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PendidikanPendidikan
- - Dokter umum FK UNSRI PalembangDokter umum FK UNSRI Palembang
-Internist FK UNPAD BandungInternist FK UNPAD Bandung
-Subspesialis Reumatologi FK UI Subspesialis Reumatologi FK UI JakartaJakarta
- Clinical Rheumatology and - Clinical Rheumatology and Osteoporosis Training – Perth - WAOsteoporosis Training – Perth - WA
Rachmat Gunadi WachjudiRachmat Gunadi WachjudiLahir di Garut 16 Januari 1955Lahir di Garut 16 Januari 1955
PekerjaanPekerjaan
Ka Div ReumatologiKa Div Reumatologi
Departemen Ilmu Penyakit Dalam Departemen Ilmu Penyakit Dalam Rumah Sakit dr Hasan Sadikin Rumah Sakit dr Hasan Sadikin BandungBandung
Organisasi: IDI, PAPDI, IRA, PEROSI, PERALMUNI
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Preventing infection in patients with autoimmune diseases
Illustrated in Lupus
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Causes of Autoimmunity
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Pick an organ, any organ . . .
Autoimmunity can affect ANY organ/organ system in the human body
Psoriasis
Multiple Sclerosis
Sjogren’s Syndrome
Rheumatic Fever
Autoimmune Hepatitis
Ulcerative Colitis
Systemic Lupus Erthematosus
Diabetes
Autoimmune Uveitis
Autoimmune hemolytic Anemia
Addison’s Disease
Rheumatoid Arthritis
Autoimmune Oophoritis
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Autoimmunity Classification
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Examples of Organ Specific
Lungs of a patient with Goodpasture’s
VitiligoHashimoto’s disease (thyroiditis)
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Autoimmune diseases…….
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Examples of Systemic Autoimmunity
SLE
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Examples of Systemic AutoimmunitySjogren’s Syndrome
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Rheumatoid Arthritis
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Major Features of Active Autoimmune disease
• Constitutional – fatigue, malaise, fever, arthralgia, myalgia
• Variable organ involvement
– Arthritis, pleurisy, pericarditis
– Raynauds phemomenon, vasculitis, stroke
– Mucocutaneous – rashes, oral ulcers, sicca syndrome,
– Kidney, CKD, NS
– Neuropsychiatric – psychosis, seizures, transverse myelitis
• Variable abnormalities in laboratory testing
– High ESR, CRP, anemia, low WBC, platelets, abnormal urinalysis
– RF, ACPA, Anti Scl-70, anti-DNA, low complement levels (C3, C4)
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The damages
• Disease damage
– CKD, cognitive dysfunction, ovarial failure
• Drug related
– Obesity, hypertension, diabetes
– osteoporosis, avascular necrosis
– Dyslipidemia
– Striae
• Premature atherosclerotic disease
– heart attack, stroke, heart failure
• Infection … opportunistic
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Life threatening
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Current Therapies• Immunosuppressive drugs
- corticosteroids, azathioprine
- slows the proliferation of lymphocytes
Cyclosporin A
• Biologic agents
• Thymectomy
• IvIg
• Plasmapheresis
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Infections• Are one of the most common causes of
– morbidity,
– hospitalization
– death
in patients with systemic lupus erythematosus
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Infection in SLE • is complex, different populations
• Hospitalized and ambulatory cohorts
• Regional differences in pathogens.
• Opportunistic infections in SLE, may be underreported
• Guidelines for antimicrobial prophylaxis exist for persons with HIV or patients undergoing hematopoietic stem-cell transplant and have decreased incidence of death and hospitalization due to opportunistic infections such as pneumocystis.
• Guidelines for Infection Prevention in SLE ?
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Systematic strategy
• In the absence of definitive studies on the use of infection prophylaxis in SLE, we propose a systematic strategy for preventing opportunistic infections in SLE patients
starting with their first clinical evaluation
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Infections
• A major cause of mortality in systemic lupus erythematosus
• In a large multicentre European cohort of 1000 patients followed over 10 years, infections represented the cause of death in 25% of cases and active SLE in 26.5%.
• Bimodal distribution to death in SLE
– Infections and active disease causing death within the first 5 years of diagnosis,
– myocardial infarctions and thrombotic events occurring later
• Infections are also responsible for 14–50% of hospitalizations in patients with SLE[and are a cause of significant morbidity. (46% RSHS)
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Risk factors for infection in systemic lupus erythematosus
• Disease-associated risk factors
• Disease activity or organ damage
• Medications
• Laboratory findings
• Other risk factors
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Immune defects seen in patients with systemic lupus erythematosus and potential pathogens
• Hypocomplementemia : Neisseria species, Streptococcus pneumoniae
• Hyposplenism: Streptococcus pneumonial , Haemophilus influenzae , Neisseria meningitidis, Salmonella species
• Impaired phagocytic cell activity: Bacterial and fungal infections (variety of potential organisms)
• Impaired T-cell activity: Herpes simplex and herpes zoster, Epstein Barr virus and CMVHuman papillomavirus, Influenza, Listeria monocytogenes , Nocardia species , Cryptococcus neoformans , Mycobacterium tuberculosis , Nontuberculous mycobacteria, Pneumocystis jirovici , Histoplasma capsulatum, Coccidiodes immitis, Toxoplasma gondii
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Glucocorticoids
• Broad effects on innate and adaptive immune system:
• Decreased cell-mediated immunity
• Decreased inflammatory response
• Decreased immunoglobulin synthesis
• Lysis of lymphoid follicles
• Broad variety of pathogens including
– Bacteria (Salmonella species, Listeria monocytogenes, Nocardia species)
– Viruses (herpes simplex virus, varicella zoster virus)
– Fungi (Pneumocsystis jiroveci,Candida species, endemic mycoses)
– Parasites: Strongyloides stercoralis
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Other immunosuppressive agents:
• Azathioprine, cyclophosphamide, mycophenolate mofetil
Lead to decline in numbers of B and T cells
– Bacteria (Salmonella species, Listeria monocytogenes, Nocardia species)
– Viruses (herpes simplex virus, varicella zoster virus)
– Fungi (Pneumocsystis jiroveci,Candida species, endemic mycoses)
– Parasites: Strongyloides stercoralis
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Bacterial Infections
• The majority of reported infectious complications in patients with SLE are bacterial
• The most frequent types of infections are respiratory, urinary tract and soft tissue infections.
• Case series also suggest an increased risk of nontyphoid salmonella infection.
• Prompt treatment of any identified or suspected infection is recommended.
• Patients with SLE in which a delay in antimicrobial therapy (> 24 h) a higher risk of mortality
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Vaccination
• Pneumococcal Vacc considered well tolerated recommended for patients with SLE.
• Although disseminated Neisserial infections have been reported in patients with SLE and some authors advocate for meningococcal vaccination, no guidelines exist to date and there is little research in this area.
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Varicella Zoster Virus
• Most commonly reported viral infections in SLE, from reactivation of latent varicella zoster virus.
• Disseminated disease in patients with SLE or may be complicated by superinfection and postherpetic neuralgia.
• Annual incidence of 6.4 events/1000 patient years. (38 HZ case in 69 SLE pts /5 yr)
• Herpes zoster is a late complication: 5 years after SLE diagnosis
• Commonly during periods of inactive or mild SLE disease activity.
• Risk factors for herpes zoster include renal disease, concurrent or prior malignancy and azathioprine and cyclophosphamide use
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H zoster vaccination
• Centre for Disease Control Advisory Committee on Immunization Practices recommends vaccination in
• patients over age 60, 2–4 weeks prior to any anticipated immunosuppression, including high dose prednisone (≥20 mg/day lasting ≥2 weeks).
• At least 1 month after discontinuation of such therapy:
• Low doses of methotrexate (≤0.4 mg/kg/week) or azathioprine (≤3.0 mg/kg/day) is not contraindicative to the administration of zoster vaccine.
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Human Papillomavirus
• A common viral infection in patients with SLE.
• HPV types 16 and 18 are associated with squamous intraepithelial lesions (SIL) and cervical cancer.
• High numbers of patients with SLE have HPV infection and SIL and women with SLE have a three-fold increase in the rate of abnormal cervical cytology smears compared with the general population.
• There are currently no recommendations or data regarding the use of this vaccine in patients with SLE, but it should be offered to patients meeting recommendations for the general population.
•
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Cytomegalovirus
• Is common in the general population with seropositivity estimated at 60–70%.
• Over 90% of SLE patients are seropositive for CMV, antigenemia is detected in 18–44% of patients, whereas overt clinical disease is rare but carries a high risk of mortality.
• Given the potential for morbidity in immunosuppressed patients with SLE who develop end-organ disease, we recommend vigilance on the part of the clinician in considering CMV as a possible cause of unexplained cytopenias, persistent fevers, colitis or retinitis in patients receiving immunosuppressive medications for the treatment of SLE.
•
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Influenza
• The annual incidence of influenza in the general population is 5–20%; however, the rate of infection in SLE patients is not well defined.
• The influenza vaccine is the most effective way to prevent infection and reduce morbidity and mortality; however, it is slightly less immunogenic in patients with SLE.
• Given the risk of potentially more severe presentations of influenza in patients with SLE, yearly vaccination is recommended.
•
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Hepatitis B and C Virus Infection
• European League Against Rheumatism (EULAR) guidelines for monitoring patients with SLE recommend screening of all patients with specific risk factors for hepatitis B and C infection at their first visit and serve as a useful guide for ensuring quality of care in patients with SLE.
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Myobacterium Tuberculosis
• The frequency of Mycobacterium tuberculosis (TB) infections in patients with SLE in endemic countries is approximately 5%. TB in SLE occurs commonly in extrapulmonary sites and may be associated with more severe pulmonary involvement.
• In a study from California, 25% of SLE patients were found to have latent TB infection.
• One of the most important risk factors for TB reactivation is corticosteroid use.
•
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American and Canadian guidelines
• Recommend that patients with prolonged therapy with corticosteroids (prednisone >15 mg/day or equivalent for 2–4 weeks), who have a positive tuberculin skin test, indicating latent TB infection, should be treated with preventive therapy.
• In endemic countries, use of isoniazid preventive therapy in patients with rheumatic disease who are treated with prednisone more than 15 mg/day for more than 3 months, independent of tuberculin skin testing, can decrease the risk of developing TB by 70%.
• Given the morbidity of TB, we recommend tuberculin skin testing in patients from endemic areas prior to the initiation of immunosuppressive therapy to identify patients with latent TB infection who are candidates for INH preventive therapy.
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Pneumocystis jiroveci (Pneumocystis carinii)
• Is a common cause of pneumonia in immunosuppressed individuals and is associated with a variety of immune deficits; however, the main risk factors include cellular immune deficiency resulting from corticosteroid and cytotoxic drug therapy
• The attack rate of P jiroveci pneumonia (PJP) in patients with connective tissue disease has been estimated at less than 2%, although the exact incidence in SLE patients is difficult to estimate.
• Infection occurred between 6 and 7 months after immunosuppression had been initiated and had a mortality rate of 20%. SLE patients infected with P jiroveci had a higher disease activity and renal involvement was more common
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Pneumocystis prophylaxis
• There is a higher rate of intolerance to TMP-SMX in SLE patients with up to 52% of patients experiencing an adverse reaction, usually cutaneous rashes.
• Sulfonamides may be associated with
– worsening SLE.
– risk of marrow suppression
– hemolysis and is not ideal in renal failure.
– hepatotoxicity, gastrointestinal intolerance and nephrotoxicity. Lastly
• TMP-SMX may interact with a number of other immunosuppressive medications including azathioprine, methotrexate and mycophenolate mofetil and potentiate neutropenia
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Pneumocystis
• Patients on at least 30 mg of prednisone daily are at higher risk for pneumocystis and infection has been reported to occur after a median of 12 weeks of therapy.
• Some experts recommended that PJP prophylaxis be considered in patients on at least 16 mg of prednisone daily for more than 8 weeks.
• Special consideration should be given to lupus patients who are receiving combination therapy with prednisone and cytototoxic agents such as cyclophosphamide.
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Strongyloides stercoralis
• Is a nematode endemic in tropical and subtropical regions and it infects up to 100 million people each year worldwide. Persons chronically infected with S. stercoralis may be asymptomatic
• Disseminated strongyloidiasis has been described in patients with SLE on immunosuppressive agents, especially corticosteroids.
• The clinical presentation of the S. stercoralis hyperinfection syndrome may be variable and may mimic some features of SLE including pulmonary hemorrhage or vasculitis.
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Srongiloides stercoralis
• It is recommended that patients from endemic areas (generally tropical and subtropical areas) be screened with serologic testing. Alternatively, microscopic evaluation of stool samples or duodenal fluid for ova and parasites may yield positive results; however, multiple samples may need to be obtained to demonstrate infection.
• If infection is detected, Ivermectin should be prescribed to eradicate infection.
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Other Rare Infections
• Other rare opportunistic infections have been reported in SLE patients including Mycobacterium avium
• Invasive fungal infections such as Cryptococcus
• Aspergillus and Candida species.
• No trials on prevention of these infections exist and diagnostic vigilance is required.
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Additional Strategies to Prevent Infection
• Basic hygiene and sanitation including frequent hand washing are the cornerstones of prevention of many infectious diseases and bear mention.
• Judicious use of immunosuppressive therapy may lessen infection risk.
• Interestingly, antimalarials may have protective effects against infections, an observation which bears further study.
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Conclusion
• Infections are a common cause of morbidity and mortality in SLE and few guidelines exist on preventing infections in SLE, especially opportunistic infections.
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A checklist to be utilized to identify patients at risk
• Yearly influenza shot – give or recommend to family medical doctor.
• Pneumococcal vaccination – give or recommend to family medical doctor (every 5 years).
• Regular pap smears to screen for cervical dysplasia caused by HPV – recommend to family medical doctor or gynaecologist. There are currently no recommendations or data regarding the use of the HPV vaccine in patients with SLE outside of recommendations for the general population.
• TB skin test prior to starting immunosuppressive agents and treatment with isoniazid (INH) for patients with latent TB infection.
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Checklist
• Hepatitis B serology at baseline in all patients.
• Hepatitis C serology at baseline in patients with risk factors.
• HIV serology at baseline in patients with risk factors.
• Screening for strongyloides in patients from endemic areas (strongyloides serology) prior to starting immunosuppressive agents and treatment with ivermectin if infected.
• Vaccination against herpes zoster should also be considered for patients with SLE who meet the criteria
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Orchestration
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Further reading
• Curr Opin Rheumatol. 2011;23(4):358-365. © 2011
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Thank you
For your participation in
Reumatologi Klinik Bandung 9-10 Feb 2013