a summary on sacrcoidosis and IgG4 diseases

1. SARCOIDOSIS AND IgG4
RELATED DISEASES
-Harrison's Principles of Internal Medicine, 19E

2. INTRODUCTION
An inflammatory disease characterized by the presence of
noncaseating granulomas.
Multisystem disorder
Requires the presence of involvement in two or more organs for a
specific diagnosis
granulomas are not specific for sarcoidosis and other conditions known
to cause granulomas must be ruled out.
Other organs commonly affected are the Liver,Skin& Eye

3. ETIOLOGY
Largely Unknown
Most likely etiology is an infectious/noninfectious environmental agent
that triggers an inflammatory response in a genetically susceptible host
Studies shown much higher incidence of Propionibacter acnes in lymph
nodes of sarcoidosis patients compared to controls
Presence of a mycobacterial protein(Mycobacterium tuberculosis catalase-
peroxidase [mKatG]) in the granulomas of some sarcoidosis patients.
Also sarcoidosis in a donor organ has occurred after transplantation into a
sarcoidosis patient.
These studies have supported the hypothesis that a genetically susceptible
host is a key factor in the disease

4. INCIDENCE AND PREVALENCE
Often occurs in young, otherwise healthy adults.
One-half of the patients were ≥40 years at the time of diagnosis
Although most cases of sarcoidosis are sporadic, a familial form of the
disease exists.Atleast 5% of patients with sarcoidosis will have a family
member with sarcoidosis.
Sarcoidosis patients who are Irish or African-American seem to have a
2/3 times higher rate of familial disease.

5. GENETICS AND PATHOPHYSIOLOGY
Haplotypes such as HLA-DRB1*1101-associated with an increased risk for
developing sarcoidosis
Granuloma is the pathologic hallmark of sarcoidosis-local accumulation of
inflammatory cells.
Extensive studies in the lung using BronchoAlveolarLavage(BAL) have
demonstrated inflammatory response is an influx of T helper cells,In
addition to accumulation of activated monocytes.
The Macrophage/Helper T cell cluster leads to activation with the increased
release of several cytokines.These include Interleukin(IL)-2 released from T-
cell and Interferon-γ& Tumor Necrosis Factor (TNF) released by the
macrophage.The T cell is a necessary part of the initial inflammatory
response.Untreated HIV patients who lack Helper T cells rarely develop
sarcoidosis.

6. GENETICS AND PATHOPHYSIOLOGY
Different HLA haplotypesare associated with different clinical
outcomes.
One form of the disease Löfgren’s syndrome, consists of erythema
nodosum & Hilar Adenopathy on chest roentgenogram.Recent studies
have demonstrated that the HLA-DRB1*03 was found in 2/3rds of
Scandinavian patients with Löfgren’s syndrome. >95% of those patients
who were HLA-DRB1*03 positive had resolution of their disease within
2 years.

7. CLINICAL MANIFESTATIONS
20–30% of pulmonary cases are detected in asymptomatic individuals
Respiratory complaints including cough & dyspneaare the most
common presenting symptoms.Symptoms related to cutaneous &
ocular disease are the next two most common complaints

8. ORGAN INVOLVEMENT-LUNG
LUNG
Involved in >90% cases
The most commonly used method for
detecting lung disease is still the chest
Roentgenogram.
Although the CT scan has changed the
diagnostic approach to interstitial lung
disease,CT scan is not usually considereda
monitoring tool for patients with sarcoidosis
Characteristic CT features-peribronchial
thickening & reticulonodular changes-
predominantly subpleural

9. ORGAN INVOLVEMENT -LUNG
Strong predilection for the
Upper Lung
Scadding's Classification
Stage 0=normal
Stage 1=Hilar LDN alone
Stage 2=Hilar LDN+parenchymal
infiltrates
Stage 3=Parenchymal infiltrates alone
Stage 4=Pulmonary fibrosis

10. ORGAN INVOLVEMENT-LUNG
DLCO is the most sensitive test for an interstitial lung disease
50% of sarcoidosis patients present with obstructive disease, reflected
by a reduced ratio of forced vital capacity expired in 1 second
(FEV1/FVC).
Airway hyperreactivity,as determined by methacholine challenge,will
be positive in some of these patients
Pulmonary arterial hypertension(PAH) is reported in atleast 5% of
sarcoidosis patients.Either direct vascular involvement or the
consequence of fibrotic changes in the lung can lead to pulmonary
arterial hypertension.

11. ORGAN INVOLVEMENT-LUNG
The DD of upper lobe disease
INFECTIOUS NON INFECTIOUS
Tuberculosis Hypersensitivity pneumonitis
Pneumocystis pneumonia silicosis
Langerhans cell histiocytosis

12. ORGAN INVOLVEMENT
SKIN
Seen in 1/3rd of Patients
A specific complex of
involvement of
the bridge of the nose,
the area beneath the eyes and
the cheeks is referred to as
lupus pernio
and is diagnostic for a chronic form of sarcoidosis.

13. ORGAN INVOLVEMENT- SKIN
Classic cutaneous lesions include
Erythema Nodosum- transient rash, more common in women
Maculopapular lesions-Painless,indurated,Most commonly seen in Chronic
form of disease
hyper-and hypopigmentation,
keloid formation &
Subcutaneous nodules
Skin Biopsy confirms the diagnosis by establishing non caseating granuloma

14. ORGAN INVOLVEMENT- EYE
The most common manifestation is an anterior uveitis,
Over 25% of patients will have inflammation at the posterior part of
the eye, including retinitis and pars planitis.
Symptoms-photophobia,blurred vision and increased tearing-leading
on to dry eyes
Therefore it is recommended that all patients with sarcoidosis receivea
dedicated ophthalmologic examination.

15. ORGAN INVOLVEMENT- LIVER
Biopsy- >50% diagnosis
LFT-20-30% diagnosed with liver involvement
Most common abnormality noticed in LFT is elevated alkaline
phosphatase which is consistent with obstructive pattern
Symptoms predominantly due to Hepatomegaly,Portal Hypertension
secondary to intrahepatic cholestasis and subsequent fibrosis
These patients rarely may require Liver transplant

16. ORGAN INVOLVEMENT- SPLEEN & BM
BM Examination will reveal Granuloma in 33% of patients
Anemia-20%
Lymphopenia-Relatively Specific due
to sequestration of lymphocytes in
the areas of inflammation
Spleenomegaly-10% of patients
Indications for splenectomy
1.Massive splenomegaly,
2.Profound pancytopenia

17. ORGAN INVOLVEMENT- KIDNEY
Relatively rare-<5% of patients
Granuloma of Kidney
Can lead to ARF secondary to Hypercalcemia
Therapy with steroids to control inflammation and treatment of
hypercalcemia improves the renal failure

18. ORGAN INVOLVEMENT- NERVOUS SYSTEM
Any part of the CNS/PNS can be involved
Most common involvements are
Cranial nerve involvement,basilar meningitis,myelopathy &
hypothalamic disease with associated diabetes insipidus
Cranial Nerve involvement-2nd,7th
Optic neuritis-Requires long term therapy needs to be differentiated
from Multiple Sclerosis
Granulomatous inflammation isoften visible on MRI studies
CSF findings include lymphocytic meningitis with amild increase in
protein,CSF glucose Normal

19. ORGAN INVOLVEMENT- HEART
Pathology-Diffuse Granulomatous infiltration of Heart
Clinical Manifestation-CHF,Arrythmias
LVEF can be as low as 10% even then Systemic steroid therapy alone can
cause significant improvement without other measures
Ventricular arrhythmias and sudden death due to ventricular tachycardia
are common causes of death-best detected using 24-h ambulatory
monitoring
Ventricular arrhythmias are usually multifocal due to patchy multiple
granulomas in the heart, ablation therapy is not useful
Implanted defibrillator have reduced the rate ofdeath in cardiac sarcoidosis
Confirmation is with MRI/PET Scanning

20. ORGAN INVOLVEMENT- MUSKULOSKELETAL
Granulomas in Bone and Muscle
Confirmation by tissue biopsy
Myalgia and Arthralgia

21. CALCIUM METABOLISM
Hypercalcemia and/or hypercalciuria occurs in 10% of patients.
Mechanism of abnormal calcium metabolism is increased production
of 1,25-dihydroxyvitamin D by the granuloma
Increased exogenous vitamin D from diet or sunlight exposure may
exacerbate Hypercalcemia

22. LABORATORY EVALUATION
Most common- CXR
CT Scan-Adenopathy >2cms in the short axis supportive of Diagnosis of
Sarcoidosis over the ILD
PET Scan to identify areas of increased granulomatous activity and aid
in planning biopsies
Serum ACE levels-level more than 50% of upper limit of Normal seen in
1.sarcoidosis,2.Leprosy,3.Gaucher’s disease,4.hyperthyroidism and
5.disseminated granulomatous infections such as miliary tuberculosis

23. DIAGNOSTIC APPROACH

24. TREATMENT-ACUTE PHASE

25. TREATMENT-CHRONIC PHASE

26. DRUG REGIMENS

27. PROGNOSIS
The risk of death or loss of organ function remains low insarcoidosis
many patients resolve their disease within 2–5 years
However, there is a form of the disease that does not resolve within
the first 2–5 years.
These chronic patients can be identified at presentation by certain risk
factors at presentation such as
fibrosis on chest roentgenogram,
presence of lupus pernio, bone cysts, cardiac or neurologic disease
(except isolated seventh nerve paralysis)
and presence of renal calculi due to hypercalciuria.

28. IgG4 RELATED DISORDERS

29. INTRODUCTION
Fibroinflammatory condition characterized by a tendency to form
tumefactive lesions
virtually every organ system affected
Brain parenchyma,joints,Bone marrow, and the bowel mucosa only
rarely (if ever).

31. MOLECULAR PATHOGENESIS

32. MOLECULAR PATHOGENESIS

33. MOLECULAR PATHOGENESIS

34. MOLECULAR PATHOGENESIS

35. MOLECULAR PATHOGENESIS

37. TREATMENT
NOT ALL MANIFESTATIONS OF IgG4 RD WARRANT TREATMENT
Prevention of fibrosis and its potentially destructive impact on organs
Spontaneous remissions or temporary remissions without treatment
have been reported
Treatment is therefore justified in most cases in which laboratory
evidence or radiology studies suggest organ dysfunction

38. TREATMENT
Multiple approaches have been reported,
• Systemic glucocorticoid
• “Steroid-sparing” immunosuppressive drugs
• Biologic agents
• Surgical resection of affected tissues
But no randomized clinical trials or formal treatment guidelines exist

39. TREATMENT

40. TREATMENT