Curriculum Vitae Natsir Akil Riwayat Pendidikan 1992 Dokter Umum UNHAS Makassar 2002 Internist UNHAS Makassar 2010 Konsultan Reumatologi FKUI/RSCM Jakarta Riwayat Pekerjaan 1992-1995 : Kepala Puskesmas Sumarorong Kabupaten Polmas Sulawesi Selatan 1996 : Staf RSUD Ampana Kabupaten Poso Sulawesi tengah 2002–2009 : Staf RSUD Dr.H.Soemarno Sostroatmojo Tanjung Selor Kabupaten Bulungan Kaltim 2010-sekarang : Staf SMF Penyakit Dalam RSU Kanujoso Djatiwibowo Balikpapan Kaltim Organisasi : IDI, PAPDI, IRA, PESLI, APLAR

Diagnosis dan Penatalaksanaan Penyakit Autoimun Natsir Akil RS Kanujoso Djatiwibowo Balikpapan

Fakta tentang Penyakit Autoimmune (AI) Etiologi belum diketahui dengan pasti Banyak menyerang wanita muda. Gambaran klinik beberapa penyakit AI juga mirip penyakit Non AI, terutama pada fase dini. Antara satu penyakit AI dengan yg lain juga kadang2 sulit membedakan. Angka kematian cukup tinggi. Pengobatan belum memberi hasil yg memuaskan Efek samping pengobatan

The immune system The immune system is a network of organs, cells and molecules that work together to defend the body against attacks by foreign (not of the body) invaders such as germs, bacteria, viruses, parasites and fungi. We will focus on adaptive responses. All these feature of an adaptive response require very specific interactions of molecules. Will describe B and T cells and their roles. Immunological memory - vaccination

The immune system Anatomic barriers (Skin,mucous membranes) Innate (non-specific) immunity Adaptive (specific) immunity Anatomic barriers (Skin,mucous membranes) Physological barriers (temperature, pH) Phagocytic Barriers (cells that eat invaders) Inflammatory barriers (redness, swelling, heat and pain) Antigen specificity Diversity Immunological memory Self/nonself recognition We will focus on adaptive responses. All these feature of an adaptive response require very specific interactions of molecules. Will describe B and T cells and their roles. Immunological memory - vaccination

Autotolerance Unresponsiveness to self antigens is known as autotolerance Both B-cells and T-cells participate in tolerence but T-cells play the primary role Yamamoto K. JMAJ 2004; 47(9): 403–406.

Clinical Importance of Tolerance 1) Organ transplantation: Introduction of tolerance may help in prevention of rejection 2) Tumor development: Tolerance to tumor antigen results in growth of the tumor without being detected by the immune mechanisms 3) Autoimmune disorders: Disturbance of self-tolerance results in autoimmune disease

HEALTHY PERSON Autotolerance AUTOIMMUNITY SUCCES HEALTHY PERSON Autotolerance FAIL AUTOIMMUNITY AUTOIMMUNE DISEASE

Faktor predisposisi Penyakit Autoimun Genetics Hormones Environment

The Spectrum of Autoimmune disease Organ specific Hashimoto Thyroiditis Primary myxedema Thyrotoxicosis Pernicious Anemia Autoimmune atrophic gastritis Addison’s disease Premature menopause (certain cases) Male infertility (certain cases) Myasthenia gravis IDDM Goodpasture’s syndrome Pemphigus vulgaris Pemphigoid Sympathetic ophtalmia Phacogenic uveitis (Multiple sclerosis) AIHA ITP Idiopathic leucopenia Primary billiaris cirhosis Active chronic hepatitis HBs-ve Ulcerative colitis Sjogren syndrome Rheumatoid arthritis Scleroderma Wegener’s granulomatpsis Poly/dermatomyositis Discoid lupus erythematosus Systemic lupus erythematosus (SLE) The Spectrum of Autoimmune disease The spectrum of autoimmune diseases is very wide. We can find one with very organ specific involvement such as can be seen in Thyroiditis of Hashimoto to the very bizarre and dynamic clinical manifestation in Lupus. There are some factors plays an important role in their pathogenesis and will involved many actors in immune systems. To date we still do not understand why the same actors will lead to a specific autoimmune disease and the others will have a overlapped syndromes. Non-organ specific Kelly et al, Text book of Rheumatology, 2005

Patogenesis Penyakit Autoimun

Type-III Hypersensitivity: Immune Complex Animation: Large quantities of soluble antigen-antibody complexes form in the blood and are not completely removed by macrophages. These antigen-antibody complexes lodge in the capillaries between the endothelial cells and the basement membrane. The antigen-antibody complexes activate the classical complement pathway and complement proteins and antigen-antibody complexes attract leukocytes to the area. The leukocytes then discharge their killing agents and promote massive inflammation. This leads to tissue death and hemorrhage

Type-II Hypersensitivity: ADCC Host cell

Type-II Hypersensitivity: ADCC Host cell

PREDICTIVE AUTOANTIBODIES DISEASE AUTOANTIBODIES Type 1 DM Rheumatoid arthritis Systemic Lupus Erythematosus SjÖgren disease Anti phospholipid syndrome Primary Biliary Cirrhosis Autoimmune hepatitis Crohn’s disease Ulcerative colitis Autoimmune Addison’s disease Autoimmune Thyroid disease Pemphigus Anti-GAD, IA-2, IAA RF (anti IgG), ACPAs/Anti CCP Ab Anti-PL, Anti-Ro, Anti-La, Anti-Sm, Anti-nuclear, Ribonucleoprotein, Anti-dsDNA, Anti-Histone, Anti HS, Anti nucleosome, Anti Ribosomal p protein Anti-Ro, Anti-La Lupus anti-coagulant, Anti cardiolipin Anti-gp120, Anti-PDC ANA ASCA pANCA ACA (adrenal cortec Ab / anti 21 hydroxylase) Anti-TG, Anti-TPO Anti-desmoglein-1 Harel M, Shoenfeld Y. Ann NY Sci Acad. 2006;1069:322-45; Bizzaro N. Autoimmun Rev. 2007; 6:325–33; BizzaroN,TozzoliR,ShoenfeldY. Arthritis Rheum. 2007; 56:1736–44.; ScofieldRH..Lancet.2004;363:1544–6.

Autoimmune disease symptoms Fatigue Achy muscles Swelling and redness Low-grade fever Trouble concentrating Numbness and tingling in the hands and feet Hair loss Skin rashes Alergi Anxiety & depression Sleep Disturbances Memory Problems

Rheumatoid arthritis Wanita : laki2 3 : 1 Artritis pada sendi2 kecil kaku sendi pagi hari lebih dari 1 jam Nodul rematoid Deformitas (swan neck, boutonniere dll) RF positif Anticcp positif

1987 Revised Criteria for classification of RA Morning stiffness * Arthritis ≥ 3 joints * Arthritis of PIP, MCP or Wrist * Arthritis is Symmetric* Subcutaneous nodules RF Radiographic Changes Patient must meet ≥ 4 criteria of the above. N.B: sensitivity 92% and specificity is 89%. * More Than 6 Weeks

ACR/EULAR Criteria 2010 a score of ≥6/10 is needed for classification of patient as having definite RA Joint involvement 1 large joint 0 2-10 large joints 1 1-3 small joints 2 4-10 small joints 3 > 10 joints 5 Serology Negative RF and negative ACPA 0 Low + RF or low + ACPA 2 High + RF or high + ACPA 3 (ACPA=anti-citrullinated protein antibody) Acute-phase reactans Normal CRP and normal ESR 0 Abnormal CRP or abnormal ESR 1 Duration of symptoms <6 weeks 0 >6 weeks 1 Aletaha, A&R, Vol 62, pp. 2569-2581

SLE (Lupus) Wanita : laki2 9 : 1 Demam subfebril Sakit kepala Artritis Malar rash Fotosensitifiti Stomatitis Kejang-kejang Sesak napas Sakit dada Psikosis Insomnia Pucat

ACR 1997 CRITERIA FOR SLE Neurologic Malar rash Pleuritis or pericarditis Cytopenia Positive immunoserology - Anti-dsDNA - Anti-sm - Anti-phospholipid antibodies 11. ANA positive Malar rash Discoid rash Photosensitivity Oral or nasal ulcers Non erosive arthritis Nephritis - Proteinuria >0.5 gm/day - Cellular casts aa Diagnosis SLE ditegakkan jika ditemukan 4 atau lebih dari 11 kriteria

SLICC Classification Criteria for Systemic Lupus erythematosus Requirements : > 4 criteria (at least 1 clinical and 1 laboratory criteria) OR biospy-proven lupus nephritis with positive ANA or Anti-DNA Clinical Criteria Immunologic Criteria Acute Cutaneus Lupus Chronic Cutaneus Lupus Oral or nasal ulcers Non-scarring alopecia Synovitis Serositis Renal Neurologic Hemolytic anemia Leukopenia (<4000) or Lymphopenia (<1000) Thrombocytopenia (<100.000/mm3) ANA Anti-DNA Anti-Sm Antiphospholipid Ab Low complement (C3,C4,CH50) Direct Coombs’ test (do not count in the presence of hemolytic anemia) Inflammatory synovitis with physician-observed swelling of two or more joints OR tender joints with morning stiffness. Renal : urine protein/creatinine (or 24 hr urine protein) representing at least 500 mg of protein/24 hr or red blood cell casts. Neurologic : seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, cerebritis (cute confusional state). Antiphospholipis antibody : lupus anticoagulant, false-positive test for syphilis, anticardiolipin-at least twice normal or medium-high titer, anti-β2 glycoprotein 1 SLICC : Systemic Lupus International Collaborating Clinics Petri M, et al. Arthritis and Rheumatism. Aug 2012

Psoriatic arthritis Oligoartritis pada tungkai bawah Bercak kemerahan di badan (psoriasis) Nyeri tulang belakang Angkilosing spondylitis Inflamatory back pain Sacroilitis Bamboo spine Angkilosis

Antiphospholipid antibody syndrome - Multiple miscarriages - Positif pemeriksaan ACA (anti cardiolipin antibody) dan LA (lupus anticoagulant).

Systemic sclerosis (Scleroderma) Penebalan dan pengerasan kulit Raynaud’s phenomenon Heart burn, GERD, kesulitan menelan

Sjogren syndrome Mata kering Mulut kering Pembesaran kelenjar dileher dan muka

Prinsip pengobatan penyakit AI Menekan aktifitas sistim imun Menggunakan steroid dan obat imunosupressan Mencari keseimbangan antara efikasi dari obat2an dan efek samping pengobatan yang mungkin timbul Mengobati komorbiditas Tindakan non farmakologis

Obat-obatan imunosupressan Steroid Klorokuin/hidroksiklorokuin Methotrexate (MTX) Azathioprine (Imuran) Siklosporin (Sandimun) Cyclophosphamide Cellcept/Myfortic IV IG Biologic agents

Kesimpulan Penyakit AI adalah kondisi dimana sistim imun tidak mengenali dirinya sendiri dan membentuk berbagai macam sel dan autoantibodi yang menyerang berbagai macam organ. Etiologi belum diketahui dengan pasti. Ada dua sel yang sangat berperan didalam patogenesis penyakit AI yaitu sel B dan sel T. Proses kejadian AI, dimulai dengan terbentuknya autoantigen, yang kemudian dipresentasikan oleh sel APC ke sel T, selanjutnya sel T mengaktifkan sel B, yang selanjutnya membentuk autoantibodi. Bertemunya autoantigen dan autoantibodi merupakan awal dari terjadinya kerusakan orga. Pengobatan belum memberi hasil yang memuaskan, beberapa obat yang sering digunakan adalah steroid, Imuran, sandimun, MTX, hydroxyclorokuin, siklofosfamid, cellcept, dan myfortic. Myfortic memiliki efektifitas di banding cellcept dan efek samping yg minimal.

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