoidosis (with/without lung inv.) involves
Leptomeninges,Parenchyma,Perivascular involvement,Localised mass lesion (rare)
Diagnosis: (1) Gadolinium enhanced MRI (Best Technique) Enhancement of
leptomeninges, also used in F/U
(2) CSF and S.ACE - Non-specific.
Management:
1. Corticosteroids : 1 mg/kg
2. Other Drugs : Methotrexate/Anti-Malarials/ Cyclophosphamide/Azathioprine.
IV cyclophosphamide preferred for pts. with severe CNS sarcoidosis refractory to OCS
therapy.
Favorable response : Methotrexate 61% pts., Cyclophasphamide 90%pts.
Compared to OCS alone 29% pts.
57. CVS : Symptomatic inv. → 5%,,,Autopsy studies → 20-47%
Manifestations : Sudden death, CCF, Pericardial effusions,papillary muscle
dysfunction, chest pain.
Diagnosis: a) 12 lead ECG
b)2D Echo: Macroscopic areas of :bright echoes reflecting granulomatous
inflammation giving a speckled or “snowstorm pattern”
c) Tc Scan : Segmental areas of ↓ uptake at rest, Defects ↓ or disappear on stress
imaging (reverse distribution) - (Diff. Myocardial sarcoidosis from IHD)
d)Endomyocardial Bx : Controversial, Low diagnostic yield.
Treatment :
Corticosteroids (Response rates : 29-90%)
Recurrent dysrythmias & sudden death may occur despite antiarrhythmic agents,
may benefit from ICD.
Recurrent disease : Life long low dose steroids + Azathioprine/HCQ.
58. Cont. EXTRA PULMONARY SARCOIDOSIS
1. Usually directly requires immunosupp. Drugs.
2. CNS and CVS – high dose steroids 1mg/kg/day or methylpred pulses.
3. Asymptomatic Hypercalciuria/ Hypercalcemia req. Rx.
4. Asymptomatic increase SGOT/PT without abnormal liver functions –
no Rx.
5. Mild asypmtomatic skin lesions – no Rx.
6. Aymptoamtic L/N, spleenomegaly, Parotid swelling – no RX.
59. Take Home Message
1. Therapy need not be given to all pts.
2. Once initiated, usual dose is pred 40mg/day and duration
at least 1 yr. of t/t reqd.
3. High risk of chronic disease.
4. Monitoring if corticosteroids discontinued.
5. Steroid sparing agents useful for chronic pts.
