Life-threatening illnesses in rheumatologic diseases

만성 류마티스 질환에서 급성 악화의 진료

가톨릭대학교 의과대학 내과학교실

민 준 기

Life-threatening illnesses in rheumatologic diseases

Exacerbation (flare-up) of pre-existing manifestations

Development of new, life-threatening manifestations

Infections resulting from immunosuppression

Adverse effects of drugs used to treat autoimmune disorders

Acute serious illnesses that are unrelated to the rheumatic disease

Life-threatening conditions in rheumatic disorders

Vocal cords Rheumatoid arthritis Juvenile rheumatoid arthritis SLE

Angioedema Subglottic obstruction

Wegener’s granulomatosis Tracheobronchial collapse Relapsing polychondritis Interstitial lung disease

Rheumatoid arthritis, Scleroderma Systemic necrotizing vasculitis Dermatomyositis Drugs

Methotrexate, Cyclophosphamide

Pneumonia SLE

Opportunistic infections Tuberculosis, Pneumocystis carinii Aspergillus, Nocardia Cytomegalovirus, Pulmonary alveolar hemorrhage

SLE, Dermatomyositis Goodpasture’s syndrome Wegener’s granulomatosis Pulmonary hypertension

Scleroderma Pleural effusions

SLE, Rheumatoid arthritis

-respiratory system-

(1) rheumatoid arthritis (2) systemic lupus erythematosus (3) systemic sclerosis (4) polymyositis/dermatomyositis (5) Sjögren syndrome

The five rheumatic diseases most frequently associated with pleuropulmonary disease

환자: 38/남 주소: 호흡 곤란 현 병력:

1년 전 전신성 홍반성 루푸스 진단, 최근 약물 복용 중단 2 주전 뺨 발진, 구강 궤양, 관절통 발생

이학적 검사 : 혈압은 90/00 mm/Hg, 맥박은 110회/분, 호흡수 20회/분, 체온 38℃

검사실 소견 :

124,000 3,000 9.8 2주전

2,800 백혈구 (/mm³)

7.2 혈색소 (g/dl)

내원 당일 96,000

혈소판 (/mm³)

방사선 검사:

경과: 내원 2병일째 객혈 발생

X-ray

exacerbation or infection?

Complement CRP Procalcitonin

Classic triad of pulmonary hemorrhage

anemia

pulmonary infiltrates

hemoptysis

Diagnosis

diffusion capacity (DLCO)

other causes of hypoxia and dyspnea should be excluded.

bronchoscopy

immunosuppressants, plasmapheresis

Treatment

systemic lupus erythematosus Wegener’s granulomatosis microscopic polyangiitis small-vessel vasculitis

anti-glomerular basement membrane disease infection

pulmonary hemosiderosis idiopathic

Conditions associated with pulmonary hemorrhage

^{환자: 39/여}주소: 호흡 곤란

현 병력: 1년 전신성 경화증 진단 받고 prednisolone 7.5mg/일, bucillamine 200mg/일, aceclofenac sodium 200mg/일로 치료 받아 오던 중 수 일 전부터 상기 증상 발생

5768 810 LDH (U/L)

UA: protein ++, blood culture: no growth, anti-GBM Ab, ACL, LAC Ab, Coomb’s test: neg, schistocytes: pos

1.4 Cr (mg/dl) 0.9

47,000 105,000 platelet (/mm³)

1.4 bilirubin 0.5

6.2 8.3 Hb (g/dl)

5^thHD 1^stHD

Sep 10

^th

June 12

^th

Clinicopathological findings in the subsets of pulmonary-renal syndrome in scleroderma

Naniwa et al Mod Rheumatol:2007;17:37–44

pulmonary-renal syndrome

systemic lupus erythematosus, mixed cryoglobulinemia, Henoch-Schonlein purpura, Wegener’s granulomatosis, Microscopic polyangiitis, Goodpasture’s syndrome systemic sclerosis

Seizures SLE

Hypertensive encephalopathy Delirium/psychosis

SLE Infections CNS vasculitis Drugs: Corticosteroids Aseptic meningitis

Drugs: NSAIDs Cerebral infarction

Takayasu’s disease Giant cell arteritis Antiphospholipid syndrome SLE, PAN Isolated CNS vasculitis

-nervous system-

Cerebral hemorrhage SLE Scleroderma Myelopathy

Atlantoaxial dislocation: RA Noncompressive myelopathy

: Behcet’s disease Polyneuropathy

SLE

Guillain-Barre syndrome Necrotizing vasculitis Myopathy

Polymyositis-dermatomyositis Drugs

Corticosteroids Neuromuscular blockade

환자: 47/여

주소: 말늘어짐, 좌측 상하지 근력 약화

현 병력: 약 10년 전 베체트 병 진단 후 간헐적으로 치료 받아오던 중 수일 전 상기 증상 발생

　　　 　　　　　 　 　 CSF findings:　　　　

WBC: 8 /mm³, RBC: 0 /mm³ protein: 25 (reference range, 15–45 mg/dL) Glucose:48 mg/dL (serum glucose, 90 mg/dL).

oligoclonal IgG band: negative.

T1W T1W/CE T2W

MRI

　　　　　

T1W T1W/CE T2W

F/U MRI

migranous headache subclincal NBS

cerebral dural venous sinus thrombosis CNS involvement

neuro-psycho-Behcet’s syndrome peripheral nervous system involvement

Primary neurological involvement in BS

Brainstem 18 Pons 14

Ventral portion 14 Tegmentum 9 Midbrain 14 Cerebral peduncle 11 Tegmentum 4 Quadrigeminal plate 1 Cerebral white matter 9

Subcortex 4 Peri-ventricular area 3 Deep white matter 2

Sites of involvement in patients with NBD

Basal ganglia 9 Caudate nucleus 3 Putamen 7 Globus pallidus 4 Internal capsule 7 Thalamus 6 Meninges 2 Spinal cord 2

Treatment of NBD

high dose steroid, cyclophosphamide, cyclosporine, azathioprine, TNF-α blocking agent

환자: 28/여 주소: 의식 저하

현 병력: 전신성 홍반성 루푸스 2 년 전 진단, 1 개월 전 부터 뺨 발진, 구강 궤양, 관절염 증상 발생

CSF findings:

WBC: 1/mm³, RBC: 5/mm³ protein: 29(reference range, 15–45 mg/dL) glucose: 54mg/dL (serum glucose, 86 mg/dL).

oligoclonal IgG band: negative.

C3 67 mg/dl, C4 12 mg/dl, CH50 11 U/ml, FANA 1:3200, homogenous 항 ds-DNA 항체 > 50 IU/ml, Hb: 11.4 g/dl, WBC: 5,500/mm³ platelet 299,000/mm³

T1W T1W/CE T2W

F/U

Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache (including migraine and

idiopathic intracranial hypertension) Movement disorder (chorea) Myelopathy Seizure disorder Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis

Acute inflammatory demyelinating polyradiculopathy (Guillain–Barre´ syndrome) Autonomic disorder Mononeuropathy, single or multiplex Myasthenia gravis

Cranial neuropathy Plexopathy Polyneuropathy

neuropsychiatric manifestations of SLE

Central nervous system Peripheral nervous system

Arthritis Rheum 1999;42:599–608.

환자: 24/여

주소: 좌측 상하지 근력 약화

현 병력: 약 7 년 전 전신성 홍반성 루푸스 진단, 3 주 전 출산

C3 75.7 mg/dl, C4 6.49 mg/dl, CH50 11 U/ml, 항 ds-DNA 항체 33.6 IU/ml, Hb: 12.3 g/dl, WBC: 7,900/mm³ platelet 69,000/mm³ 　　　 　　

ACL (IgG) : 26 PL 43 PL ACL (IgM): 7 PL 14 PL Lupus anticoagulant: positive positive β2-GPI Ab: ND 11.0

　　 at admission 　　 　　

　　 before pregnancy 　　

TIW TIW /CE

T2W DWI

Clinical Criteria Vascular thrombosis

• One or more clinical episodes of arterial, venous, or small-vessel thrombosis, occurring within any tissue or organ

Complications of pregnancy

• One or more unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation; or

• One or more premature births of morphologically normal neonates at or before the 34th week of gestation; or

• Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation

Laboratory Criteria

Anticardiolipin antibodies, Lupus anticoagulant antibodies

Criteria for the Classification of the Antiphospholipid Syndrome (APS)

A diagnosis of definite APS requires the presence of at least one of the clinical criteria and at least one of the laboratory criteria.

환자: 48/여

주소: 어지럽고 넘어지려고 함.

현 병력: 전신성 홍반성 루푸스 8년 전 진단 받고 prednisolone 10mg/일 복용 중 상기 증상 발생

Hb: 10.6 g/dl, WBC: 3,000/mm³ (seg 86.5%, lym 8.1%, mono 5.4%) CD3: 71.1%, CD4:12.6%, CD8:70.3%

C3 : 29.55 mg/dL C4 : 2.82 mg/dL, CH50 < 5 U/mL FANA : 1:3200, anti-ds DNA Ab : >50 IU/mL

CMV IgG/IgM (+/-), EBV IgG/IgM (+/-), VZV IgG/IgM (+/-), HIV (-)

CSF findings:

WBC: 0/mm³, RBC: 0/mm^3, protein: 37(reference range, 15–45 mg/dL), glucose: 52mg/dL (serum glucose, 76 mg/dL), oligoclonal IgG band: negative.

T1W T1W/CE

T2W T2/FLAIR DW

PCR for JC virus; CSF (-), biopsy specimen (+)

brain biopsy

Luxol fast blue stain

EM

33nm-sized viral particles

Rheumatologic disease associated with progressive multifocal leukoencephalopathy (PML)

• cause of PML is a type of polyoma virus called the JC virus

• characterized by progressive damage or inflammation of the white matter of the brain at multiple locations

• It occurs almost exclusively in people with severe immune deficeincy

• 35 cases of PML in patients with rheumatic diseases – Twenty-two of these were in SLE patients

• The intensity of immunosuppression in the 6-month period before the onset of neurologic symptoms was highly variable.

Leonard H et al Arthritis Rheum 2007:56;2116-2128

환자: 29/여 주소: 하반신마비

현 병력:전신성 홍반성 루푸스로 6개월 전 진단 받고 prednisolone 7.5mg/

일 hydroxychloroquine 300mg/일, 복용 중 상기 증상 발생

신경학적 검사:

knee and ankle reflexes, extensor plantar responses: absence decreased sensory below T4 level

검사실 소견:

CSF study: oigoclonal IgG band: negative. 　　 　　 　　 　　

Hb: 7.8 g/dl, WBC: 8,000/mm³ , platelet 253,000 /mm³ C3/C4(mg/dl) 35/7, FANA : 1:3200, anti-ds DNA Ab : >50 IU/mL LAC, ACL Ab, β2-GPI Ab: neg

T2W

transverse myelitis in SLE

an acute or subacute inflammatory disorder of the spinal cord 1–2% of SLE patients

a discrete sensory level with lower limb weakness was the most common presenting feature.

MRI is the diagnostic tool of choice

strong association between TM in SLE and the presence of aPL corticosteroids and/or immunosuppression

: methylprednisolone & cyclophosphamide anticoagulation remains controversial.

acute transverse myelopathy in a patient with

multiple sclerosis

Coronary artery syndromes SLE, Churg-Strauss granulomatosis Polyarteritis nodosa Kawasaki disease Wegener’s granulomatosis Anticardiolipin antibody syndrome Myocarditis

SLE, PM/DM

Cardiac arrhythmias/conduction blocks Scleroderma, CREST syndrome Marantic endocarditis

SLE

Valvular abnormalities RA, AS, Behcet’s syndrome Reiter’s syndrome

-cardiovascular system-

Aortic aneurysm/dissection Rheumatoid arthritis Behcet’s syndrome Takayasu’s disease (aortoarteritis) Giant cell (temporal) arteritis Hypertensive emergencies

Scleroderma, SLE

Juvenile rheumatoid arthritis with vasculitis Takayasu’s disease (aortoarteritis) Pericardial effusion/tamponade

SLE Rheumatoid arthritis Mixed connective tissue disease

환자: 26/여, 주소: 호흡 곤란

현 병력: 2 개월 전 전신성 홍반성 루푸스 진단 받고 prednisolone 15mg/일 복용 중 상기 증상 발생

활력 징후: 혈압 100/70 mmHg, 맥박 125/분, 호흡수 20/분, 체온 38℃

청진 소견: gallop rhythm without murmur 검사실 소견:

Creatine kinase 420 U/l (normal 10–80 U/l).

Chest radiography showed cardiomegaly with normal lung fields.

EKG: T wave changes Echocardiogram:

moderate mitral regurgitation, mild tricuspid regurgitation, global hypokinesia, left ventricular ejection fraction (LVEF): 36%.

Myocarditis clinical features

Fever, tachycardia out of proportion to fever, myalgias, headache, rigors

Chest pain due to coexisting pericarditis Pericardial friction rub

Severe cases may have CHF symptoms

Myocarditis Diagnosis and Differential

EKG-nonspecific changes, AV block, prolonged QRS suration, or ST elevation (with pericarditis)

CXR-normal

Cardiac Enzymes- may be elevated

Differentail-ischemia or infarct, valvular disease, and sepsis

Myocarditis treatment

immunosuppressants - steroid pulse therapy - azathioprine,cyclophosphamide - IVGV

standard cardiac medications - salt restriction, digitalis, diuretic agents, - angiotensin-converting enzyme inhibitors

Gastrointestinal bleeding SLE

Henoch-Schonlein purpura Polyarteritis nodosa Drugs: Anticoagulants, NSAIDs,

Corticosteroids Secondary amyloidosis Pancreatitis

SLE Kawasaki disease Henoch-Schonlein purpura Drugs: Corticosteroids, Furosemide

-gastrointestinal system-

Hepatic failure Still’s disease, Drugs

Intestinal ischemic strictures/perforation Necrotizing vasculitis,

Wegener’s granulomatosis Essential mixed cryoglobulinemia Goodpasture’s syndrome, SLE Henoch-Schonlein purpura

환자: 30/여 주소: 복통, 설사

현 병력: 2년 전 전신성 홍반성 루푸스 진단, prednosolone 10mg　일 　　 hydroxychloroquine 400mg/일 복용 중 상기 증상 발생

Hb: 10.6 g/dl, WBC: 2,700/mm^3, platelet 120,000/mm³ C3: 19.4 mg/dL C4: 2.5 mg/dL, CH50 < 5 U/mL FANA : 1:3200, anti-ds DNA Ab : >50 IU/mL ACL IgG/IgM: neg/neg, LAC: neg, β2-GPI: neg UA: protein (-), blood (-)

　　　 　　　

CT scan of abdomen

mesenteric vasculitis in SLE

1–2% of patients with SLE manifesting as abdominal pain

rarely recurrent

an acute gastrointestinal distress syndrome (AGDS):

rapidly reverse

IV methylprednisolone

Renal crisis systemic sclwerosis Renovascular hypertension

Aortoarteritis Scleroderma Interstitial nephritis

SLE Sjogren’s syndrome

-renal system-

Thyroiditis SLE Hypothyroidism

Sclerodrema Adrenal insufficiency

Corticosteroid therapy Sudden omission Acute stress Hypoglycemia

Drugs : hydroxychloroquine

-metabolic & endocrine system-

Severe anemia Gastrointestinal hemorrhage Autoimmune hemolytic anemia SLE, Myelofibrosis Leukopenia

Rheumatoid arthritis, SLE Cytotoxic drugs Immune thrombocytopenia

SLE Pancytopenia

Felty’s syndrome Drug-induced marrow toxicity Cytotoxic drugs, Sulphasalazine

-hematologic manifestations-

Coagulopathy

Autoantibodies against clotting factors: SLE Lupus anticoagulant-hypoprothrombinemia syndrome

: SLE Thrombotic syndromes

Antiphospholipid syndromes, SLE Thrombotic thrombocytopenic purpura

SLE

Reactive hemophagocytic syndrome Juvenile chronic arthritis, SLE

환자: 47/여 주소: 정신 혼란

현 병력: 전신성 홍반성 루푸스 1년 전 진단 받고 prednisolone 10mg/일, hydroxychloroquine 400mg/일 복용 중 상기 증상 발생

Hb: 7.1 g/dl, WBC: 4,300/mm³, platelet 5,000 /mm³, LDH: 2185 U/L, bilirubin: 2.7 mg/dL, haptoglobin: not detectable.

C3 : 30.4 mg/dL C4 : 5.1 mg/dL, CH50 < 5 U/mL, FANA : 1:3200, anti-ds DNA Ab : >50 IU/mL

serum creatinine,coagulation profile, fibrinogen degradation products, anticardiolipin antibodies, lupus anticoagulant: within normal limit

Brain MRI: a small ischemic cortical lesion on the left side.

활력 징후: 혈압 100/70 mmHg, 맥박 90/분, 호흡수 16/분 체온 37.5℃

Thrombotic Thrombocytopenic Purpura

thrombocytopenia.

microangiopathic hemolytic anemia.

reduced level of ADAMTS13.

normal coagulation tests.

elevated serum LDH.

neurologic and renal abnormalities, fever

Shah et al Nat Clin Pract Rheumatol. 2007;3:357-62.

treatment of TTP

emergently with large-volume plasmapheresis coupled with infusion of fresh-frozen plasma

glucocorticoids

treatment of acute flare

Corticosteroids

except: scleroderma, Kawasaki disease, Henoch-Schonlein purpura Cytotoxic drugs

Plasmapheresis

Intravenous immunoglobulin

Angiotensin-converting enzyme inhibitors: scleroderma renal crisis