32세 여자

(1)

(2)



32세 여자



CC: 열이 나고 가슴이 아파요



PI: 1달 전 시작된 intermittent fever,

pleuritic chest pain으로 개인병원 경유하 여 감염내과에 입원. mycoplasma

pneumonia로 진단 후 치료받고 일시적으 로 좋아지다가 증상 다시 지속되어 류마티 스 내과로 전과됨

(3)



ROS



Skin rash (-), photosensitivity (-), oral/nasal ulcer (-), alopecia (-)



arthralgia (+)



PE



Arthritis (-)



Laboratory finding



CBC 9600-10.4(30.7)-360K ( 63.6%)

 C3 78.5 C4 15.3, DNAT 1:80

 AIT titer homogeneous 1:80, speckled level 1:2560



ACA-IgG/IgM (-/-), Lupus anticoagulant screening (+)

Beta_2GP_G/beta_2GP_M (-/-), VDRL-non reactive



Anti SM(-), anti nRNP(+), anti SS-A/SS-B (+/-), anti SCL- 70 (-)



RUA WBC-0~4 RBC-0~2 albumin (-)

(4)

(5)

(6)

① 1개

② 2개

③ 3개

④ 4개

⑤ 5개

1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers

5. Arthritis 6. Serositis

7. Renal disorder

8. Neurologic disorder 9. Hematologic disorder 10. Immunologic disorder 11. Antinuclear Antibody

(7)

① 예

② 아니오

1997 Criteria

6. Serositis

• Pleuritis

• Pericarditis

10. Immunologic Disorder a. Anti DNA

b. Anti sm

c. Antiphospholipid Ab -Anticardiolipin ab -Lupus anticoagulant

-False-positive serological test for syphilis

11. Antinuclear Antibody SLE (-): 3/11

(8)

1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging

(atrophic scarring may occur in older lesions) 3. Photosensitivity Skin rash as a result of unusual reaction to

sunlight, by history or physician observation

(9)

4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician

5. Arthritis Nonerosive arthritis involving _2 peripheral joints (characterized by tenderness, swelling, or effusion)

6. Serositis

-Pleuritis- pleuritic pain or rub heard by a

physician or evidence of pleural effusion -Pericarditis- documented by ECG or rub or

evidence of pericardial effusion

(10)

7. Renal disorder - Persistent proteinuria (0.5 g/d)

( 3+ if quantitation not performed) - Cellular casts

8. Neurologic disorder

- Seizures - Psychosis

(in the absence of offending drugs or metabolic derangements )

(11)

9. Hematologic disorder

- Hemolytic anemia: with reticulocytosis

- Leukopenia: 4000/mm3 total on _2 occasions - Lymphopenia: 1500/mm3 on _2 occasions - Thrombocytopenia: 100,000/mm3

(in the absence of offending drugs)

10. Immunologic Disorder

a. Anti DNA b. Anti sm

11. Antinuclear Antibody

(12)

• SLICC (Systemic Lupus International Collaborating Clinics) revised the criteria

• New knowledge on autoantibodies, neuropsychiatirc lupus, and importance of low complements

• Need for lupus nephritis to be a “stand alone”

criterion

• 32 sites (Multinational SLICC centers)

• Initiated in March 2006

• Petri M et al. Arthritis & Rheumatism 2012 Aug:

64(8);2677

(13)

Petri M et al. Arthritis & Rheumatism 2012 Aug: 64(8);2677

(14)

Petri M et al. Arthritis & Rheumatism 2012 Aug: 64(8);2677

(15)

Biopsy-proven Lupus Nephritis with ANA or anti-dsDNA 4 criteria, including at least ONE clinical & at least ONE immunologic OR

Clinical criteria Immunologic criteria 1. Acute cutaneous lupus 1. ANA

2. Chronic cutaneous lupus 2. Anti-dsDNA 3. Oral/Nasal ulcers 3. Anti-Sm

4. Nonscarring alopecia 4. Antiphospholipid antibody 5. Inflammatory synovitis 5. Low complement

6. Serositis 6. Direct Coombs test

7. Renal 8. Neurologic

9. Hemolytic anemia

10. Leukopenia or Lymphopenia 11. Thrombocytopenia

(16)

1. Acute cutaneous lupus

- Lupus malar rash - Bullous lupus

- Toxic epidermal necrolysis variant - Maculopapular rash

- Photosensitive lupus rash - Subacute cutaneous lupus

2. Chronic cutaneous lupus

- Classical discoid rash

· localized (above the neck)

· generalized (above and below the neck)

- Hypertrophic (verrucous) lupus - Lupus panniculitis (profundus) - Lupus erythematous tumidus - Chilblains lupus

- Discoid lupus/lichen planus overlap 3. Oral/Nasal ulcers - Oral ulcers (palate, buccal, tongue)

- Nasal ulcers

(17)

4. Nonscarring alopecia - Diffuse thinning or hair fragility with visible broken hairs

5. Inflammatory synovitis - Physician-observed swelling of two or more joints at the same visit

6. Serositis

- Typical pleuritic pain (≥1 day) or pleural effusions or pleural rub

- Typical pericardial pain (≥1 day) or pericardial effusion or pericardial rub or pericarditis by EKG

7. Renal diseases - Urine Prot/Cr (or 24hrU Prot)≥500mg or red blood cell casts

(18)

8. Neurologic diseases

- Seizures - Psychosis

- Mononeuritis multiplex - Myelitis

- Peripheral or cranial neuropathy - Acute confusional state

(encephalopathy or organic brain synd.)

9. Hemolytic anemia - With reticulocytosis 10. Leukopenia or

Lymphopenia - < 4000/mm³ at least once or - < 1000/mm³ at least once 11. Thrombocytopenia - < 100,000/mm³ at least once

(19)

1. ANA

2. Anti-dsDNA - Except ELISA : twice above laboratory reference range

3. Anti-Sm

4. Antiphospholipid Ab

- Lupus anticoagulant

- False-positive test for syphilis - ACA IgG,M,A(medium-high titer) - Anti-ß 2 glycoprotein 1 IgG,M,A

5. Low complement

- Low C3 - Low C4 - Low CH50

6. Direct Coombs test (+) - In absence of hemolytic anemia

(20)

• Better sensitivity than ACR (94% vs. 86%)

• Roughly equal specificity (92% vs. 93%)

• Significantly fewer misclassifications (p=.0082)

Derivation set

Validation set

(21)

1997 Criteria New criteria

6. Serositis

• Pleuritis

• Pericarditis 6. Serositis 10. Immunologic Disorder

a. Anti DNA b. Anti sm

1. ANA

2. Anti-dsDNA

4. Antiphospholipid antibody 11. Antinuclear Antibody 5. Low complement

SLE (-): 3/11 SLE (+): Clin 1 & Imm 4

(22)



27세 여자



CC: both hip pain



PI: 2년 전 타 대학병원에서 루푸스 신염으 로 진단받고 고용량 스테로이드와 면역억 제제 치료 받았던 환자로 최근 발생한 고 관절 통증으로 AVN 검사 및 치료 위해 본 원 정형외과 입원. 단백뇨 및 루푸스에 대 한 협진 의뢰됨 (24시간 단백뇨: 약 1g)

(23)

1997 Criteria New criteria

7. Renal disorder

• Persistent proteinuria (0.5 g/d)

• Cellular casts

(lupus nephritis III + V)

 Lupus nephritis III + V

 ANA

11. Antinuclear Antibody: diffuse

granular level 2 (1:80) 5. Low complement

SLE (-): 2/11 SLE (+): Biopsy proven LN &

ANA

(24)



22세 여자



CC: Easy bruisibility



PI: 3개월전 쉽게 멍이 드는 증상으로 본원 혈액종양내과에서 검사후 ITP로 진단받고 고용량 스테로이드 사용 후 호전되었으나 용량 줄이면서 다시 혈소판 감소하는 소견 보여 루푸스 등의 류마티스질환 감별위해 협진 의뢰됨

(25)

1997 Criteria New criteria

9. Hematologic disorder

•Hemolytic anemia

•Leukopenia

•Lymphopenia

•Thrombocytopenia:

100,000/mm3

11. Thrombocytopenia

1. ANA

10. Immunologic Disorder a. Anti DNA (1:10)

b. Anti sm

c. Antiphospholipid Ab [ACA IgM (+)]

2. Anti-dsDNA

4. Antiphospholipid antibody [anti-beta 2 GP1 IgM (+) &

ACA IgM (+)]

11. Antinuclear Antibody:

speckled level 3 5. Low complement

SLE (-): 3/11 SLE (+): Clin 1 & Imm 4

(26)

• Reflect the importance of biopsy proven nephritis and autoantibodies

• New criteria may be more useful in clinical trial / clinical practice.

• Early diagnosis of early disease

• Validation should be performed in variable

settings (ethnic, racial, subspecial)

(27)

Susceptibility genes + triggering environmental factors

Pathogenic autoantibodies

Immune complex formation

Tissue inflammation and organ damage

(28)

Reduced apoptotic cell clearance

TLR stimulation by Autoantigen (dsDNS, RNA…) release Type I Interferon signaling

activation

Autoreactive immune cell (T, B, plasma cell) activation Immune complex formation

Tissue deposition and inflammation

(29)

 34세 64kg의 여자환자

 6 개월 전부터 시작된 전신부종

 BUN 25mg/dl, creatinine 1.0mg/dl,

C3/C4 24/3 mg/dl, antinuclear Ab 1:640, anti-dsDNA Ab 430 IU/ml,

spot urine protein/creatinine 2.8

 신장조직검사: ISN/RPS class IV-G LN,

activity index 12/24, chronicity index 2/12, crescent (-)

(30)

① High dose steroid (1mg/kg/day)

② Cyclophosphamide IV pulse only

③ Cyclophosphamide IV pulse + high dose steroid

④ Cyclosporine + high dose steroid

⑤ Azathioprine + high dose steroid

(31)

J Am Soc Nephrol. 2004;15:241

(32)

(33)

Arthritis Care Res. 2012;64:797

Class III/IV induction therapy

To be continued

(34)

(35)

Treatment of class V

[without proliferative changes and with nephrotic range proteinuria (3

gm/24 hours)]

(36)

• The first-line treatment for patients with mild SLE

• Effective in the treatment of mild SLE manifestations, as well as in preventing the occurrence of new mild SLE

manifestations, but it is ineffective in preventing the occurrence of severe SLE manifestations

• Inhibit phagosome function, thereby inhibiting Toll-like

receptor (TLR) activation, leading to a downregulation of IFN- α and decreasing the antigen processing necessary for

autoantigen presentation

• SE: Retinal damage, agranulocytosis, aplastic anemia, ataxia,

cardiomyopathy, dizziness, myopathy, ototoxicity, peripheral

neuropathy, pigmentation of skin, seizures, thrombocytopenia

(37)

• The mainstay of treatment in patients with SLE, especially at the beginning of a flare

• Strong antiinflammatory effects on both acquired and innate immune pathways

• 0.5–1 mg/kg per day for severe SLE

• 0.07–0.3 mg/kg per day or qod for milder disease

• SE: Infection, VZV infection, hypertension, hyperglycemia, hypokalemia, acne, allergic reactions, anxiety, aseptic

necrosis of bone, cushingoid changes, CHF, fragile skin, insomnia, menstrual irregularities, mood swings,

osteoporosis, psychosis

(38)

• Useful analgesics/anti-inflammatories, particularly for arthritis/arthralgias

• Higher incidence of aseptic meningitis, transaminitis, decreased renal function, vasculitis of skin; entire class, especially COX-2-specific inhibitors, may increase risk for myocardial infarction

(39)

• Pulse cyclophosphamide defined the standard of care for lupus nephritis for many years

• 7–25 mg/kg q month x 6; consider mesna administration with dose

• NIH protocol versus low dose(mini-pulse) (500mg fixed q 2wks x 6): no difference in efficacy

• SE: Infection, VZV infection, bone marrow

suppression, leukopenia, anemia, thrombocytopenia, hemorrhagic cystitis (less with IV), carcinoma of the bladder, alopecia, nausea, diarrhea, malaise,

malignancy, ovarian and testicular failure

(40)

• The prodrug of mycophenolic acid, an inhibitor of inosine monophosphate

dehydrogenase; enzyme controls the de novo synthesis of guanosine nucleotides, a step essential for DNA synthesis in lymphocytes.

• An inhibitor of purine synthesis and blocks the proliferation of activated T and B lymphocytes

• Results of a large multinational trial examining the efficacyof MMF compared with that of intravenous cyclophosphamideover 6 months as induction therapy and either MMF orazathioprine as maintenance therapy in patients with lupus nephritis for 36 months : comparable in the MMF and cyclophosphamide groups. Moreover, no safety

advantage was shown forMMFduring the induction phase. In contrast, the

maintenance phase demonstrated a clear advantage of MMF over azathioprine.

• As effective as CYC and tended to have a better safety profile as an induction

• therapy for LN than CYC

• Infection, leukopenia, anemia, thrombocytopenia, lymphoma, lymphoproliferative disorders, malignancy, alopecia, cough, diarrhea, fever, GI symptoms, headache, hypertension, hypercholesterolemia, hypokalemia, insomnia, peripheral edema, transaminitis, tremor, rash

(41)



6개월 cyclophosphamide (NIH protocol) 치료 후에도 proteinuria 지속되어 MMF로 6개월 치료하였으나 호전되지 않고

creatinine이 상승한다면 다음에 고려해야 할 것은?

(42)

(43)

(44)

(45)

March 9, 2011

• Belimumab is the first drug licensed for use in SLE in ≥ 50 years.

• For SLE patients with refractory/life threatening disease

• Biologically agents will be increasingly used in the near future and will have a significant impact on the management of SLE patients

(46)

 자연유산 경험이 2회 (15주, 22주) 있었던 30세 여자가 임신 20주에 산부인과에서 의뢰되었다.

 백혈구 3,200/mm³, 헤모글로빈 10.4g/dL, 혈소판 60,000/mm³,

 항핵항체 1:1280 양성, 항이중가닥 DNA 항체 양성,

 프로트롬빈시간 (PT) 98%,

 활성부분 트롬보플라스틴 시간(aPTT) 43초,

 lupus anticoagulant (+),

 anticardiolipin antibody (+)

(47)

① Low dose steroid (5-10mg/day)

② Low-dose aspirin

③ Prophylactic heparin + low-dose aspirin

④ Warfarin

⑤ Hydroxychloroquine

(48)

J Thromb Haemost 2006;4:295

Definite APS is present if at least one of the clinical criteria and one of the labor atory criteria are met

Clinical Criteria

Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ

Pregnancy morbidity

One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th wk of gestation, or

One or more premature births of a morphologically normal neonate before the 34th wk of gestation because of eclampsia, severe preeclampsia, or recognized features of placental ins ufficiency or

Three or more unexplained consecutive spontaneous abortions before the 10th wk of gestat ion, with maternal anatomic or hormonal abnormalities and paternal and maternal chromos omal causes excluded

Laboratory Criteria

Lupus anticoagulant present in plasma on two or more occasions at least 12 wk apart, detected according to the guideline s of the International Society on Thrombosis and Hemostasis

Anticardiolipin antibody of immunoglobulin (Ig)G or IgM isotype in serum or plasma, present in medium or high titer (>40 GPL or MPL, or >99th percentile), on two or more occasions at least 12 wk apart, measured by a standardized ELISA

Anti–β₂-glycoprotein I antibody of IgG or IgM isotype in serum or plasma (in titer >99th percentile) present on two or mo re occasions at least 12 wk apart, measured by a standardized ELISA

(49)

Kelley's Textbook of Rheumatology, 9th ed.

(50)

Clinical Circumstance Recommendation

Asymptomatic No treatment*

Venous thrombosis Warfarin INR 2.5 indefinitely

Arterial thrombosis Warfarin INR 2.5 indefinitely

Recurrent thrombosis Warfarin INR 3-4 ± low-dose aspirin

Pregnancy:

•First pregnancy No treatment

•Single pregnancy loss at <10 wk No treatment

•≥1 Fetal or ≥3 (pre)-embryonic losses, no

thrombosis Prophylactic heparin + low-dose aspirin throughout pregnan cy, discontinue 6-12 wk postpartum

•Thrombosis regardless of pregnancy histor

y Therapeutic heparinor low-dose aspirin throughout pregnan

cy, warfarin postpartum

Valve nodules or deformity No known effective treatment; full anticoagulation if emboli or intracardiac thrombi demonstrated

Thrombocytopenia >50,000/mm³ No treatment

Thrombocytopenia <50,000/mm³ Prednisone, IVIG

Catastrophic antiphospholipid syndrome Anticoagulation + corticosteroids + IVIG or plasmapheresis

(51)

• Classification criteria for SLE

– 1987 updated ACR criteria – New SLICC criteria

– Various clinical manifestations and immunologic laboratory findings

• Lupus nephritis: ACR guidelines for treatment

• Diagnosis and treatment for antiphospholipid SD in SLE