Pharmaceutical Care Pd Systemic Lupus Erythematosus ( Sle)

PHARMACEUTICAL CARE PD SYSTEMIC LUPUS ERYTHEMATOSUS SLE)

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PENDAHULUAN  Systemic lupus erythematosus - Autoimmune diseases  connective tissue diseases multisistem - Disebabkan oleh kompleks autoantibodies dan immune  abnormal immunologic function and formation of antibodies against "self-antigens” - Manifestasi penyakit tgt pd the tissues targeted dan musculoskeletal involvement - Pd umumnya melibatkan satu sistem organ pd onset, ttp dpt mempengaruhi sistem organ lain - Tjd pd wanita usia 16-45 thn

• Etiologi -Genetic  histocompatibility complex genes ( human leukocyte antigen genes), non major histocompa-tibility complex genes (immunoglobulin receptor genes and mannose-binding protein genes) - Environmental agentssunlight (i.e., ultraviolet light), drugs, hydrazine (found in tobacco),aromatic amines (found in hair dyes), diet, environmental estrogens,infection with viruses or bacteria (Epstein Barr virus ), hormonal

• Hormonal  androgen may inhibit and estrogen may enhance the expression of autoimmunity, elevated circulating prolactin levelsassociated with lupus in males and females

- SLE can be diagnosed if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.

PATOFISIOLOGI

• An excessive and abnormal autoantibody produc-tion and the formation of immune complexes Against multiple nuclear, cytoplasmic, surface components of multiple types of cells in various organ systems in addition to soluble markers (immunoglobulin G & coagulation factors)  the multipleorgan system involvement of the disease o Excessive autoantibody production results from hyperactive B lymphocytes

• Mekanisme hiperaktivitas sel B : loss of immune self-tolerance and high antigenic load (environmental and self-antigens presented to B cells by other B cells or specific antigen-presenting cells, a shift of T-helper type 1 cells to T-helper type 2 cells)

B-cell antibody production , defective Bcell suppression Impairment in other immune regulatory processes ( T lymphocytes (suppressor T cells), cytokines ( IL, interferon, TNF, transforming growth factor), natural killer cells )

• Antinuclear antibodies (autoantibodies that are directed against nuclear constituents of the cell ) Penegakan diagnosis SLE -The SLE patient  have > 1 antigen-specific antinuclear antibody Against nuclear constituents as - double-stranded DNA (dsDNA) - single-stranded, or denatured DNA (ssDNA) - RNA - Antibodies to dsDNA  highly specific for SLE ( 70% to 80% of patients)

MANIFESTASI KLINIK

• Diagnosis - based on clinically sign & symptom - serologic tests  the fluorescent antinuclear antibody (ANA) test ( kurang spesifik krn bisa (+) pd peny lain) - dsDNA and to Sm antigen  quite specific for diagnostic of SLE

PROBLEMA MEDIK 1. SLE 2. CKD 3. Liver disease 4. Diabetes mellitus 5. Cardiovascular disease 6. Peptic ulcer disease 7. Melena 8. Haematologic disorder 9. Infection 10. Pregnancy 11. Marital status

Penatalaksanaan Problema medik 1. SLE - Desired treatment outcomes of SLE : ) Management of symptoms & induction of remission during times of disease flare ) Maintenance of remission for as long as possible between disease flares - Macam terapi : a. Nonpharmacologic Therapy - A balanced routine of rest and exercise, while avoiding overexertion - Avoidance of smoking ( hydrazines in tobacco smoke  trigger of lupus and accelerated CAD - Limit exposure to sunlight and use sunscreens

b. Pharmacology • NSAIDS - Mild disease, arthritis - Short therm used - Patients with SLE  higher incidence of hepato-toxicity because of NSAIDs than do other ,asso-ciated with aseptic meningitis ( reaksi hipersensitivi-tas) - Monitor : efektivitas, ESO → lihat pd pharm care RA / OA

• Antimalarial Drugs - chloroquine,hydroxychloroquine - manifestations of SLE that can be managed with antimalarials  cutaneous , arthralgia, fatigue, fever - long-term used - Response to chloroquine 1 to 3 months - Maximal effect of hydroxychloroquine may occur for 6 to 12 months - Hydroxychloroquine first choice ( safer than chlo-roquine )

-The mechanism of action  interfere with T-lymphocyte activation  inhibition of cytokines  decreased sensitivity to ultraviolet light  anti-inflammatory activity  antiplatelet effects  antihyperlipidemic activity  immunomodulation without causing overt immuno-suppression - Dosage and duration of therapy depend on :  patient response  tolerance of side effects  development of retinal toxicity ( irreversible )  long-term therapy (chloroquine )

 Dose : - hydroxychloroquine 200 to 400 mg/day - chloroquine 250 to 500 mg/day ( btk basa ) - After 1 or 2 years of treatment  gradual tapering of dosage - 1 or 2 tablets / week to suppress cutaneous manifestations  ESO : - CNS effects (headache, nervousness, insomnia) - reversible ocular toxicities such as cycloplegia and corneal deposits - Potentially serious retinal toxicity (permanent damage )  retinopathy ophthalmologic evaluation every 3 months (chloroquine ), 12 months ( HCQ )

• Corticosteroids -For mild disease (fever, arthralgia, pleuritis, or skin manifestations)  as NSAIDs or antimalarials -For severe lupus nephritis, but evidence suggests  corticosteroids are also effective in the management of severe cases (CNS disease, pneumonitis, myositis, vasculitis, thrombocytopenia ) - The goal of treatment  to suppress and maintain suppression of active disease with the lowest dose possible

- Dose : * For mild disease  low-dose therapy (prednisone 10 to 20 mg/day) * For more severe disease (severe hemolytic anemia or cardiac involvement) higher doses ( prednisone 1 to 2 mg/kg daily) - Once adequate suppression of disease is achieved,  the dose should be tapered to the minimum amount required for continued disease suppression - In clinical practice → methyl prednisolon ( commonly used ) → dose equivalency with prednison ( prednison 10 mg ~ 8 mg methyl prednisolon )

-Consider to conditions of corticosteroid therapy  infection, hypertension, atherosclerotic disease, dia-betes, obesity, osteoporosis, psychiatric disease -Steroid pulse therapy * short-term, high-dose i.v corticosteroids * inducing remission in SLE patients with serious, life-threatening disease ( severe active nephritis, CNS in-volvement, hemolytic disease) A standard pulse regimen i.v methylprednisolone 500 to 1,000 mg for 3 to 6 consecutive days - Pulse therapy usually is followed by high-dose prednisone (1 to 1.5 mg/kg/day) therapy that is tapered to low-dose maintenance therapy

- Potential advantages :  quicker response and avoidance of side effects ( longterm therapy required with oral steroids) - ESO : infection, gastrointestinal disturbances, rapid increases in BP, arrhythmias, seizures, sudden death, hyperglycemia

Immunosuppressant Agents - Act as immunosuppressives, cytotoxic and anti-inflammatory agents - It’s indicated if disease symptoms are : *severe, organ damage is occurring, symptoms are not responding to other therapies  Cytotoxic Drugs - Alkylating agent (cyclophosphamide ) , antimetabolite (azathioprine)

 Cyclophosphamide - The mechanism of actioninvolve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells - i.v (intermittent pulse doses) to minimize toxicity - To decrease the risk of bladder toxicity :  hydrated with oral or intravenous fluids  monitor urinary output  + Mesna  prevent hemorrhagic cystitis  dose : 20% of the total cyclophosphamide

- Combination prednisone + cyclophosphamide *standard treatment for focal and diffuse proliferative lupus nephritis * It’s superior to prednisone  the mainstays of immunosuppressive therapy * to suppress and stabilize extrarenal disease activity * focused on lupus nephritis  a major factor asso-ciated with morbidity and mortality in SLE * Controlled clinical trials  cyclophosphamide im-proves long-term outcomes in lupus nephritis

- No studies have evaluated cyclophosphamide in earlier stages of nephritis -Corticosteroids  treatment of choice for the initial treatment of nephritis - Pulse i.v cyclophosphamide + prednisone  more effective at slowing progression to end-stage renal disease than either prednisone alone or prednisone plus azathioprine

- Dose :  combination with corticosteroids  cyclophosphamide : 1 to 3 mg/kg for p.o and 0.5 to 1 g/m2 BSA (i.v) better than oral )  the optimal duration of treatment  no evidence  empirical experience dosed monthly for 6 to 7 months and then every 3 months for a period of either 2 years or for 1 year after the nephritis is in remission  ESO : serious toxic effects  suppression of hema-topoiesis, opportunistic infections, bladder compli-cations ( hemorrhagic cystitis and cancer), sterility, teratogenesis

 Azathioprine - Antagonizes purine metabolism and inhibits syn-thesis of DNA, RNA, proteins  decrease prolife-ration of immune cells lower autoimmune activity - It has “steroid-sparing" agent reduction of cortico-steroid doses - Data do not support the use of azathioprine as a part of an induction regimen - Long-term maintenance therapy → prevent renal flares after successful induction with cyclophos-phamide - Dose : 1 to 3 mg/kg per day,combination with corticosteroids ( severe disease)

- less toxic than cyclophosphamide, but adverse reactions may be serious → myelosuppression, opportunistic infections including (herpes zoster), cancer, hepatotoxicity, and ovarian failure • Methotrexate - used for managing resistant arthritis, serositis, cuta-neous - It blocks purine synthesis and 5-aminoimidazole4-carboxamide ribonucleotide (AICAR)  increasing anti-inflammatory adenosine concentration at sites of inflammation - Dose : 5–15 mg orally ( single weekly dose) or three divided doses per week every 12 hours

 Mycophenolate mofetil - Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes inhibiting their proliferation and antibody production. - effective treatment → severe renal and nonrenal lupus refractory to conventional cytotoxic agents - In an open-label trial  more effective than standard cyclophosphamide therapy ( higher rate of complete and partial remissions) - + corticosteroid  mild to moderate nephritis and good renal function

New therapeutic agents (phase I, II, III trials) (As immunomodulator) - restore the potential to minimize self-immunity

 Belimumab - it was approved by FDA in 2011 - It is a human monoclonal antibody - It is a B-lymphocyte stimulator (BLyS) specific Inhibitor - It is indicated to treat patients with active disease,who are auto-antibody (+), and already receiving treatment for SLE - ADR : risk of serious infections, hypersensitivity reactions, depression and suicide

Monitor Adverse drug reaction

2. CKD - Problema medik pemakaian NSAID pada penyakit SLE dgn CKD identik dgn OA/RA - Methotrexate menyebabkan renal disfunction → kenaikan Cr dan BUN , penurunan vol. urin ( dosis tinggi, presipitasi obat) - Penyesuaian dosis MTX perlu dilakukan pd CKD * Clcr 10-50 ml/mnt : turunkan dosis ad 30-50% * ClCr < 10 ml/mnt : avoid use * pada HD , PD : tdk terdialisa, tdk perlu penambah-an dosis - Pada chloroquin : * Clcr < 10 ml/mnt: turunkan dosis 50% * Terdialisis minimal

- Metilprednisolon dpt tingkatkan TD, retensi Na yg dpt percepat progresivitas renal disease - Azathioprine : -Clcr 10-50 ml/mnt : 75% dr dosis lazim - Clcr < 10 ml/mnt : 50% dr dosis lazim

- Cyclophosphamide : menyebabkan SIADH ( dosis > 50 mg/kg), renal tubular necrosis * Clcr : < 10 ml/mnt : gunakan 75% dr dosis lazim * terdialisis moderat ( 20-50%), perlu penambahan dosis - Mycophenolate mofetil : not removed by haemodia-lysis and PD, tingkatkan BUN, Cr - Monitor : kadar Cr, BUN ( tiap 3 hari) , vol urin, TD,oedema

• Liver disease - - Pemberian NSAID akan meretensi Na ( perberat ascites ) dan picu hematemesis melena pd CH - Azathioprine bisa sebabkan hepatotoxicity - Methotrexate akan sebabkan cirrhosis & portal fibrosis ( jk lama ), peningkatan akut liver enzyme ( dosis besar ) - Kortikosteroid : ulcerative esophagitis, picu gastric bleeding ( pada pasein CH) - Mycophenolate : LFT abnormal ( 25%), hepatotoxi-city ( transaminase, ALP ,bilirubin and GGT increased, jaundice , cholestatic jaundice → 3-20%)

- Cyclophosphamide : * Hepatotociicity ( < 1%) * PK unchanged in hepatic insufficiency * Bilirubin 3,1-5 mg/dL or transaminase > 3 x ULN → administer 75% dose * avoid use if serum bilirubin > 5 mg/dL - Monitor : BB, warna faeses, ALT, AST,bilirubin total, ALP, GGT)

3. Diabetes mellitus - Penggunaan kortikosteroid akan perparah hiperglikemia - Mechanism of action : * Impairs both glucose transport in fat and muscle cells and the ability of glucose to stimulate its own utilization (glucose effectiveness) →reducing glucose clearance * To direct harmful effects on insulin-secreting beta cells of the pancreatic islets by inducing apoptosis * Reduced GLUT-2 expression and decrease in glucose transport into the beta cells

- The risk of corticosteroids - induced hyperglycemia increases : * corticosteroid dosage * duration of therapy * advanced patient age * family history of DM * obesity * high blood glucose concentrations before therapy * it depends on the route of administration - Monitor ketat kadar glukosa darah

4. Cardiovascular disease - Penggunaan NSAID akan meretensi Na, hambat prosta-glandin →tingkatkan TD, perburuk HF - Cyclophosphamide akan perberat HF - Mychophenolate → cause HT, aritmia, CHF, AF dll - Chloroquin bs sebabkan cardiomyopathy ( fre-quency not defined), aritmia - Kortikosteroid ( t.u sediaan injeksi) → retensi Na → tingkatkan TD, edema - Monitor ketat : TD, edema, profil ECG

5. Peptic ulcer disease - Pemasalahan pemakaian NSAID pd pasien SLE dgn PUD ~ OA - Kortikosteroid : perparah PUD terkait hambat PG - Methotrexate : sebabkan perforasi intestinal - Cyclophosphamida : mual dan muntah - Mycophenolate : esofagitis, gastritis, GIT haemor-rhage, melena - Perlu pemberian profilaksis stress ulcer - Monitor : GI discomfort, gastric bleeding ( warna faeses )

6. Melena - Pemberian NSAID akan perparah melena → life threatening → pemakaian ditunda - Tramadol , Cox-2 inhibitor adalah pilihan bila kondisi melena teratasi - Monitor : warna faeses

7. Haematologic disorder - Penggunaan NSAID menyebabkan anemia, trombositopenia - Penggunaan immunosupressant menyebabkan myelosupressant effect → haematologic disorder - Azathioprine : bleeding, trombositopenia, leukopenia, pansitopenia terkait efek myelosupressive - Cyclophosphamide : trombositopenia, anemia - Methotrexate : leukopenia, trombositopenia - Chloroquine : anemia aplastik, trombositopenia, neutropenia - Mychophenolate : leukopenia, thrombocytopenia - Monitor secara ketat leukosit, trombosit, Hb, eritrosit

8. Infection - Penggunaan obat imunosupressan ( t.u kortikosteroid ) dpt menekan sistem imun (immuno-deficiency → picu opportunistic infection - Dosis yg digunakan sekecil mgkn dan jk pendek bila memungkinkan - Monitor : tanda – tanda infeksi ( leukosit, suhu,kondisi umum )

9. Pregnancy - exacerbation of SLE :  early postpartum period  a greater incidence of spontaneous abortion  a greater chance of developing preeclampsia or pregnancyinduced hypertension - Disease exacerbations,managed by :  aggressively with corticosteroids  hydroxychloroquine - Cyclosporine, methotrexate, mycophenolate mofetil  contraindicated in pregnancy ( teratogen,fetal loss) - Azathioprine  safe - NSAIDs  safe in pregnancy  discontinued during the last weeks of pregnancy due to risk of premature closure of the ductus arteriosus

10. Marital status - Pemberian imunosupresive drug pd pasien SLE sering menimbulkan problema fertilitas • Cyclophosphamide : menyebabkan infertilitas ( ganggu oogenesis & spermatogenesis), irreversible, supresi gonad ( amenorrhea) ,premature ovarian failure - Methotrexate : defective oogenesis & spermatogenesis - Mycophenolate : impotence ( 3% - < 20%)

asessement Drug related problem 1.Drug induce a. Drug-Induced Lupus ( DIL) - Procainamide and hydralazine  most commonly with DIL (definite) - Chlorpromazine, methyldopa, INH, mynocy-cline, quinidine (definite) - Estrogen-containing oral contraceptives * Uncontrolled trials oral contraceptives exacerbate SLE - Symptoms : musculoskeletal (i.e., arthralgias,myalgias), constitutional (i.e., fatigue and fever), pleuropericarditis → procainamide

- The

patient may have an ANA (+), but will rarely test positive for the lupus-specific antibodies

risk of thrombotic events for estrogentreated women and thrombosis in SLE  antiphospholipid antibodies should be measured  oral contraceptives should be avoided if antibodies (+) - Recomendation : stop the drug ( if factual), closely monitored the simptoms of SLE, ANA/dsDNA ,the simptom of SLE ( if potential ) - It is not advisable to rechallenge with the drug, especially when alternatives are available - Monitor : simptoms of SLE, ANA/dsDNA test

b. Gangguan hematologi (anemia, trombositopenia, leukositosis, leukopenia) - pemakaian immunosupresan, kortikosteroid, NSAID c. Gastric bleeding : pemakaian NSAIDs, kortikoste-roid d. Gastritis : pemakain NSAIDs, kortikosteroid e.Drug induce hyperglikemia : pemakaian kortiko-steroid f. DILI peningkatan ALT, bilirubin > 3 x nilai baseline - Pemakaian MTX, azathioprine, mycophenolate, kortikosteroid g.Drug induce kidney diseaseBUN dan Cr  (  30%) - pemakaian NSAID, MTS, azathioprine, cyclophos-phamide

h.Drug induce hipertensi - Pemakaian NSAID, kortikosteroid ( t.u injeksi),cyclophosphamide,mycophenolate,chlor oquin  Rekomendasi - Stop obat yg dicurigai penginduce - Ganti dgn obat lain yg lbh aman - Pemberian obat utk mengatasi akibat drug induce - Turunkan dosis obat ( dechallenge) bila masih diperlukan & tdk ada alternatif lain

Monitoring ketat - Data klinik : TD, warna BAB, abdominal discomfort, nyeri, inflamasi - Data lab : nilai ALT/ALP, bil. total, Cr serum, BUN, Hb, trombosit, leukosit, glukosa drh

2. Kegagalan terapi  dosis subterapetik  tidak respon / resisten pd obat  non adherence  lama terapi kurang  adanya underlying disease, komorbid  sosio – ekonomi

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Rekomendasi Tingkatkan dosis Tingkatkan dosis / kombinasi / ganti dgn alternatif obat lain Edukasi ttg penyakit & tujuan terapi obat Pengatasan underlying disease/komorbid dgn terapi obat yg tdk berinteraksi scr bermakna dgn obat utk SLE - Pilihkan dgn obat yg lbh murah tapi cost-effective  Monitor - Respon obat thd progresifitas SLE  Kondisi klinik : malar rash, alopecia,athralgia,-arthritis, photosensitivity, neurologic dysorder  data lab : leukosit, Hb, trombosit, Cr, BUN, ALT/AST

3. Inappropriate drug  pemberian imunosupresan yg mengganggu proses reproduksi → cyclophosphamide, MTX  Rekomendasi - stop obat dan ganti dgn azathioprine atau myco-phenolat ( bila pasien wanita ) 4. Overdose  dosis obat lebih pd SLE dgn renal impairment  Rekomendasi - Dose adjustment  Monitor - Data klinik : symptom of SLE - Data lab : Cr, BUN

• Konseling - Non farmakologi : hentikan merokok, limitasi ter-papar matahari ( gunakan sunscreen) - Farmakologi :  kepatuhan minum obat  longtherm therapy  efek samping obat  hepatotoksisitas krn azathioprine

1. Ny. Es usia 23 tahun, tinggi 160 cm, BB 55 kg, masuk rumah sakit husada dengan keluhan atralgia, kekakuan sendi, demam naik turun selama 1 minggu. Riwayat penyakit adalah gastritis. Pasien adalah ibu muda yang belum punya anak . Data klinik : malar ( butterfly) rash ,pada kedua pipi, fotosensitivitas pada kedua tangan dan kaki, suhu 38 C, nadi 90x / mnt, RR 20 x / mnt, TD 150 / 100 mmHg, . Data lab : leukosit 14.000 / mm3 , Hb 8,5 g/dL, trombosit 90.000 g/dL, dsDNA (+). Pasien didiagnosis SLE. Dokter memberi terapi : NaCl : RL = 2 : 2, metilprednisolon 3 x 16 mg, siklofosfamida 1 x 800 mg infus i.v, amoksisillin 3 x 500 mg.

2. Pasien a.n Nn S, usia 26 thn, MRS di RS Semangat tgl 6 Oktober 2014 dgn keluhan kemerahan pada kulit wajah dan dada, kejang. Pasien rujukan dari RS. Buana yg sdh mendapat terapi prednison oral.Pasien memiliki riwayat perawatan kulit wajah dgn kosmetka. Pasien belum menikah. Data klinik : TD, nadi, RR dbn, suhu 38oC; data lab. WBC 11.300 / mm3,, HB 7,5 g/dL ,GDA 96 g/dL, ANA test (+) . Pasien terdiagnosis SLE dan mendapat terapi metilprednisolon inj. i.v 2 x 500 mg selama 3 hari, fenitoin inj. 3 x 2 amp dilanjutkan fenitoin kapsul 3 x 1,cefoperazon 3 x 1 g, mychophenolate tab. 2 x 1, chloroquin 2 x 250 mg. Kondisi pasien makin menurun, malar rash pada wajah semakin melebar.

3. Pasien a.n Nn S, usia 29 thn, MRS di RS Saudara tgl 10 Nopember 2015 dgn keluhan nyeri pada persendian lengan dan kaki , terdapat bercak kehitaman pada kulit tangan. Keluhan dirasakan 2 minggu sebelum MRS. Pasien baru nikah dan hamil 4 bulan. Data klinik : TD, nadi, RR dbn, suhu 38oC. Data lab. WBC 12.000 / mm3,, HB 8,3 g/dL, glukosa dbn, trombosit 50.000 / mm3,ANA test (+) . Pasien mendapat terapi kloroquin 2 x 250 mg , metilprednisolon inj. i.v 2 x 250 mg selama 3 hari, micophenolat mofetil 1 x 1 tab, ceftriaxone 1 x 2 g. Setelah terapi, pasien tetap demam dan TD 150/90 mmHg.