Lymphadenopathy in SLE Division of Rheumatology R4 송 란

Pyrexia & lymphadenopathy

(Lymphocyte dominant) 35-year-old, male Moderate-grade, intermittent fever, weight loss (10 kg /3 months) No history of skin rash, photosensitivity, arthritis, oral ulcer, alopecia, urinary,bowel complaints P/Ex. V/S> BP 130/80 mmHg- PR 110/min-RR 22/min-39°C lymph nodes : multiple, 1-cm, nontender, firm, Cervical & axillary regions left pleural effusion and hepatosplenomegaly - Rheumatol Int.2005;25 Initial laboratory data (CBC/DC, ESR,Urinalysis, electrolytes, coagulation profile, kidney and liver function tests): normal Exudate (Lymphocyte dominant) Chest X-ray : Lt.hilar lymphadenopathy, pleural effusion ANA : negative, anti-dsDNA antibody: within normal limits Mantoux test: 12-mm induration Cervical lymph node biopsy : reactive follicular hyperplasia BM biopsy: No granuloma, AFB & fungus staining(-) Liver biopsy: normal Tuberculosis  empirical anti-Tb therapy Pancytopenia, direct Coomb’s test(+) ANA: positive(1:320), homogenous pattern, low C3, anti-dsDNA: positive Proteinuria, hematuria Kidney Bx.: Lupus nephritis class IV

Cause of peripheral lymphadenopathy Examples Infections Bacterial Localized Generalized Streptococcal pharyngitis; skin infections; tularemia; plague; cat scratch disease; diphtheria; chancroid; Brucellosis; leptospirosis; lymphogranuloma venereum; typhoid fever Viral HIV; EB virus; herpes simplex virus; CMV; mumps; measles; rubella; hepatitis B Mycobacterial Mycobacterium tuberculosis; atypical mycobacteria Fungal Histoplasmosis; coccidioidomycosis; cryptococcosis Protozoal Toxoplasmosis; Leishmaniasis Spirochetal Secondary syphilis; Lyme disease Cancer Metastatic; lymphoma; leukemia Lymphoproliferative Angioimmunoblastic lymphadenopathy with dysproteinemia Autoimmune lymphoproliferative disease Rosai-Dorfman's disease Hemophagocytic lymphohistiocytosis Immunologic Serum sickness; drug reactions (phenytoin) Endocrine Hypothyroidism; Addison's disease Miscellaneous Sarcoidosis; amyloidosis; histiocytosis; chronic granulomatous diseases; Castleman's disease; Kikuchi's disease; Kawasaki disease; systemic lupus erythematosus; RA; Still's disease; dermatomyositis

Total 82 patients During the first year of the clinic

Frequency of symptoms of systemic lupus erythematosus Percent at onset Percent at anytime Fatigue 50 74-100 Fever 36 40-80 Weight loss 21 44-60 Arthritis or arthralgia 62-67 83-95 Skin 73 80-91 Raynaud's phenomenon 17-33 22-71 Renal 16-38 34-73 Gastrointestinal 18 38-44 Pulmonary 2-12 24-98 Cardiac 15 20-46 Lymphadenopathy 7-16 21-50 Splenomegaly 5 9-20 Hepatomegaly 2 7-25 Central nervous system 12-21 25-75 Von Feldt et al. Postgrad Med 1995; 97

Evaluation of peripheral lymphadenopathy in SLE Characteristics of lymph nodes Soft Nontender Discrete Size : 0.5 ~ several centimeters Location : cervical, mesenteric, axillary, inguinal areas – M/C hilar, mediastinal, retroperitoneal - unusual Lymph node enlargement Onset of disease Exacerbation Result of infection  tender Lymphoproliferative disease in SLE

Pathology of Lymph Node in Lupus Follicular hyperplasia and necrosis Castleman’s disease, T-zone dysplasia with hyperplastic follicles, Nonspecific follicular hyperplasia Hematoxylin bodies(LE cell)

Differential Diagnosis of Lymphadenopathy in SLE Chronic infectious disorder Viral or bacterial infections Tuberculosis Lymphoproliferative disorder Lymphoma Castleman’s disease Sarcoidosis Kikuchi’s disease Negative serological tests for virus Blood, urine, tissue culture: negative PPD test : negative LN biopsy: absence of granuloma with caseous necrosis BM biopsy or LN biopsy : presence of neoplastic lymphoid cell LN biopsy : absence of granuloma LN biopsy : patchy, paracortical necrotizing process with prominent histiocytes, absent neutrophil, hematoxylin body and rare plasma cell

Y.Shapira et al. Clinical rheumatology,1996; 15

Lymphadenopathy: significantly younger than non-lymphadenopathy (age 36.2 ± 3.0 vs. 45.0 ± 1.9 years, p = 0.012) No difference : sex ratio, education, ethnic origin Y.Shapira et al. Clinical rheumatology,1996; 15

Malignant Lymphoma - Non-Hodgkin Lymphoma -

Glucocorticoid therapy  intermittent spiking night-time fever 37-year-old, Female Heavy proteinuria, microscopic hematuria, malar rash, leukopenia, lymphopenia, painless elastic LN(<1cm) on Rt. Neck, tender firm LN(1cm) on Lt. groin ANA, direct Coombs’ test, lupus anticoagulant Ab, anticardiolipin Ab.  positive Renal Bx.: lupus nephritis-membranous glomerulonephritis(MGN) Glucocorticoid therapy  intermittent spiking night-time fever progressive LN enlargement over neck and groin  LN bx.: EBER-1 positive Diffuse large B-cell lymphoma(DLBL) NHL(DLBL) presenting with SLE and MGN Ming-Hsien Lin et al. Lupus, 2003; 12

RE pooled SIR for SLE of 7.4  7.4-times increase in the incidence - Elias Zintzaras et al.Arch Intern Med. 2005;165 Figure. Standardized incidence rate (SIR) estimates of development of non-Hodgkin lymphoma with the corresponding 95% confidence intervals of studies included in the meta-analysis for systemic lupus erythematosus (SLE) = 7.4 RE pooled SIR for SLE of 7.4  7.4-times increase in the incidence 126 cases per 100,000 patient-years

9547 subjects with definite SLE 23 clinical center Canada, America, the UK (England and Scotland), Sweden, Iceland, Korea 9547 subjects with definite SLE NHL: 42 cases Mean age: 55.3 years Average SLE duration: 6.7 years 22 (52%) of the 42 cases: death Median of 1.2 yrs after lymphoma Dx. Total NHL(n) 21 DLBL(%) 11(52) Small lymphocytic(%) 4(19) Follicular(%) 3(14) Burkitt’s 1 Peripheral T cell MALT

Kikuchi-Fujumoto Disease

Kikuchi-Fujimoto's disease (KFD) Histiocytic necrotizing lymphadenitis, Young women Symptoms : upper respiratory tract infection Fever, leukopenia : 50 % of patients Lymphadenopathy: cervical - M/C Benign and self-limited lymphadenitis LN biopsy Necrotising lymphadenitis (cortical and paracortical area) Hematoxylin bodies, neutrophil  absent Mahajan et al. Proc (Bayl Univ Med Cent) 2007;20

KFD associated with SLE Shares clinical features: arthralgia, fever, leukopenia, lymphadenopathy Common hyperimmune reaction directed against different antigenic stimuli MEDLINE and LILACS database KFD associated with SLE: 35 cases Santana et al. Clin Rheumatol 2005; 24

Hemophagocytic syndrome

Hemophagocytic syndrome Histiocytic reactive process of strong immunologic activation, such as Severe infection, malignancy, autoimmune diseases, and Metabolic diseases Diagnosis : 5 out of the 8 criteria Fever Splenomegaly Bicytopenia A. Hb <9.0 g/dL (In infants <4 weeks: Hb <10.0 g/dL) B. Platelets (<100x109/L) C. Neutrophils (<1.0x109/L) Hypertriglyceridemia and/or hypofibrinogenemia : fasting TG >265 mg/dL, fibrinogen ≤1.5 g/L Hemophagocytosis in bone marrow, spleen, or lymph nodes : no evidence of malignancy Low/absent NK-cell activity Hyperferritinemia and/or high sCD25

Clinical Presentation High fever, lymphadenopathy, hepatosplenomegaly, coagulopathy organ system dysfunction (especially skin, liver, CNS) High mortality Laboratory features Pancytopenia (especially leukopenia), low ESR, high ferritin low fibrinogen, elevated liver enzymes Morphologic features: macrophages hemophagocyting blood cells Incidence Unknown : very rarely diagnosed (missed in many cases) Hemophagocytic syndrome combined with necrotizing lymphadenitis : 8 cases (~2003 yr) 2 patients : systemic lupus erythematosus Kim et al.J Korean Med Sci 2003; 18

Clinical Suspicion Pathologic Finding