kuliah reumatologi

5/24/2018 kuliah REUMATOLOGI

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Prof. Dr.dr. H. Zainal Arifin Adnan, SpPD-KR

Divisi Reumatologi Departemen Ilmu Penyakit Dalam

FK UNS/RSUD dr. Moewardi

Surakarta


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PENYAKIT REUMATIK

Reumatik jaringan lunak

Osteoartritis

Penyakit sendi metabolik

Penyakit autoimun sistemik Kondisi emergensi reumatik

REUMATIK JARINGAN LUNAK

Tendonitis

Bursitis

Nyeri Myofascial


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SYSTEMIC RHEUMATICAUTOIMMUNE DISEASES

Viral athritis

Reiters syndrome

Psoriatic arthritis

Rheumatic fever

Henoch-Schonlein purpura

Systemic lupus erythematosus

Other vasculitides and CTDs


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SERIOUS RHEUMATIC DISORDERS

Examples : infection, malignancy, vasculities

WARNING SIGNS OF A SERIOUS RHEUMATICDISEASE

- Persistent, worsening pains

- Pains unrelieved by NSAIDs or analgesics

- Nerve pains, vascular pains, bone pain- Accompanying fever, weight loss, pallor etc.

- Elderly


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LABORATORY SERIOUSRHEUMATIC DISORDER

Anemia, thrombocytopenia, leucocytosis,

leucopenia

Elevated ESR (corrected for age and anemia)

Active urine sediment

Abnormal radiographs e.g. pulmonary mass,

lytic/blastic lesions on skeletal x-rays Others: elevated alkaline phosphatase, acid

phosphatase, creatinine


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ARTRITIS GOUT

Disebut juga artritis pirai

Akibat deposisi krital monosodium urat metab purin

Akut atau kronis berulang-ulang tidak

tergantung kadar as.urat dlm darah Tofus timbunan dalam jaringan sendi, tulang jaringan

lunak

Nefropati gout timbunan dalam ginjal batu

Makin tinggi sosek. insiden meningkat

Prefalensi laki-laki jauh lebih tinggi dp.wanita

(menopouse)


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GAMBARAN KLINIS

Sering bersama obesitas, DM, hipertensi, aterosklerosis,

alkoholisme, dislipidemi.

4 stadium :

1. Hiperurisemi asimtomatik : pria, defek enzim sejak lahir2. Artritis gout akut : sangat nyeri biasanya malam hari,

tanda radang (+), 60% pd MTP-1, sembuh sendiri stlh 10 hr

3. Gout interkritikal : interval 2 serangan akut, biasanya

banyak sendi, lebih berat, lebih lama, demam.

4. Artritis gout kronik bertofus : mederita lebih 11 th,

as.urat tinggi, batu ginjal, tanda radang sendi (+)


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TOFUS

Timbunan kristal monosodium urat

As.urat < 9,1 mg/dl tofus (-)

As.urat 10-11 mg/dl tofus minimal

As.urat > 11 mg/dl multiple tofus

Timbunan as.urat pd rawan sendi, sinofial,

tendo, kapsul sendi

Timbunan as.urat diluar sendi: miokard, katub

mitral, sistem konduksi jantung, mata, laring.


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KOMPLIKASI Distruksi sendi

Nefropati :

1. Kristal MSU dlm jar.interstisial ginjal lbh 1/3 kasus

hipertensi, protein urin, gagal ginjal.

biasanya kadar > 13 mg/dl

2. Nefropati akibat peningkatan ekskresi oleh ginjal

batu ginjal gagal ginjal (kadar > 20 mg/dl),

oligouri, anuria,

Defisiensi enzim HGPRT (Hipoxantine Guanin PhosphoribosilTransferase) produksi as.urat tinggi

Batu as.urat : 1025% pnd gout 1000 kali

Meningkat 50% pnd gout kadar as.urat > 13 mg/dl, atau

dalam urin > 1100 mg/dl


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DIAGNOSIS Menurut kriteria ACR (1977) :

a. Kristal MSU (+) dlm sendi

b. Tofus (+)

c. didptkan 6 dari 12 kriteria :

1. Radang dihari pertama

2. Serangan akut lebih 1 kali

3. Mono artritis4. Sendi berwarna merah

5. Bengkak pd MTP-1

6. Serangan pd MTP unilateral

7. Serangan pd Tarsal unilateral8. Tofus

9. Hiperurisemi

10. Gambaran radiologi (+) bengkak sendi

11. Gambaran radiologi (+) kista subkortikal tanpa erosi

12. Kultur bakteri c. sendi (-)


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PEMERIKSAAN PENUNJANG

1. LED dan CRB

2. C. sendi, jml leukosit atr. 20.000-100.000 /ml

3. C. sendi

kristal MSU (+)4. As.urat dara dan urin 24 jm : 750-1.000 mg/24 jm

5. Ureum, kreatinin, CCT gangguan ginjal

6. Radiologi sendi

7. Pemeriksaan pnykt yg mendasari


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FAKTOR RESIKO

Hiper urisemi

Obesitas

Genetik

Alkoholism

Asupan purin berlebih

Dislipidemia

Hipertensi

Obat-obatan

Berobat tdk teratur

Gangguan fungsi ginjal

Gangguan fungsi tiroid

Gangguan metabolisme

Toksemia gravidaru

hipoksemia


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PENGELOLAAN

Tujuan menghilangkan rasa sakit, mencegah seranganulang, mencegah kerusakan sendi dan tofi, mencegahgangguan fungsi ginjal

1. Non farmakologis :

edukasi, meningkatkan aktivitas, menurunkan berat

badan, diet rendah purin, hidup manfaat.

2. Farmakologis :

a. Fase akut1. Colchicine

2. NSAID

3. Steroid


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b. Fase Kronis

1. diet rendah purin

2. koreksi hiperurisemia dan faktor resiko

3. obat penghambat xantin oksidase (alopurinol) - gangguan fungsi ginjal

- hipersensitive thd urikosurik

- batu ginjal (+)

- tofus yg besar

- hiperurisemia sekunder


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c. Profilaksis fase interkritikal :

- mengurangi frekuensi serangan tergantung penyebab

- penurunan BB

- penurunan kadar lipid- menghindari alkohol

- hindari obat2 yg menigkatkn as.urat

- vol.urin > 1 ml/mnt

- diet rendah purin


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3. Terapi rehabilitasi medik :

mencegah/mengurangi beratnya cacat sendi

4. Terapi bedah, mengoreksi cacat sendi

5. Terapi komplemen :

- perbanyak buah2an

- akupuntur

- obat herbal


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PENDAHULUAN

OA :

- Misteri ?

- Penyebab ?

- Patogenesis ?

- Pengobatan ?

- Pencegahan ?

SEL :

Aksi : - dari luar sel

- dari dalam sel

Respon : 1 a. Membran selb. Sitosol / dan Organelanya

2 a. Homeostasis

b. Apoptosis / dan Nekrosis

PERHATIKAN : GALS (Gait-Arms-Legs-Spin)


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Definisi OA :

Kelainan tulang rawan sendi, yang ditandai

dengan perubahan morfologi, biokimia,biomolekuler dan biosintesis pada sel dan

substansi dasar, sehingga mengalami proses

fibrilasi, keradangan dan perubahan komposisi

tulang rawan, sklerosis dan kerusakan tulang subkondral, serta munculnya osteofit.

OSTEOARTRITIS


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Fungsi sintesis dan degradasi ECM

Homeostasis rawan sendi

StimulusApoptosis ? Nekrosis ?

KONDROSIT


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IL-1, TNF- IL-1 +b-FGF or PDGF

(IL-1 effect enhanced)

Glucocorticoids (therapeutic levels) IL-1, IL-1 + PDGF (IL-1 effect inhibited) TNF- -interferon Retinoids

IL-1 + -interferon (IL-1 effectinhibited)

Glucocorticoids (therapeuticlevels)

IL-1 + TGF- or IGF-1 or -interferon (IL-1 effect inhibited)

IL-6 (TIMP increased)

TGF- (TIMP increased)

TGF- IGF-1 bFGF PDGF


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Struktur lapisan rawan sendi yang mengalami OA dengan tampilan kondrosit dan matriks ekstra sel.(Dikutip dari A. Robin Poole and David S. Howel, 2001)


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PATOGENESIS OA

1 Kondrosit MMP gangguan ECM

2 Produk kerusakan rawan sendi inflamasi

rusak

3 Enzymatic jar.sendiproinflamasi

- protease

- sitokin


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ETIOPATOGENESIS

Gambaran sendi dengan perbandingan normal dan kasus OA yang telah berlangsung

beberapa tahun (Dikutip dari Poole AR, 1995)


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Perubahan yang diamati pada tulang rawan dan tulang dalam OA dan hubunganya dengan faktor yangmelindungi dari akselerasi atau yang berhubungan dengan proses terjadinya OA. (A. Robin Poole, 2001).


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THE DEVELOPMENT OF OSTEOARTHRITIS


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Biomekanik Biokimia

Abnormalsendi

Sendi infeksi

Rusak

RemodelingNormal Gagal OA


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OSTEOARTRITIS

1. Sendi abnormal gg. fungsi sus. kalogen

tergg.

2. Sendi normal gagal dalam respon fungsi

rawan sendi rusak


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RANGSANG

TNF-

PERAN TNF- DAN IL-1 DALAM KERADANGANDAN DESTRUKSI RAWAN SENDI

IL-1

Inflamasi sinovial Distruksirawan sendi

ECM tergangguOA


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Etiopatogenesis OA

Teori : keradangan, degenerasi, maupun infeksi OA

Beberapa sitokin maupun hormon pertumbuhan

berperan pada kejadian OA

Masih diperlukan penelitian yang sangat luas untuk

mengungkap misteri OA

KESIMPULAN


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DIAGNOSIS OA

Gejala :

Nyeri dan kaku sendi

Gangguan fungsi, krepitus

Bentuk sendi berubah

Tanda :

Keterbatasan dan nyeri gerak

Krepitus, nyeri tekan, tanda radang (+)

Tulang menonjol dan bengkak

Deformitas, instabilitas, pincang

Kelemahan otot/atrofi otot


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LANGKAH KRITERIA DIAGNOSIS

Klinis :

1. Nyeri sendi sudah beberapa waktu

2. Krepitus saat gerak

3. Kaku sendi kurang 30 menit4. Pembesaran tlg. Sendi

5. Umur diatas 35 th

Diagnosis OA jika :

Butir 1,2,3/dan 4 atau 1,2,4/dan 1 dan 5

Sensitifitas 89%, spesifisitas 88%


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KLINIS, LAB DAN RADIOLOGIS

1. Nyeri sendi

2. Osteofit

3. Cairan senofial (+) OA

4. Umur > 40 th

5. Kaku sendi pagi < 30 menit

6. Repitus sendi pd gerakan

Diagnosis OA jika :

Butir 1 dan 2 / butir 1,3,5,6 atau 1,4,5 dan 6

Sensitifitas 94%, spesifisitas 88%

(Altman R. et al. 1986)


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KLINIS OA TANGAN

1. Nyeri tangan, ngilu, kaku sendi-sendi

2. Bengkak sendi >2 diantara 10 sendi tangan

3. Bengkak MCP < 3

4. Bengkak sendi > 2 DIP5. Deformitas > 2 diantara 10 sendi tangan

6. Diagnose OA jika : butir 1,2,3,4 atau 1,2,3,5

Sensitifitas 92%, spesifitas 98%

10 sendi adl: DIP-2 dan 3, PIP-2 dan 3, CMC-1



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DIAGNOSIS OA PINGGUL

1. Nyeri sendi coxa

2. Osteofit femoral/dan asetabular

3. LED < 20 mm/jam

4. Diagnosis OA jika 1,2 atau 1,3,4

sensitifitas 91%, spesifisitas 89%



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PENYULIT OA VERTEBRA

Malaligment :

- Instabilitas segmental

- Spondilolistesis

-

Spondilolisis- Kifosis senilis

Intervertebral disk displacement

- Annular bulge, Prolapsus diskus, ekstrusi diskus dansekwestrasi diskus

- Stenosis kanalis spinalis neuropati kompresi

G O O


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PENGELOLAAN OAPerhatikan

- lamanya, lokasi, dan jumlah sendi

- Sejak kapan, eksaserbasi, atau remisi

- Pengobatan sebelumnya, perkembangan dan efeknya- Pengobatan alternatif, efek sampingnya

- Injeksi intra artikuler, tindakan bedah, artroskopi

- Penggunaan tongkat, deker, korset, dll

- Riwayat tukak peptik, prdhn.lambg, PJK, dll

Saat ini diobati apa?


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TUJUAN PENGOBATAN

1. Menghilangkan nyeri dan radang

2. Mengoptimalkan fungsi

3. Menghambat progresifitas4. Mencegah komplikasi

5. Mengurangi ketergantungan denganmeningkatkan kualitas hidup


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PILAR PENGOBATAN

Non farmakologis :- Merubah pola hidup, edukasi

- Modifikasi aktifitas, menurunkan berat badan

- Alat bantu, rehabilitasi medik

Farmakologis :

- Sistemik : analgetik, NSAIDs

- Lokal : analgetik, steroid, hyaluronan, injeksi

intera artikular

Terapi operasi : osteotomi, debridemen, fusisendi,artropasti


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Tendonitis

Your son just spent two weeks paintinghis house. Now, his shoulders hurt

whenever he reaches overhead, even toput on a shirt. He has never had anyshoulder pain before and his other jointsare fine.


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Tendonitis

Diagnosis = shoulder tendonitis.Tendonitis = inflammation of a tendon. A

tendon is a tissue cord that holds amuscle onto a bone.

Treatments

reduce/stop doing whatever caused it non-steroidal anti-inflammatory agents

steroid injections

physical therapysplinting, heat, ice


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Bursitis

Bursitis = inflammation of a bursa. A bursais a sac that lays over bony projections, to

reduce friction as tissue rubs over thebone.

Common sites of bursitis

outer shoulder areaouter hip area

elbow

over and below the knee cap


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AR : peny.autoimun sinovitis erosif simetris

Sifat : kronis, fluktuatif kerusakan sendi, progresif

cacat sendi, kadang kematian

Diagnosis berdasar kriteria ACR 1987

Variasi klinis dlm tanda (ireversibel) dan gejala (reversible)

Staging peny., prognosis dan terapi lambat dan cacat


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FAKTOR RESIKO AR

AR Peny.multifaktor : genetik, lingk., host, hormonal.

Tanda-tanda peny.multifaktor :

1. Pengaruh bnyk faktor genetik, lingk.

2. Fenotipik heterogen variasi klinis

3. Poligenik dipengaruhi bnyk gena

4. Genetik heterogen bnyk gen mcm fenotipe

5. Variasi onset peny. usia muda / tua


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IMUNO PATHOGENESIS AR

Fase inisiasi, tergantung :

- sel - sel B

- Monosit - sinoviosit

- Makrofag - molekul adesi- Sitokin

Fase perpetuasi (kronis) :

- stad.spreading- organogenesis limfoid

- erosi sendi


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PERAN RF dalam PATOGENESIS AR

1. Peningkatan RF AR aktif dan berat2. Produksi RF dalam sinovia

3. RF konstituan utama kompleks imun AR

4. RF jar.inflamasi

5. RF dlm AR asimtomatik resiko tinggi AR

- Antibodi lain pd RA

1. ANA (anti nuclear antibodies)

2. ANCA (anti nuclear cytoplasmic antibodies)3. Otoantibodi thd epitopsitrolin

4. Otoantibodi thd HSP 73

5. Otoantibodi thd E.coli dnaJ

6. Otoantibodi thd kartilago


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Kontrol toleransi otoantigen


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MANIFESTASI KLINIS

Radang sinovium AR aktif, kdg efusi (+)

Kaku sendi pagi hari, kdg tdk jelas

Kerusakan struktur rawan sendi, kdg keluar sendi

Deformitas sendi ok sinofitis berat

nyeri

gerak

kontraktur sendi

Tendo, ligamen, jar.sinovia radang luksasi sendi

Perjalanan klinis :

1. monosiklik kambuh & sembuh (20%)2. polisiklik intermiten & kontinyu (70%)

3. progresif bnyk sendi & kontinyu (10%)


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MANIFESTASI EKSTRA ARTIKULER

Kulit nodule reumatoid ok vaskulitis

Mata keratokonjungtivitis sikka (Sjogrens)

Sal.nafas disfonia, fibrosis paru

Jantung

efusi perikardial, perikarditis

chest pain Sal.cerna serostomia (Sjogrens), iskemik usus

Ginjal biasanya efek samping terapi

Saraf instabilitas vertebra, gg. saraf tepi, mononeuritis

/ multi Darah an. mikrositik hipokromik ok prdrhn kronis GIT


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DIAGNOSIS AR

Dasar : American College of Rheumatology (ACR)

1. Kaku sendi pagi hr lbh 1 jm

2. Artritis > 314 sendi, PIP, MCP, wrist, siku, lutut,angkel, MTP simetris

3. Artritis : PIP, MCM, wrist

4. Artritis simetris

5. Nodul reumatoid

6. FR serum (+)7. Radiologis perubahan (+), erosi, dekalsifikasi

AR (+) : > 47 kriteria, selama lbh 6 mgg.


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LABORATORIUM AR

RF 85% (+) prognosis buruk LED meningkat

CRP (+)

Hipergamaglobulinemia, hipokomplemenemia

Trombositosis, eosinofilia

Gambaran perubahan radiologi

OP periartikular erosi marginal

Radang periartikular permuk snd rusak Penyempitan ruang sendi sub/dis lokasi snd OA sekunder, osteofit fusi snd std lanjut


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PILAR PENGELOLAAN AR

1. Edukasi

2. Terapi non farmakologi latihan/prgm. rehabilitasi

3. Terapi farmakologis : DEMARDs, OAINS, kort.steroid

4. Pembedahan

5. Lain-lain : sinovectomy tanpa op, transplantasi ss.tl

6. Pengelolaan khusus : AR pd kehamilan, AR refrakter

DEMARDs (DISEASES MODIFYING


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DEMARDs (DISEASES MODIFYINGANTI RHEUMATIC DRUGS)

Mengurangi/mencegah kerusakan sendi

Metroteksat (MTX), sulfasalazin, leflunomide,

hidroksiklorokuin, siklosporin, azatioprin, DPenicillamin, garam emas.

Anti TNF-(etanercept, infliximab)

Sifat slow actingstlh 16 bln

Monitor toksisitas tunggal/kombinasi


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KRITERIA REMISI AR (ACR 1987)

1. Kaku sendi pagi hr < 15 mnt

2. Kelelahan (-)

3. Nyeri sendi (-)4. Nyeri tekan / gerak (-)

5. Bengkak sendi (-)

6. LED pria < 20 mm/jm, LED wnt < 30 mm/jm

Remisi bila minimal 5 kriteria dlm > 2 bln


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ISTILAH PENTING PENGOBATAN AR

1. AR dingin kurang 1 th

2. Terapi agresif AR DEMARDs segera, kp kombinasi

3. Skor prgsfts nilai diseases activity score(DAS) 28

yaitu DAS 28 = 0.56 TJC + 0.70 ln ESR + 0.014 GH

TJC : tender joint count(jml snd 28) : wrist, MCP, PIP,

lutut, angkel, MTP kiri & kananESR : erythrocyte sedimentation rate(1 jm)

GH : general healthIndex(indek kesehatan umum),menggunakan metode visual analog scale(VAS)


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KRITERIA RESPON TERAPI (ACR)

1. Kriteria respon 20% / 50% / 70%

2. Kriteria yg dinilai :

- jml snd yg bengkak

- jml snd yg sakit

- 3 dari 5 dibawah ini :

a. patient global disease activity (VAS: 0-10)

b. physician global disease activity (VAS: 0-10)

c. patient assessment of paind. acute phase reactant (LED atau CRP)

e. disability


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PROGNOSE BURUK AR

1. FR (+) dgn titer tinggi

2. Erosi snd dini < 12 bl

3. Gejala ekstra (+)

4. CRP/LED terus menerus tinggi setelah terapi DEMARDs

5. HLA DR4 (+) dan shared epitope (+)

6. Bnyk sendi terlibat7. Tingkat diksosek rendah


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HENOCH SHCONLEIN PURPURA

1. Palpabel purpura hemorrhagic skin lesions

2. Age 20 yrs or younger

3. Bowel angina diffuse abdominal pain. Worse

after meals, or the diagnosis of bowelischemia, usually including bloody diarrhoea

4. Wall granulocytes on biopsy in the wallarterioles or venules

Sensitivity 87,1 % & specificity 87,7 %


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HYPERSENSITIVITY VASCULITIS

1. Age at disease onset > 16 yrs

2. Medication at disease onset precipitatingfactor

3. Palpable purpura thrombocytopenia (-)

4. Maculopapular rash

5. Biopsi including arteriole and venule

If at least 35 criteria are present


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POLYARTERITIS NODOSA

1. Weight loss 4 kg

2. Livedo reticularis extremities or torso

3. Testicular pain or tenderness it is not causes

4. Myalgias, weakness or leg tenderness5. Mono/polyneuropathy

6. Diastolic BP > 90 mmHg

7. Elevated BUN > 40 mg/dl, or creatinine > 1.5 mm/dl

8. Hepatitis B virus

9. Arteriographic abnormality

10. Biopsy of artery containing PMN


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SJOGRENs SYNDROME

1. Ocular symptoms

2. Oral symptoms3. Ocular signs

4. Histopathologic feature

5. Salivary gland involvement6. Auto antibodies


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GOUT


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G t


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Gout Introduction Etiology

Primary vs secondary gout Epidemiology

Age, gender and race

Pathophysiology Predisposing factors Associated conditions Presentation

History, PE, Lab and Radiology work-up Differential Diagnosis Treatment Summary

Pharmacologic Non-pharmacologic

Obj ti


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Objectives

To review the etiology and

pathophysiology of gout

To recognize predisposing factors for gout

To review diagnostic criteria and

evaluation for gout

To select appropriate treatment for apatient presenting with gout

Epidemiology


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Most common of microcrystalline arthropathy. Incidencehas increased significantly over the past few decades.

Affects about 2.1million worldwide Peak incidence occurs in the fifth decade, but can occur

at any age

Gout is 5X more common in males than pre-menopausal

females; incidence in women increases after menopause.After age 60, the incidence in women approaches therate in men.

People of South Pacific origin have an increasedincidence.

Affects less than 0.5% of the population Due to familial disposition, incidence may be as high as

80% in families affected by disorder.

Stoffey et al, Emed 2002

P th h i l


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Pathophysiology

Primary goutis caused by inborn defects inpurine metabolism or inherited defects of therenal tubular secretion of urate.

Secondary goutis caused by acquireddisorders that result in increased turnover ofnucleic acids, by defects in renal excretion ofuric acid salts, and by the effects of certain

drugs

P th h i l


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Pathophysiology

Primary gout: Overproducers: 10%

Under-excretors: 90%

Secondary gout: Excess nucleoprotein turnover (lymphoma,

leukemia)

Increased cell proliferation/death (psoriasis)

Rare genetic disorder Lesch-Nyan Syndrome

pharmaceuticals

P th h i l


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Pathophysiology

Urate saturates in plasma at 7 mg/dLAssuming pH, temp, Na are WNL

MSU deposits in less vascular tissue Cartilage

Tendons/ligaments

There is a predilection for peripheraljoint/tissue

D fi iti


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Definition Gout is a heterogeneous disorder that results in the

deposition of uric acid salts and crystals in and aroundjoints and soft tissues or crystallization of uric acid in theurinary tract.

Uric acid is the normal end product of the degradation ofpurine compounds.

Major route of disposal is renal excretion Humans lack the enzyme uricase to break down uric

acid into more soluble form. Metabolic Disorder underlying gout is hyperuricemia.

Defined as 2 SD above mean usually 7.0 mg/dL. This

concentration is about the limit of solubility for(monosodium urate) MSU in plasma. At higher levels,the MSU is more likely to precipitate in tissues.

Overview of the pathogenesis of gout


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Choi, H. K. et. al. Ann Intern Med 2005;143:499-516

Urate production pathways implicatedin the pathogenesis of gout$


94/250Urate transport mechanisms in

h i l t b l


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human proximal tubule

Gout


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Goutencompasses a group of disorders that

occur alone or in combination and include:

(1) hyperuricemia

(2) attacks of acute, typically monarticular,

inflammatory arthritis

(3) tophaceous deposition of urate crystals in

and around joints

(4) interstitial deposition of urate crystals in

renal parenchyma

(5) urolithiasis

Gout


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Gout

Typical sequence involves progression

through:

asymptomatic hyperuricemia

acute gouty arthritis

interval or intercritical gout

chronic or tophaceous gout

Stages of Classic GoutAsymptomatic hyperuricemia


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Asymptomatic hyperuricemia Very common biochemical abnormality Defined as 2 SD above mean value Majority of people with hyperuricemia never develop

symptoms of uric acid excess Acute Intermittent Gout (Gouty Arthritis)

Episodes of acute attacks. Symptoms may be confinedto a single joint or patient may have systemicsymptoms.

Intercritical Gout Symptom free period interval between attacks. May

have hyperuricemia and MSU crystals in synovial fluid Chronic Tophaceous Gout

Results from established disease and refers to stage ofdeposition of urate, inflammatory cells and foreign bodygiant cells in the tissues. Deposits may be in tendons orligaments.

Usually develops after 10 or more years of acute

intermittent gout.

Classification of Hyperuricemia


99/250

Uric acid overproduction Accounts for 10% of hyperuricemia Defined as 800mg of uric acid excreted Acquired disorders

Excessive cell turnover rates such asmyleoproliferative disorders, Pagets disease,

hemolytic anemias Genetic disorders: derangements in mechanisms that

regulate purine neucleotide synthesis. Deficiency HGPRT, or superactivity PRPP synthetase

Uric acid underexcretion

Accounts for >90% of hyperuricemia Diminished tubular secretory rate, increased tubular

reabsorption, diminished uric acid filtration Drugs, other systemic disease that predispose people

to renal insufficiency

Predisposing Factors


100/250

Predisposing Factors

Heredity

Drug usage

Renal failure

Hematologic Disease Trauma

Alcohol use

Psoriasis

Poisoning

Obesity

Hypertension Organ transplantation

Surgery

Pathogenesis of Gouty Inflammation


101/250

Pathogenesis of Gouty Inflammation

Urate crystals stimulate the release of numerousinflammatory mediators in synovial cells andphagocytes

The influx of neutrophils is an important eventfor developing acute crystal induced synovitis

Chronic gouty inflammation associated withcytokine driven synovial proliferation, cartilage

loss and bone erosion

Mechanisms of monosodium urate crystalformation and induction of crystal-induced

i fl ti


102/250

inflammation

Signs and Symptoms


103/250

Signs and Symptoms

Acute attack: Over hours frequently nocturnal

Excruciating pain

Swelling, redness and tenderness

Podagra: 1stMTP classic presentation May effect knees, wrist, elbow, and rarely SI and

hips.

Chronic: Destructive tophacous

Much greater chance if untreated

Rarely presents as a chronic

Putative mechanisms for chronicmonosodium urate-induced inflammation
http://www.hkma.com.hk/english/cme/pictquiz/pictquiz200112img2b.jpghttp://www.hkma.com.hk/english/cme/pictquiz/pictquiz200112img2b.jpg


104/250

monosodium urate-induced inflammationand cartilage and bone destruction

Associated Conditions


105/250

Associated Conditions

Cardiovascular Disease

Pagets disease

Arthritis- rheumatoid and osteoarthritis

Septic Arthritis

Metabolic syndrome

Signs and Symptoms


106/250

Renal lithiasis Uric acid nephropathy

Urate nephropathy

CRYSTAL ARTHRITIS

GOUT (monosodium urate) PSEUDOGOUT (calcium pyrophosphate)

HYDROXYAPATITE

Drugs - Increased Urate Pool


107/250

Drugs - Increased Urate Pool

DIURETICS (RR 1.77, CI 1.4-2.2)

Low Dose salicylates

B-blockers

PZA, ethambutol

Cyclosporin, tacrolimus

Insulin Cytostatic

Drugs - Decreased Urate Pool


108/250

Drugs - Decreased Urate Pool

High dose Salicylate Losartan

Fenofibrate

AmlodipineVitamin C

Probenecid, sulfinpyrazone,

benzbromaroneAllopurinol, uricase, febuxostat

Hyperuricemia Preclinical Period


109/250

HyperuricemiaPreclinical Period

6.8mg/dl based on urate supersaturation 5-8 % - most asymptomatic20% get

gout

Onset males age 30, femalespostmenopausal

Duration 10-15 yrs before gout

80% due to undersecretion, 20% due tooverproduction Determined by 24 hr urine collection

GOUT


110/250

GOUT

Urate precipitation leads to acute goutyarthritis

Local factorstemperature, pH, trauma, jointhydration

Systemic factorshydration state, fevers,

meds, alcohol, co-morbid conditionsAttack resolves spontaneously 10-15 days

GOUT


111/250

GOUT

ACUTE GOUT

First attack 4th-6thdecade for men

Women almost always postmenopausal

Classically monoarticular LEpodagra(50%), (vs pseudopodogra) >ankle>gonagra >upper extremity.

Proximal joint, central arthropathyuncommon

Diagnosis


112/250

Diagnosis

Evidence-based medicine based on EULAR(ESCISIT)10 key points Acute attack 6-12 peak intensity with S/W/E/T Aspiration always recommended if possible Prompt polarized microscopic analysis performed Definitive Dxrequires crystal confirmation Gout and Sepsis can coexistfluid should be sent

Grams stain, culture Serum uric acid levels neither confirm nor exclude

gout Radiographs not necessary Risk factor assessment

Intercritical Period


113/250

Intercritical Period

70% prevelance of MSU crystals remain inthe joint

Lasts months to years for 75-80%, 20%

never have another attack

CHRONIC GOUT


114/250

CHRONIC GOUT

USUALLY PRESENT AFTER 10 YEARS OFACUTE INTERMITTANT GOUT

TOPHI DEPOSITION

CHRONIC SWOLLEN JOINTS

JOINT DESTRUCTION

ABSOLUTELY REQUIRES ALLOPURINOL

CHRONIC GOUT


115/250


116/250

Diagnosis and

Management of GoutThe best medicine I know for rheumatism is

to thank the Lord that it ain't gout.

Presenting Symptoms


117/250

Presenting Symptoms

Systemic: fever rare but patients may have fever, chillsand malaise Musculoskeletal: Acute onset of monoarticular joint

pain. First MTP most common. Usually affected in 90%of patients with gout. Other joints knees, foot and

ankles. Less common in upper extremities Postulated that decreased solubility of MSU at lowertemperatures of peripheral structures such as toe and ear

Skin: warmth, erythema and tenseness of skin overlyingjoint. May have pruritus and desquamation

GU: Renal colic with renal calculi formation in patientswith hyperuricemia

Differential Diagnosis


118/250

Differential Diagnosis

Trauma Infections

septic arthritis, gonococcal arthritis, cellulitis

Inflammatory

Rheumatic arthritis, Reiters syndrome, Psoriaticarthritis

Metabolic pseudogout

Miscellaneous Osteoarthrtis

Diagnosis


119/250

Diagnosis

Definitive diagnosis onlypossible by aspirating andinspecting synovial fluidor tophaceous materialand demonstrating MSU

crystals Polarized microscopy, the

crystals appear as brightbirefringent crystals thatare yellow (negativelybirefringent)

Synovial Fluid Findings


120/250

Synovial Fluid Findings

Needle shapedcrystals ofmonosodium uratemonohydrate that

have been engulfedby neutrophils

Diagnostic Studies


121/250

Uric Acid Limited value as majority of hyperuricemic patients will never

develop gout Levels may be normal during acute attack

CBC Mild leukocytosis in acute attacks, but may be higher than

25,000/mm

ESR mild elevation or may be 2-3x normal

24hr urine uric acid Only useful in patients being considered for uricosuric therapy or

if cause of marked hyperuricemia needs investigation Trial of colchicine

Positive response may occur in other types of arthritis to includepseudogout.

Treatment Goals


122/250

Treatment Goals

Gout can be treated withoutcomplications.

Therapeutic goals include

terminating attacks providing control of pain and inflammation

preventing future attacks

preventing complications such as renal

stones, tophi, and destructive arthropathy

ACUTE GOUT


123/250

ACUTE GOUT

THERAPY (for all crystal diseases): Corticosteroids: intrarticular > systemic

NSAIDsfast acting full dose if nocontraindications

Colchicine (PO,IV route dangerous) narrow therapeutic window

Bone marrow suppression, myopathy, neuropathy

purgative effectsPt often run before they walk

ACTH

NEVER ALLOPURINOL

Acute Treatment


124/250

Acute Treatment

Colchicine Inhibits microtubule aggregation which disrupts

chemotaxis and phagocytosis

Inhibts crystal-induced production of chemotatic

factors Administered orally in hourly doses of 0.5 to 0.6mg

until pain and inflammation have resolved or until GIside effects prevent further use. Max dose 6mg/24hr

2mg IV then 0.5mg q6 until cumulative dose of 4mgover 24hr

Acute Gout Treatment


125/250

NSAIDs

Most commonly used. No NSAID found to work better than others

Regimens:

Indocin 50mg po bid-tid for 2-3 days and then taper

Ibuprofen 400mg po q4-6 hr max 3.2g/day Ketorolac 60mg IM or 30mg IV X1 dose in patients65yo, or with patients who are renally impaired

Continue meds until pain and inflammation haveresolved for 48hr

Acute treatment contd


126/250

Corticosteriods

Patients who cannot tolerate NSAIDs, or failed NSAID/colchicinetherapy

Daily doses of prednisone 40-60mg a day for 3-5 days then taper1-2 weeks

Improvement seen in 12-24hr

ACTH Peripheral anti-inflammatory effects and induction of adrenal

glucocorticoid release

40-80IU IM followed by second dose if necessary

Intra-articular injection with steroids Beneficial in patient with one or two large joints affected Good option for elderly patient with renal or PUD or other illness

Triamcinolone 10-40mg or Dexamethasone 2-10mg alone or incombination with Lidocaine

Non- Pharmacologic

T t t


127/250

Treatments Immobilization of Joint Ice Packs Abstinence of Alcohol

Consumption can increase serum urate levels by increasing

uric acid production. When used in excess it can beconverted to lactic acid which inhibits uric acid excretion inthe kidney

Dietary modification Low carbohydrates

Increase in protein and unsaturated fats Decrease in dietary purine-meat and seafood. Dairy and

vegetables do not seem to affect uric acid Bing cherries and Vitamin C

Uric Acid Lowering Therapy


128/250

g py

Lifestyle, dietary modification Diet high in vegetables, dairy, water

beneficial

Initiate uric acid lowering therapy after1(?) or 2 episodes of acute gouty arthritis

Always prophylaxis for first 6 months with

low dose steroids, NSAIDs, or colchicine

Prophylaxis


129/250

Frequent attacks >3/year, tophi development or urateoverproduction

Avoid use of medications that contribute to hyperuricemia:Thiazide and loop diuretics, low-dose salicylates, niacin,cyclosporine, ethambutol Losartan promotes urate diuresis and may even normalize

urate levels. This action does not extend to other membersof the ARB class.

Useful in elderly with HTN and gout Colchicine

Colchicine 0.6mg qd-bid

Use alone or in combination with urate lowering drugs Prophylaxis without urate lowering drugs may allow tophi

to develop

Prophylaxis


130/250

Urate Lowering drugs Used for documented urate overproduction Goal is for serum urate concentration to 6mg/dL or less Start of therapy can precipitate acute attack; therefore, may need to use

colchicine as a long as six months Xanthine oxidase inhibitors

Allopurinol: blocks conversion of xanthine to uric acid. works forunderexcretors and overproducers.

Start typically 300mg/day and titrate weekly 100mg/day until optimalurate levels achieved.

Start lower doses with renally impaired patients Uricosuric drugs

Probenecid or Sulfinpyrazone: increase renal clearance of uric acid by

inhibiting tubular absorption Side effects may prohibit use-GI and kidney stones Need measurement of 24hr urine in anyone for whom Probenecid

therapy is initiated

URICOSURICS - Drugs Uricosurics


131/250

Uricosurics

probenecid 1-3 grams / day

sulfinpyrazone 200-400 mg / day

Benzbromarone 100-200 mg / day

(not available)

Contraindications

Tophi

CRI (GFR >35ml/min)

H/O urolithiasis

Intolerance

Rapid cell turnover states

25% failure ratemild CRI

Interact with ASA, NSAIDs, PCN, captopril

Watch for rash , GI,HA, dyscrasias,nephrosis

Uricostatic Drugs


132/250

g

Allopurinol - developed 1957 Reduce annual gout attacks 4.4 to .06 / yr

Gradual resolution of tophi w/ uric acid < 6

Titrate dose up to 600 mg /day

Uncreased toxicity with CRI Allopurinol hypersensitivity rxnrare but can be fatal

Densensitization can be useful for mild SEs Oxypurinol is an option but 50% intolerance

Multiple interactionsimuran, 6MP, warfarin,theophylline, ampiciliin, diuretics

Treatment is lifelong

URICOSTATICSFEBUXOSTAT


133/250

FEBUXOSTAT Not yet FDA approved

?? Hepatic toxicity, HA, diarrhea 80-120 day safer, more effective No dose reduction for renal, hepatic insufficiency

Combination uricourics and uricostatics offer additional benefit URICASEconverts uric acid to allantoin

Recombinant uric acid oxidase RASURICASE parenteral routecan be given only once due to antibody

production Black box warninganaphylaxis, hemolysis, methemoglobinemia

Pegylated preparation approved for urate nephropathy in tumor lysissyndrome.

Expensive Sq administration

Fenofibrate, Lozartan E3040new class of antiinflammatory compounds Y-700, scopoletin

Newer Therapies


134/250

Uricase Enzyme that oxidizes uric acid to a more soluble form

Natural Uricase from Aspergillus flavus and Candida utilis underinvestigation

Febuxostat New class of Xanthine Oxidase inhibitor

More selective than allopurinol Little dependence on renal excretion

Losartan ARB given as 50mg/dL can be urisuric. When given with HCTZ, it can

blunt the effect of the diuretic and potentiate its antihypertensive

action Fenofibrate

Studies note when used in combo with Allopurinol producedadditional lowering of the urate

Complications


135/250

p

Renal Failure ARF can be caused by

hyperuricemia, chronicurate nephropathy

Nephrolithiasis

Joint deformity

Recurrent Gout


136/250Chronic Tophaceous Gout


137/250

p

Chronic Tophaceous Gout


138/250Chronic Tophaceous Gout


139/250


140/250


141/250


142/250


143/250


144/250


145/250


146/250


147/250


148/250


149/250


150/250


151/250


152/250


153/250CPPD DISEASE


154/250

(Calcium Phyrophosphat Dehydrate

Deposition)

Chondrocalcinosis

Heriditary (rarely )

CPPD Associations

CPPD Presentations


155/250

Acute Pseudogout Positive birefringent rod shaped crystals

More likely in OA jointknee> wrist> MCPs>hips,shoulders,ankles

Pseudo-rheumatoid pattern

Osteoarthritis with/out pseudogout

Chondrocalcinosis

Neuropathic joint

Tumoral CPPD deposition

PSEUDOGOUT


156/250

HYPERPARATHYROIDISM HEMOCHROMATOSIS

HYPOTHYROIDISM

HYPOMAGNESIEMIA

HYPERCALCEMIA

HYPOPHOPHATASIA

Basic Calcium Phosphate BCP Dz


157/250

Usually in the form of hydroxyapatiteAge related arthropathy except for

pseudopodagra in young women

Milwaukee Shoulder Calcific Periarthritis

Soft tissue calcification

Osteoarthritis (found in 70% of OAsynovial fluid)


158/250

PENDAHULUAN


159/250

WHO dekade sehat tlg dan sendi 2000-2010

Usia harapan hidupmanula / wulan

Osteoporosis Primer dan Sekunder

Kepedulian thd masyarakat PEROSI

OSTEOPOROSIS (OP)


160/250

Kelainan sistemik massa tlg berkurang

Resorbsi tlg > formasi tlg

Tlg mudah fraktur

Dibagi OP Primer dan OP Sekunder

Wanita >> Pria

OSTEOPOROSIS


161/250

Tidakbergejala

Bergejala Diketahui

TidakDiketahui

Pencegahan AmanManulaBahagia

PatahTulang Masalah Luar biasa


162/250


163/250


164/250


165/250

Fraktur tlg tergantung


166/250

Usia

Kepadatan massa tlg

Gender, wanita 2 x pria

Aktifitas

Rasial

Umur

Pe1 dekade bhb dgn resiko 1, 4 - 1, 8 kali


167/250

GenetikEtnis (Kaukasus/Oriental > org hitam/Polinesia)

Gender (Perempuan > Laki-laki)

Riwayat keluarga + tubuh yg kurus

Lingkungan

Makanan, defisiensi Ca

Aktifitas fisik dan pembebanan mekanik

Obat-obatan, mis: kortikosteroid, anti konvulsan, heparinMerokok, alkohol

Jatuh (trauma), kurang gerak (OR)

Hormon endogen dan penyakit kronik

D fi i i


168/250

Defisiensi estrogen

Defisiensi androgen

Gastrektomi, sirosis, tirotoksikosis, hiperkortisolisme

Sifat fisik tlg mempengaruhi OP

Densitas massa tlg

Ukuran dan geometri tlg

Mikroarsitektur tlg

Komposisi tlg


169/250

OP PRIMER


170/250

Pengurangan massa tlg ok :

1. Kegagalan mencapai massa tlg puncak scr optimal

2. Peningkatan resorbsi tlg

3. Penurunan pembentukan tlg

Kekuatan tlg = kuantitas tlg + kualitas tlg

(BMD) (Bone Turn Over)

FAKTOR-FAKTOR PATOGENIK OP PRIMER

D f h ( d ) h b k ifi


171/250

1. Def. hormon sex (gonade) estrogen menghambat aktifitas

osteoklast2. Mediator lokal tidak ada hormon sistemik berperan mutlak

pengurangan massa tlg tdk seragam

kadar lokal sitokin, prostaglandin, hormon

pertumbuhan

3. Nutrisi dan gaya hidup

- Intake Ca terpenting sejak usia dini

- Jaringan lemak proteksi massa tlg ok konversi androgen

mjd estrogen dlm jar. lemak

- Penurunan testosterone - binding globulin

4. Faktor genetik

- COLIA 1 dan COLIA 2 sbg regulator densitas tlg dan resiko fraktur

- Alel pada gen yg menyandi reseptor vit.D

OP SEKUNDER


172/250

1. Hipogonadisme estradiol amenoreHiperprolaktinemi amenore

Laki-laki 15-30% Def. testosteron (sindrom

Klinefelter, sindrom Kalman)

2. Penyakit GIT

Radang usus, CH osteoblast terganggu, malabsorbsi Ca hiperparatiroidisme OP

Def. vit D OP

3. Keganasan (MM, Mastosistosis Sistemik, LNH,

Leukemia Kanker tlg)


173/250

Leukemia, Kanker tlg)

4. Glukokortikoid OP 612 bln pertama, ok

- aktifitas osteoblast , osteoklast

- peestrogen, testosteron, androgen adrenal

- Ca urin

5. Hiperparatiroidisme demineralisasi, tumorkistik, resorbsi perios fraktur

6. Penyakit tiroid tirotoksitosis osteoklas

OP


174/250

OP

7. Rematoid artritis OP periartikuler ok terapi

kortikosteroid OP sistemis

8. Obat-obatan

- Obat epilepsi enzim hati meningkat

25 (OH)D ,Ca alk fosfatase OP

- Heparin resorbsi tlg , pembentukan tlg

- Imunosupresan.

9. Rokok

2Hidroksilasi estradiol di hati


175/250

- 2Hidroksilasi estradiol di hati

- Estrogen bioaktif

- Estrogen protektif panggul

10. Alkohol

- Osteopenia fraktur- Ethanol proliferasi osteoblast

- Androgen bioaktif OP

DIAGNOSIS OP


176/250

1. Gambaran klisnis

2. Pemeriksaan biokimia

3. Pemeriksaan pencitraan

4. Biopsi tlg

Pembentukan tulang (Serum) Resorpsi Tulang (Urine and Serum)

1 Total Alk Phosphatases (TAP) 1 Hydroxyproline (urine)

BIOKIMIA OP


177/250

1. Total Alk. Phosphatases (TAP)

2. Bone Alk. Phosphatases (BAP)3. Osteocalsin

4. PIPC (Carboxy Terminal

Propeptide of type I Procollagen)

5. PINP (Amino Terminal Pro-

peptide of type Procollagen)

1. Hydroxyproline (urine)

2. Pyridinoline Pyd (urin)3. Deoxy PyridinolineDPI (urine)

4. INTP, NTX (Amino-Terminal

Cross Inked Telopeptide of Type

I Collagen (urine)

5. Hydroxylysine glycosides (urine)

6. ICTP (Carboxy-Terminal Cross

Inked Telepeptide of Type I

Collagen (Serum)

7. TRAP (Tartate-Resitent AcidPhosphatase)

8. GLA (Free-Carboxy Glumatic

Acid) (Serum, urin)

(Tjokroprawiro A 2000)

PEMERIKSAAN PENCITRAAN

Radiologi konvensional (photo densitometry = radiographic


178/250

Radiologi konvensional (photo densitometry = radiographic

absorbtiometry)

Radio isotop (single photon berasal dari I-125, dual photon

dari Gd-135) SPA (Single Photon Absorbtiometry) dan

DPA (Dual Photon Absorbtiometry) QCT (Quantitative Computerized Tomography)

MRI (Magnetic Resonance Imaging)

Sonodensitometry : QUS (Quantitative Ultra Sound) X-ray absorbtiometry : SXA (Single X-ray Absorbtiometry)

dan DXA = DEXA (Dual Energy X-ray Absorbtiometry)

DISKRIPSI PENGERTIAN


179/250

BMD normal BMD diatas1 SD BMD dewasa

muda normal (T-score)

BMD rendah / osteopenia BMD antara1 SD sampai2.5 SD

Osteoporosis BMD kurang dari - >= 2.5 SD

Osteoporosis berat BMD kurang dari ->= 2.5 SD fraktur

Dikutip dari WHO Technical Report Series, 1994

BMD = bone mineral density; SD = standard deviation

OSTEOBLAS

Asal : stromal stem cell (connective tissue


180/250

Asal : stromal stem cell (connective tissue

mesenchymal stem cell) Satu asal dgn Kondrosit, miosit, adiposit, dan sel

ligamen

Untuk pematangan perlu :

- FGF (Fibroblast Growth Factor)

- BMPs (Bone Morphogenic Proteins)

- Wnt Proteins

- Cbfa-1 (Core Binding Factor-1)

- Osx (Osterix) dan Runx-2

- OSE-2 (Osteoblast Specific Cis Acting Element)

OSTEOBLAS MATUR

Memproduksi matriks tlg (Osteoid)


181/250

Memproduksi matriks tlg (Osteoid)

Mengekskresi osteokalsin (OG-2), osteoblast specific

gene

Mengandung reseptor : PTH, GH (IGF-1-2), PG

estrogen, vit.D3, sitokin

Sitokin CSF-1 (Colony Stimulating Factor)

RANKL (Receptor Anti Nuclear Factor K

Ligand)

OPG (Osteoprotegrin), yang menghambat

RANKL

IGF (Insulin Like Growth Factor)


182/250

Mereplikasi osteoblas

Medegradasi kolagen

Mempertahankan massa tlg

Dipengaruhi : estrogen, PTH, PGE-2, BMPs (Bone

Morphogenic Proteins)

Terikat protein IGFBPs, dihambat PDGF (PlateletDerived Growth Factor) dan glukokortikoit

TGF

M i kl h b b i l


183/250

Meapoptosis osteoklas menghambat resorbsi tlg

Mereplikasi osteoblas dan sintesis kolagen

FGF

Angiogenik, neovaskularisasi, penyembuhan luka

Reparasi tlg, sintesis kolagen tlgMe ekskresi MMP-13

BMPs

Family TGF ada BMPs 1 7


184/250

Family TGF, ada BMPs 1-7

Disintesis oleh jar. skeletal dan ekstra skeletal

medeferensiasi osteoblas, osifikasi endokondral dan

kondrogenesis.

Protein Wnt

Menginduksi deferensiasi osteoblas

Membutuhkan LRP-5 (Lipoprotein Receptor Related

Proteins)

PDGF

F i i i FGF


185/250

Fungsi mirip FGF

mereplikasi osteoblas, sintesis kolagen, jmlh osteoklas

Macamnya : A, B, AB, dan BB dgn karakter yg berbeda

VEGF (Vascular Endothelial Growth Factor)

Angigenesis

Penulangan endokondral

me apoptosis kondrosit

Osteoblas mengekspresi reseptor VEGF R1 dan R2

OSTEOKLAS


186/250

Berfungsi resorbsi tlg Asal : sel fagosit mononuklear

Memiliki reseptor

- RANK, berikatan dgn ligand (RANKL) maturasi sel

- Kalsitonin dan vitronektin (integrin-3)

Fisiologis mengalami apoptosis

IL-1 dan , IL-6 mpngh resorbsi tlg

Resorbsi lakuna Howship dan cutting cone

SITOKIN


187/250

IL-1 dan

remodeling tulang Monosit, osteoblas, sel tumor IL-1 resorbsi tlg,

replikasi sel tlg, sintesis IL-6

IL-1 berhub. fungsi RANKL, limfotoksin, dan TNF-

Osteoblas dirangsang PTH, 1.25 (OH)2D3dan IL-1 IL-6

IL-6 dihambat estrogen, dirangsang RANKL dan TGF-osteoklas aktif

TGF- merangsang PG Osteoklas aktif dan osteoblasproliferasi

KESIMPULAN

OP fenomena alamiah


188/250

wanita terut. post menopouse >> pria

OP dpt dicegah dan diperbaiki

Konsumsi Ca dan vit.D sejak dini mrpkn konsumsi yg

bijaksana Prosedur diagnosis : evaluasi klinis, faktor resiko, lab.

marker remodeling tlg dan pem. BMD

Penatalaksanaan OP : meningkatkan BMD dan mencegahfraktur

Terapi pilihan OP : sulih hormon, bisfosfonat, SERM dan

kalsitonin.


189/250

SYSTEMIC LUPUS ERYTHEMATOSUS(SLE)- DEFINITION/DIAGNOSIS


190/250

Prototype of auto-immune, multi-systemdisease

Onset maybe acute, episodic, or insidious

Anything can happen to any organsystem

Antinuclear antibodies are almost always

present Serositis & Immune complexes

SLE - EPIDEMIOLOGY


191/250

20% of all SLE is pediatric age group Incidence 0.6/100,000

Prevalence 5-10/100,000

Overall 5-10,000 children in U.S.A.Approximately 5% of new diagnoses in

Pediatric Rheumatology clinics

SLE : JRA/1:10 ratio

Pediatric SLE versus Adult Onset SLE

More severe symptoms at onset


192/250

More aggressive clinical course than adults

Increased need for corticosteroid; 77% vs 16%

Children tend to die during acute SLE phase

Adults tend to die secondary to complications

African American and Hispanic children have a higherincidence of disease

African American patients have higher prevalence and severity of renal

higher prevalence neuropsychiatric SLE

higher titers of anti-DNA and anti-SSA antibodies in associationwith cardiac disease

Genetics in SLE


193/250

Eight of the best supported SLE susceptibility loci are thefollowing

1q23

1q25-31

1q41-42

2q35-37

4p16-15.2

6p11-21

12p24

16q12Tsao, BP, Curr Opinion Rheum, 2004; 16: 513-521

THE 1982 REVISED CRITERIA FOR

CLASSIFICATION OF SLE


194/250

Malar rash SerositisDiscoid rash Renal disorder

Photosensitivity Neurologic disorderOral ulcers Hematologic disorder

Arthritis Immunologic disorder

Antinuclear antibody

Revised 1997

THE 1982 REVISED CRITERIA FORCLASSIFICATION OF SLE

F th f id tif i ti t i


195/250

For the purpose of identifying patients inclinical studies, a person shall be said tohave SLE if any 4 or more of the 11 criteriaare present, serially or simultaneously,

during any interval of observation. Sensitivity 96%

Specificity 96% in adults

Similar percentages in pediatric group.

MALAR RASH


196/250

Fixed erythema,flat or raised, overthe malareminences

tending to sparethe nasolabial folds

DISCOID RASH


197/250

Erythematousraised patches withadherent keratoticscaling andfollicular plugging;

Atrophic scarringmay occur in olderlesions

PHOTOSENSITIVITY


198/250

Skin rash as aresult of unusualreaction to sunlight

by patient historyor physicianobservation

ORAL ULCERS


199/250

Oral ornasopharyngealulceration

Usually painless,observed by aphysician

ARTHRITIS


200/250

Nonerosive arthritis involving 2 ormore peripheral joints

Characterized by tenderness,swelling, or joint effusion.

SEROSITIS

A) Pleuritis - convincing history of pleuritic


201/250

A) Pleuritis convincing history of pleuritic

pain or rub heard by a physician orevidence of pleural effusion

OR

B) Pericarditis - documented by ECG orrub or evidence of pericardialeffusion

RENAL DISORDER

A) Persistent proteinuria greater


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A) Persistent proteinuria greater

than 0.5 grams per day orgreater than 3+ if quantitationnot performed

ORB) Cellular casts - may be red

cell,hemoglobin, granular, tubular, or

mixed

NEUROLOGIC DISORDER

A) Seizures in the absence of offending


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A) Seizures - in the absence of offendingdrugs or known metabolicderangements, e.g., uremia,ketoacidosis, or electrolyte imbalance

OR

B) Psychosis - in the absence of offendingdrugs or known metabolic

derangements, e.g. uremia, ketoacidosis,or electrolyte imbalance

HEMATOLOGIC DISORDER

A) Hemolytic anemia - with reticulocytosis


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ORB) Leukopenia - less than 4,000/mm3 total on

2 or more occasions

ORC) Lymphopenia - less than 1,500/mm3 on 2or more occasions

OR

D) Thrombocytopenia - less than100,000/mm3 in the absence of offendingdrugs

IMMUNOLOGICDISORDER

A) Anti-dsDNA: antibody to native DNA in


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A) Anti dsDNA: antibody to native DNA inabnormal titer

ORB) Anti-Sm: presence of antibody to Sm nuclear

antigenOR

C) Antiphospholipid antibodies by positive IgG or

IgM anticardiolipin antibodies or positive testfor lupus anticoagulant

ANTINUCLEAR ANTIBODY

An abnormal titer of antinuclear antibody


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An abnormal titer of antinuclear antibodyby immunofluorescence or an equivalentassay

at any point in time

and in the absence of drugs known to beassociated with

drug-induced lupus syndrome

Drug-Induced Lupus


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Minocycline (Minocin) Phenytoin (Dilantin)

Carbamazepine (Tegretol)

Ethosuximide (Zarontin)

ANTINUCLEAR ANTIBODY

1:20 - 1:40 Screening titer


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1:20 1:40 Screening titer

1: x titer

Pattern

speckled - + ENAs

rim - ds DNA

homogeneous - DNA (LE prep)

nucleolar - Scl - 70

SLE

Tissue Specific Nuclear


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Tissue Specific NuclearAntibodies Antibodies

ATA Ro/SSA

Anti ASMA La/SSBAnti-MITO RNP

Anti-LKM Sm

Anti-PC ds DNAHep-2 ss DNA

Arthralgia and Positive ANA or RF Remember that objective signs of joint inflammation

substantiate diagnosis of arthritis


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Comprehensive review of systems may uncover clues Perform a critical, complete physical examination

Serial re-evaluations may be necessary

Most children do not progress to a C.T.D.

Positive serologies may be seen in: Normal children - approximately 3-12% Response to infection

Persistent ANA

24/108 children with musculoskeletal problems had positive


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24/108 children with musculoskeletal problems had positiveANA

21/24 had persistent ANA, mean duration 38 mo

No patient developed an overt autoimmune or inflammatory

disease, mean F/U 61 mo (13-138) Conclusion: a child with positive ANA and musculoskeletal

problems , but with no evidence at presentation of AID orinflammatory disease is at low risk of developing such a

disease.

Cabral, DA, et al Pediatrics 1992, 89(3):441-444

Outcome of Children referred to PediatricRheumatology Clinic with a positive ANA but

without AID


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500 new patients reviewed, 113 had positive ANA 72 (64%) had an autoimmune disease AID,

10 (9%) were lost to F/U, 31 (27%) had no AID,

Mean ANA titer 1:160, varied pattern

Mean clinical F/U 37 mos 25 (81%) cleared their symptoms, 5 (16%) had

improvement, 1 developed autoimmune hepatitis

Prognosis with +ANA is excellent in absence of AID atpresentation

Deane, PMG, et al, Pediatrics 1995, 95:892-895

Clinical Utility of Antinuclear ANA Tests inChildrenMcGhee JL et al, BMC Pediatrics 2004, 4: 13

110 pts referred to Rheum for +ANA


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p 80 children with musculoskeletal problems syndromes

10 pts subsequently dxdSLE, 1 MCTD, 1 Prim Raynauds, 18with JIA Nonurticarial rash more common in SLE, p=0.007 Children with SLE were older 14.2 vs 11 yrs, p=0.001

ANA > 1:640 was +predictor for SLE while titers of


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Most common signs/symptoms

Unexplained fever, any pattern Malaise

Weight Loss

Arthralgia

SLE - MUCOCUTANEOUS INVOLVEMENT


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Butterfly Rash - 1/3 at onset

Angiitic papules

Periungual erythema Urticaria / angioedema

Palatal ulcer / aphthous ulcer

Alopecia


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http://www.meddean.luc.edu/lumen/MedEd/Radio/sarc/ns10.jpghttp://www.pedrheumonlinejournal.org/nov-dec/Images/figure2.jpg


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SLE - MUCOCUTANEOUS INVOLVEMENT
http://www.meddean.luc.edu/lumen/MedEd/Radio/sarc/ns10.jpghttp://www.pedrheumonlinejournal.org/nov-dec/Images/figure2.jpg


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Discoid lupus Subacute cutaneous lupus

Livedo reticularis

Nailfold capillary changesVasculitic ulceration

Panniculitis

Nasal septal perforation


219/250

Ulceratedleukocytoclastic

vasculitis in SLE

SLE - MUSCULOSKELETAL DISEASE


220/250

Arthralgia / Arthritis

Myalgia / Myositis Ischemic necrosis of bone - AVN

SLE - VASCULOPATHY


221/250

Small vesselvasculitis

Palpable purpura

Raynaudsphenomenon

Antiphospholipid

antibody syndrome

SLE - CARDIAC INVOLVEMENT


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Pericarditis

Myocarditis

Endocarditis, Libman-SacksAccelerated atherosclerosis

SLE - PLEUROPULMONARY DISEASE

Pleuritis/Pleural effusion


223/250

/

Infiltrates/Atelectasis

Acute lupus pneumonitis

Pulmonary hemorrhageShrinking lung - diaphragm

dysfunction

Subclinical restrictive disease


224/250

SLE - GASTROINTESTINAL

MANIFESTATIONS


225/250

Anorexia, weight loss, nonspecificabdominal pain

Pancreatitis Mesenteric arteritis

Esophageal dysmotility

SLELIVER , SPLEEN & LYMPH NODE


226/250

Generalized lymphadenopathy

Lupoid hepatitis vs SLE hepaticinvolvement

Functional asplenia

SLE - NEUROPSYCHIATRIC

MANIFESTATIONS


227/250

Must be differentiated from infection orhypertensive or metabolic complications

Any level of the CNS/PNS can be affected Thorough evaluation necessary - CSF, EEG,

CT, MRI, EMG / NCV, NP testing


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SLE - NEUROPSYCHIATRIC

INVOLVEMENT


229/250

Behavior/Personality changes, depressionCognitive dysfunctionPsychosisSeizures

StrokeChoreaPseudotumor cerebriTransverse myelitisPeripheral neuropathyTotal of 19 manifestations described

SLE - RENAL INVOLVEMENT


230/250

Usually asymptomatic

Gross hematuria

Nephrotic syndromeAcute renal failure

Hypertension

End stage renal failure

SLE - NEPHRITIS


231/250

Nephritis remains the most

frequent cause of disease-related death.

WORLD HEALTH ORGANIZATIONCLASSIFICATION OF LUPUS NEPHRITIS

Class I Normal


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Class II Mesangial

IIA Minimal alteration

IIB Mesangial glomerulitis

Class III Focal and segmental proliferativeglomerulonephritis

Class IV Diffuse proliferativeglomerulonephritis

Class V Membranous glomerulonephritisClass VI Glomerular sclerosis

SLE - LABORATORY EVALUATION

Antinuclear antibody profile


233/250

Anti dsDNA abs, Sm abs

C3, C4, IgA, IgG, IgM

Direct Coombs, DATAntiphospholipid antibodies

ACLA - Anticardiolipin antibodies

LAC - Lupus anticoagulant CBC with Diff, U/A, CMP, TSH, ESR

Comprehensive Evaluation of aChild with SLE


234/250

Cumulative medication burden

Serial DEXA while on corticosteroids

Lipid panels

Repeat APA profile, ? Frequency HRQL and damage indices, SLEDAI, SDI

Neuropsychiatric testing ?

ECHO

Complement factor deficiency (C1q)

Long-term Management Issues

Long term morbidity of corticosteroids:


235/250

short stature, cataracts, osteoporosis How to manage ongoing active disease after multiple

medications during childhood

Long term morbidity of immunosuppressive agents

Non-sustained durable disease: ? remission

Cumulative risk re: malignancy andpremature ovarian failure

Therapeutic Goals in SLE: StillUnmet Expectations

Rate of renal remission after first line therapy still 81%


236/250

at best Renal relapse in 1/3 pts mostly still immunosuppressed

5- 20% experience ESRD 5-10 yrs after disease onset

Treatment related toxicity remains a concern;

osteoporosis, premature ovarian failure, severeinfections, etc.

Prognostic factors have been identified but are difficultto modify in order to improve outcomes

Treatment Regimens for LN

Glucocorticoids plus cyclophosphamideinduction &


237/250

maintenance for 3 years

NIH protocol

Glucocorticoids plus low dose cyclophosphamide withmaintenance with MMF or AZA

Immunoablative doses of cyclophosphamide

Autologous stem cell transplantation

Plasmapharesis is not recommended

Reviewed: Houssian FA, J Am Soc Nephrol 2004; 15: 2694

Sequential Therapies for WHO III- V 60 adult SLE pts randomized 3 groups

12 Class III, 46 Class IV and 1 Class Vb

All received initial therapy with Cyclophosphamide 0.5-1.0


238/250

gm/m up to 7 pulses

Contd on 1) cyclophosphamide, 2) azathioprine 1-3mg/kg, or3)M ycophenolate mofetil (Cellcept, MMF)0.5-3.0 gm/d for 1-3years

5 pts died- 4CYC, 1 MMF; 5 CRF- 3 CYC,1 AZA, 1 MMF 72 month event free survival rate higher in MMF and AZA

than in CYC (P=0.05 and P=0.009, respectively)

Incidence of hosp, amenorrhea, infections, nausea andvomiting lower in the MMF and AZA groups than in the CYC

group

Contreras, G et al: NEJM 350(10): 971-980, 2004

Targeted Immune Intervention

Directed against B Cells: Rituximab, anti-CD20 B cell


239/250

depleting monoclonal antibody LJP 394, anti-dsDNA-producing B cells

Co-stimulatory signalsCD40-CD40L (CD154) blockade

CTLA41g, abatacept: binding to CD80 andCD86 prevents engagement to CD28 to T cellsthereby prevents co-stimulation

Cytokine blockade

IL10, INF-

Houssian FA, J Am Soc Neprol, 2004; 15: 2694-2704

Major Clinical Syndromes inSLE Requiring Vigilance


240/250

Antiphospholipid Antibody Syndrome withthrombosis

Premature atherosclerosis and marked risk

of myocardial infarction Neurocognitive dysfunction with

deterioration of mental capacity

Iatrogenic syndromes of osteoporosis andpremature ovarian failure 2therapy


241/250

Antiphospholipid Antibodies in cSLE Associated with venous and arterial thrombosis,

thrombocytopenia, neurologic disorders and fetal loss


242/250

Found in 65% of children with SLE +LAC, ACLA and false positive VDRL

Prolonged partial thromboplastin time

All are associated with thrombosis; esp LAC and ACLA

Anticoagulation required if a patient has a thromboticevent

Aspirin in everybody else

Seaman DE, et al, Pediatrics. 1995; 96: 1040-5

Management Goals for cSLE Counseling, education

Recommend adequate rest and activity


243/250

Decrease inflammation; prevent end-organ injury failure Preserve renal function; provide HBP Rx; prevent flare

Provide photo protection

Maintain up-to-date immunizations

Management of infection Minimize osteoporosis

Identify patients at risk of thrombo-occlusive events

Evaluate and treat ASHD risk; dyslipoproteinemia, etc.

Family planning/contraceptive issues

Combined Oral Contraceptives Are NotAssociated with an Increased Rate of Flare

in SLE Patients in SELENA

SELENA- Safety of Estrogen in Lupus Erythematosus-National


244/250

Assessment 183 premenapausal pts, mean age 30 y Inactive 76%, stable/active 24% Randomized, double blind OC vs placebo for 12 28-day OC cycles Primary end point, severe flare, rare; 7/91 (7.7%) OC vs 7/92

(7.6%) placebo Mild/moderate flares 1.41 vs 1.40 flares/person-year (OC vs P)

RR= 1.01, P= 0.96 3 or more mild/moderate flares 15% vs 16% OC does not increase rate of severe or mild/moderate flare in

SLE

Petri,M, Arthritis Rheum 2004, 50(9): S239, abstract 523

Adjunct Therapy for SLE Antimalarials; hydroxychloroquine

Nonsteroidal anti-inflammatory drugs

ASA


245/250

Folic Acid ACE Inhibitors

Glucocorticoids; variable dose ranges

Immunosuppressives non CYC, azathioprine,

mycophenalate mofetil MMF, cyclosporin, methotrexate Herpes Zoster prophylaxis

Vaccinations

Organ specific medications; e.g. anti-HTN, osteoporosis,

infection, etc.

Risk Factors for Damage in Childhood-Onset SLE

d d


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Disease activity and damage in 66 pts SLICC/ACR Damage Index 1.76 (mean FU

3.3 y)

Cumulative disease activity single bestpredictor of damage (R2= 0.30)

Corticosteroid treatment, APA, acutethrombocytopenia

Immunosuppressive agents protective

Brunner, HI, et al.Arthritis and Rheumat.2002;46:436-44.

Long-term Followup of

SLE Nephritis: Toronto*

67 M F 1 3 8 FU 11


247/250

67 pt, M:F 1:3.8, FU mean 11 y 15 Class II, 8 Class III, 32 Class IV, 11

Class V

4/67 died, 6/67 ESRD, 94% survival rate Non-Caucasian pts may be at increased

risk for renal failure

Azathioprine most commonly employedimmunosuppressive agent

Hagelberg, S. J Rheumatol. 2002;29:2635-42.

Long-Term Outcomes of Childhood-Onset SLE

77 pts (prev 9.6/100,000; F:M 10:1), 39 interviewed Mean age at dx 14.6 yrs, 57% Cauc, 40% AA and 3% Asian

8 t di d (86 9% i l) F/U 7 6


248/250

8 pts died (86.9% survival) mean F/U 7.6 yrs Mean SLEDAI score 6.2 (range: 0-26), 42% SDI>0, mean 1.4 (0-10)

NPL, renal, ocular, and MS accounted for 79% of damage

AA had higher SLEDAI and SDI scores cSLE pts develop 2 times damage of adults and continue to have

active disease CYC used in 39%,

higher rate of ovarian damage (36%); dose related

HRQL compared to healthy controls much lower mental andphysical component

Brunner et al, Lupus 2006, in press

Conclusion(s) SLE in children has the same clinical

expression as in adults but a more

i di


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aggressive disease course. Numerous potential complications loom

behind the scenes and must be anticipated

and monitored. Better understanding of the pathogenesis

will enable better targeted and safertherapy.

Multiple trials are ongoing at CCHMC toinvestigate better health outcomes for cSLE.


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