SarcoidosisSarcoidosisAt A GlanceAt A Glance

Presented by Presented by

Dr.Al-Hussain M. Assiri , MBBS , ArBIM Dr.Al-Hussain M. Assiri , MBBS , ArBIM

SSC-Med , JBIMSSC-Med , JBIM

Specialist in internal medicine Specialist in internal medicine &Rheumatology (ACH)&Rheumatology (ACH)

SARCOIDOSISSARCOIDOSISSarco = flesh; Eidos = like; Osis = conditionSarco = flesh; Eidos = like; Osis = conditionMultisystem disorder of unknown origin Multisystem disorder of unknown origin characterized by the accumulation of characterized by the accumulation of lymphocytes and mononuclear phagocytes lymphocytes and mononuclear phagocytes that induce the formation of noncaseating that induce the formation of noncaseating epithelioid granulomas with secondary epithelioid granulomas with secondary derangement of normal tissue or organ derangement of normal tissue or organ anatomy and function.anatomy and function.Acute sarcoid = less than 2 years.Acute sarcoid = less than 2 years.Chronic sarcoid = lasting longer than 2 years.Chronic sarcoid = lasting longer than 2 years.

Diagnosis is one of exclusionDiagnosis is one of exclusion::

Requires 3 criteria Requires 3 criteria 1)1)Compatible clinical or radiologic picture, Compatible clinical or radiologic picture,

or bothor both

2)2) histologic evidence of non-caseating histologic evidence of non-caseating granulomasgranulomas

3)3) Negative special stains and cultures for Negative special stains and cultures for acid-fast bacilli, fungi acid-fast bacilli, fungi and bacteria.and bacteria.

EpidemiologyEpidemiology►►Exact prevalence (estimated at 10 to 20 per Exact prevalence (estimated at 10 to 20 per

100,000 population) .100,000 population) .►► Annual incidence of sarcoidosis are not known with Annual incidence of sarcoidosis are not known with

certaintycertainty►► Incidence peaks in winter and early spring.Incidence peaks in winter and early spring.

Women greater incidence.Women greater incidence.

African ethnicity greater incidence.African ethnicity greater incidence.

More common in non-smokers.More common in non-smokers.

Immunology of SarcoidosisImmunology of Sarcoidosis

EtiologyEtiology

Speculative Speculative

Familial cases – positive association with HLA-1, -Familial cases – positive association with HLA-1, -B8, -B13, -DR3 and –B27.B8, -B13, -DR3 and –B27.

Rare autosomal dominant granulomatous syndrome Rare autosomal dominant granulomatous syndrome (Blau Syndrome – 16p12-q21) – lacks pulmonary (Blau Syndrome – 16p12-q21) – lacks pulmonary involvement.involvement.

High rate of detection of HHV-8 in sarcoid tissue.High rate of detection of HHV-8 in sarcoid tissue.

Unlikely mycobacterial (gets better with steroids; no Unlikely mycobacterial (gets better with steroids; no reduction with BCG; anti-tb meds ineffective).reduction with BCG; anti-tb meds ineffective).

Clay, talk, pine pollen, oxalosis, beryllium can cause Clay, talk, pine pollen, oxalosis, beryllium can cause similar picture.similar picture.

Clinical ManifestationsClinical Manifestations

Constitutional SymptomsConstitutional Symptoms

found in 33%found in 33%

fever, weight loss, fatiguefever, weight loss, fatigue

+/- night sweats+/- night sweats

LungsLungsFoud in >90%Foud in >90%

dyspnea, dry cough, chest pain (intensified after alcohol), dyspnea, dry cough, chest pain (intensified after alcohol), hemoptysis, asymptomatic.hemoptysis, asymptomatic.

4 Stages:4 Stages:

Stage 0: normalStage 0: normal

Stage I: bilateral hilar lymphadenopathy with right Stage I: bilateral hilar lymphadenopathy with right paratracheal adenopathy without pulmonary paratracheal adenopathy without pulmonary infiltrates.infiltrates.

Stage II: bilateral hilar lymphadenopathy with Stage II: bilateral hilar lymphadenopathy with pulmonary infiltrates.pulmonary infiltrates.

Stage III: pulmonary infiltrates without hilar Stage III: pulmonary infiltrates without hilar adenopathy.adenopathy.

Stage IV: end-stage fibrosis, bullae and honey-Stage IV: end-stage fibrosis, bullae and honey-combing.combing.

Sarcoid – Cutaneous manifestationsSarcoid – Cutaneous manifestations

• 25-37%25-37%• Often occuras at onset of disease.Often occuras at onset of disease.• Does not show correlation with extent of disease Does not show correlation with extent of disease

in general.in general.• Skin lesions – more likely to have Skin lesions – more likely to have

lymphadenopathy & hepatosplenomegaly than if lymphadenopathy & hepatosplenomegaly than if no skin lesions.no skin lesions.

• May portend prognosis.May portend prognosis.• Classified as:Classified as:

• Specific (lesions contain granulomas)Specific (lesions contain granulomas)• Non-specific (lesions are reactive processes and do notNon-specific (lesions are reactive processes and do not contain granulomas). contain granulomas).

Specific LesionsSpecific LesionsMaculopapular sarcoid Maculopapular sarcoid Nodular sarcoidNodular sarcoidPlaque sarcoid Plaque sarcoid Darier-Roussy Nodules (Subcutaneous)Darier-Roussy Nodules (Subcutaneous)Scar sarcoidScar sarcoidLupus pernioLupus pernioAcquired ichthyosisAcquired ichthyosisUlcerative sarcoidUlcerative sarcoidRare variants:Rare variants:

Psoriasiform, Hypopigmented, Verrucous, folliculitis, Psoriasiform, Hypopigmented, Verrucous, folliculitis, Eruptive, Lichenoid, Erythrodermic, Cicatricial Eruptive, Lichenoid, Erythrodermic, Cicatricial alopecia, Erythematous plaques of palms and soles, alopecia, Erythematous plaques of palms and soles, Nodular fingertip lesions, Unilateral lower extremity Nodular fingertip lesions, Unilateral lower extremity edema, granulomatous cheilitis, palmar erythema, edema, granulomatous cheilitis, palmar erythema, morpheaform, angiolupoid, perforating, lupus-morpheaform, angiolupoid, perforating, lupus-erythematosus-like, umbilicated, rosacea-like erythematosus-like, umbilicated, rosacea-like syndrome.syndrome.

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Non-specific Skin LesionsNon-specific Skin Lesions

Erythema nodosumErythema nodosumLofgren’s Syndrome: EN + bilateral hilar adenopathy +/- Lofgren’s Syndrome: EN + bilateral hilar adenopathy +/- migratory polyarthritis, fever and iritis. Good prognosis (83% migratory polyarthritis, fever and iritis. Good prognosis (83% remit in 2 years).remit in 2 years).

CalcificationsCalcificationsPrurigoPrurigoErythema multiformeErythema multiformeClubbingClubbingOnychodystrophy +/- underlying bone cystsOnychodystrophy +/- underlying bone cystsSubungual hyperkeratosis/onycholysis.Subungual hyperkeratosis/onycholysis.

OcularOcularFound in 22-50%Found in 22-50%

Granulomatous uveitis (anterior (80%)>posterior)Granulomatous uveitis (anterior (80%)>posterior)

Uveitis – acute or chronic (adhesions)Uveitis – acute or chronic (adhesions)

Keratoconjunctivitis, retinal hemorrhages, band Keratoconjunctivitis, retinal hemorrhages, band keratopathy, proptosis.keratopathy, proptosis.

Peripheral LymphadenopathyPeripheral LymphadenopathyFound in 75%Found in 75%

Cervical, axillary, epitrochlear and inguinalCervical, axillary, epitrochlear and inguinal

HeartHeartFound in 5% - conduction disturbances; MI; Found in 5% - conduction disturbances; MI; pericardial disease; sudden death & cor pericardial disease; sudden death & cor pulmonale.pulmonale.

LiverLiver20% hepatomegaly (autopsy granulomas 63-87%)20% hepatomegaly (autopsy granulomas 63-87%)

Usually asymptomaticUsually asymptomatic

SpleenSpleen15% splenomegaly; usually silent (50% on 15% splenomegaly; usually silent (50% on autopsy)autopsy)

KidneysKidneys

Found in 4-40%Found in 4-40%

From hypercalcemia/hypercalciuria; From hypercalcemia/hypercalciuria; granulomatous infiltration of the renal granulomatous infiltration of the renal parenchyma, glomerular disease or renal arteritis parenchyma, glomerular disease or renal arteritis secondary to granulomas.secondary to granulomas.

Salivary GlandsSalivary Glands

found in 6% parotidomegaly; subclinical 50% found in 6% parotidomegaly; subclinical 50% (but usually only with hilar adenopathy); sarcoidal (but usually only with hilar adenopathy); sarcoidal ranula; tongue, tonsils.ranula; tongue, tonsils.

Upper Respiratory TractUpper Respiratory Tract found in 5-20%found in 5-20%

Nasal granulomas.Nasal granulomas.

Laryngeal involvement 5%.Laryngeal involvement 5%.

MuscularMuscularProgressive proximal muscle weakness; myopathic Progressive proximal muscle weakness; myopathic pattern EMG, increased CpK.pattern EMG, increased CpK.

NeurologicalNeurological found in 5%found in 5%Mononeuritis multiplex, Guillian-Barre, pure motor, pure Mononeuritis multiplex, Guillian-Barre, pure motor, pure sensory polyneuropathies, meningitis, seizure, sensory polyneuropathies, meningitis, seizure, arachnoiditis, myasthenia gravis-like symptoms, arachnoiditis, myasthenia gravis-like symptoms, myelopathy.myelopathy.Uhthoff phenomenon reported (visual loss after Uhthoff phenomenon reported (visual loss after exposure to heat).exposure to heat).CNVII > but any cranial nerve.CNVII > but any cranial nerve.

EndocrineEndocrinePituitary & hypothalamus – diabetes,.Pituitary & hypothalamus – diabetes,.Multinodular goiter and hyperthyroidismMultinodular goiter and hyperthyroidismMay see elevated prolactin.May see elevated prolactin.Intermittent hypercalcemia – 17-19%.Intermittent hypercalcemia – 17-19%.

RheumatologicRheumatologic25-39% joint involvement; 2 forms – acute and chronic 25-39% joint involvement; 2 forms – acute and chronic (<6 months).(<6 months).May precede other manifestations by yearsMay precede other manifestations by yearsKnees > ankles > elbows > wrists > small joints of hands Knees > ankles > elbows > wrists > small joints of hands (typically 2-6 joints).(typically 2-6 joints).Periarticular swelling > effusionsPeriarticular swelling > effusionsSynovial fluid often non-inflammatorySynovial fluid often non-inflammatoryTenosynovitis and heel pain may occurTenosynovitis and heel pain may occurChronic: Chronic:

knees, PIPs (associated with chronic cutaneous sarcoid knees, PIPs (associated with chronic cutaneous sarcoid lesions).lesions).transient or chronictransient or chronicdactylitis.dactylitis.Cystic lytic lesions often noted in middle & distal phalanges Cystic lytic lesions often noted in middle & distal phalanges of hands; trabecular changes that give the bone a of hands; trabecular changes that give the bone a honeycomb appearance; always associated with chronic skin honeycomb appearance; always associated with chronic skin lesions. lesions.

Basic Sarcoidosis Work-upBasic Sarcoidosis Work-upHistory/PEHistory/PE

CBC, BUN, Cr, LFTs, electrolytes, Ca.CBC, BUN, Cr, LFTs, electrolytes, Ca.

UrinalysisUrinalysis

ACE levelsACE levels

CXRCXR

PFTs (spirometry, volumes, diffusion PFTs (spirometry, volumes, diffusion measurements)measurements)

Tuberculin test with anergy panel.Tuberculin test with anergy panel.

Ophthalmologic examination with both slit-lamp Ophthalmologic examination with both slit-lamp and fundus.and fundus.

Histology.Histology.

Laboratory ManifestationsLaboratory Manifestations CBCCBC

Anemia 5%Anemia 5%Leukopenia – reflects bone marrow involvement – Leukopenia – reflects bone marrow involvement – 28%28%Eosiniphilia 24-34%Eosiniphilia 24-34%

ESRESR 66%; Elevated haptoglobin 40%.66%; Elevated haptoglobin 40%.

HypercalcemiaHypercalcemia (increased intestinal Ca (increased intestinal Ca absorption due to production of (3H)1,25(OH)absorption due to production of (3H)1,25(OH)22DD33 – – 19%19%

ACEACE 60% (false + DM, alcoholic liver disease, 60% (false + DM, alcoholic liver disease, Hep C, tuberculosis, leprosy, lymphoma, Hep C, tuberculosis, leprosy, lymphoma, hyperthyroidism, Whipple’s, PBC, silicosis, hyperthyroidism, Whipple’s, PBC, silicosis, histoplasmosis, berylliosis, Gaucher’s); serum histoplasmosis, berylliosis, Gaucher’s); serum lysozyme, Blysozyme, B22-microglobulins.-microglobulins.

Cutaneous anergyCutaneous anergy 66% 66%

CD4:CD8CD4:CD8 – normal 1.8:1; low-activity sarcoid 1.4:1; – normal 1.8:1; low-activity sarcoid 1.4:1; high-intensity alveolitis 0.8:1.high-intensity alveolitis 0.8:1.

HypergammaglobulinemiaHypergammaglobulinemia 50% 50%

Bronchoalveolar lavageBronchoalveolar lavage – fluid lymphocyte count – fluid lymphocyte count >7% lymphocytes; CD4/CD8 >3.5.>7% lymphocytes; CD4/CD8 >3.5.

6767Gallium scanGallium scan may demonstrate panda or lambda may demonstrate panda or lambda signs (from parotid & lacrimal gland granuloma gallium signs (from parotid & lacrimal gland granuloma gallium uptake [panda] and bilateral hilar lymph node involvement uptake [panda] and bilateral hilar lymph node involvement [lambda]).[lambda]).

Kviem-Siltzbach testKviem-Siltzbach test (90% with hilar adenopathy). (90% with hilar adenopathy).

Prognosis of SarcoidosisPrognosis of SarcoidosisHighly variable, with a tendency to wax Highly variable, with a tendency to wax and wane, either spontaneously, or in and wane, either spontaneously, or in response to therapy response to therapy Spontaneous remissions occur in nearly Spontaneous remissions occur in nearly 2/3 of patients, but the course is chronic or 2/3 of patients, but the course is chronic or progressive in 10 to 30 % progressive in 10 to 30 % Serious extrapulmonary involvement (eg, Serious extrapulmonary involvement (eg, cardiac, central nervous system, hepatic) cardiac, central nervous system, hepatic) occurs in 4 to 7 % of patients with occurs in 4 to 7 % of patients with sarcoidosis at presentationsarcoidosis at presentationthe incidence is higher as the disease the incidence is higher as the disease evolves evolves

Adverse prognostic factorsAdverse prognostic factorsLupus pernio Lupus pernio Chronic uveitis Chronic uveitis Age at onset greater than 40 years Age at onset greater than 40 years Chronic hypercalcemia Chronic hypercalcemia Nephrocalcinosis Nephrocalcinosis Black race Black race Progressive pulmonary sarcoidosis Progressive pulmonary sarcoidosis Nasal mucosal involvement Nasal mucosal involvement Cystic bone lesions Cystic bone lesions Neurosarcoidosis Neurosarcoidosis Myocardial involvement Myocardial involvement Chronic respiratory insufficiency Chronic respiratory insufficiency

Sarcoidosis Syndromes:Sarcoidosis Syndromes:Lofgren’s SyndromeLofgren’s Syndrome

Hilar lymphadenopathy, erythema nodosum, migratory Hilar lymphadenopathy, erythema nodosum, migratory polyarthritis, fever, iritis.polyarthritis, fever, iritis.

Darier-Roussy TypeDarier-Roussy TypePresence of subcutaneous non-painful nodules.Presence of subcutaneous non-painful nodules.

Heerfordt-Waldenstrom SyndromeHeerfordt-Waldenstrom SyndromeFever, parotid enlargement, anterior uveitis, facial Fever, parotid enlargement, anterior uveitis, facial nerve palsy (can get lethargy, papilledema, nerve palsy (can get lethargy, papilledema, meningism)meningism)

Mikulicz’s SyndromeMikulicz’s SyndromeBilateral sarcoidosis of the parotid, submandibular, Bilateral sarcoidosis of the parotid, submandibular, sublingual and lacrimal glands.sublingual and lacrimal glands.

Sarcoidosis in pregnancySarcoidosis in pregnancySarcoidosis does not affect pregnancy Sarcoidosis does not affect pregnancy adversely, but the disease may worsen adversely, but the disease may worsen after parturition; therefore, a chest after parturition; therefore, a chest roentgenogram should be obtained within roentgenogram should be obtained within 6 months of delivery. 6 months of delivery.

The incidence of spontaneous abortion, The incidence of spontaneous abortion, miscarriage, and congenital fetal miscarriage, and congenital fetal abnormalities for patients with sarcoidosis abnormalities for patients with sarcoidosis is no different from that found in mothers is no different from that found in mothers without sarcoidosis .without sarcoidosis .

TreatmentTreatment►► 60% experience spontaneous resolution (83% with 60% experience spontaneous resolution (83% with

acute). acute).

►► An additional 10-20% have resolution with steroids. An additional 10-20% have resolution with steroids.

Major goalMajor goal: : prevent fibrosisprevent fibrosis..

Steroids first lineSteroids first line::– Help prevent fibrosis.Help prevent fibrosis.

Scarring cutaneous lesionsScarring cutaneous lesionsHypercalcemiaHypercalcemiaSevere lung diseaseSevere lung diseaseLiver diseaseLiver diseaseCardiac inflammationCardiac inflammationPosterior uveitisPosterior uveitisNeurosarcoidosisNeurosarcoidosisSevere sarcoidosis of other organsSevere sarcoidosis of other organs

ATS GuidelinesATS Guidelines

Prednisolone 20-40 mg daily Max, 60 mgPrednisolone 20-40 mg daily Max, 60 mg

For 8-12 weeks then taper down to keep For 8-12 weeks then taper down to keep patient on 5-10 mg and contiue for 1 yearpatient on 5-10 mg and contiue for 1 year

Rheumatology GuidelinesRheumatology Guidelines

Prednisone 0.5 mg/kg/day; single Prednisone 0.5 mg/kg/day; single daily dose, tapered by 5 mg q2 weeks daily dose, tapered by 5 mg q2 weeks until at 0.15 mg/kg/day, maintained for until at 0.15 mg/kg/day, maintained for 4-8 months, then tapered off 4-8 months, then tapered off completely. Follow PFTs.completely. Follow PFTs.

Steroid sparing: Methotrexate.Steroid sparing: Methotrexate.

Arthritis: colchicine, salicylates.Arthritis: colchicine, salicylates.

Dermatology Guidelines:Dermatology Guidelines: Systemic SarcoidosisSystemic Sarcoidosis::

Prednisone 1 mg/kg/d x 4-6 weeks followed by a slow taper over 2-3 Prednisone 1 mg/kg/d x 4-6 weeks followed by a slow taper over 2-3 months.months.Hydroxychloroquine 2-3 mg/kg/day x 12 weeks (30-50% success).Hydroxychloroquine 2-3 mg/kg/day x 12 weeks (30-50% success).MTX 15 mg/week in 3 divided doses at 12 hour intervals x 9-11 months MTX 15 mg/week in 3 divided doses at 12 hour intervals x 9-11 months (94% success).(94% success).Thalidomide (TNF blocker)Thalidomide (TNF blocker)Infliximab (Ab against TNF-Infliximab (Ab against TNF-άά); Etanercept (receptor for TNF).); Etanercept (receptor for TNF).

Cutaneous SarcoidosisCutaneous Sarcoidosis::Superpotent topical corticosteroids (+/- occlusion).Superpotent topical corticosteroids (+/- occlusion).Intralesional triamcinolone qmonthlyIntralesional triamcinolone qmonthlyIntralesional chloroquine (50 mg/mL monthly)Intralesional chloroquine (50 mg/mL monthly)Minocycline 200 mg qd; doxycycline 100 mg bidMinocycline 200 mg qd; doxycycline 100 mg bidCarbon dioxide laserCarbon dioxide laserPulse dye laserPulse dye laserAllopurinol 100-300 mg qd for 4 weeksAllopurinol 100-300 mg qd for 4 weeksThalidomide 200 mg/d x 2 weeks followed by 100 mg/d x 11 weeks, then Thalidomide 200 mg/d x 2 weeks followed by 100 mg/d x 11 weeks, then 100 mg every other day.100 mg every other day.PUVAPUVAOral isotretinoin 1 mg/kg/day x 8 months.Oral isotretinoin 1 mg/kg/day x 8 months.Systemic steroids, hydroxychloroquine, MTX.Systemic steroids, hydroxychloroquine, MTX.