A rare cause of pyrexia during Pregnancy Dr JM Futtermenger, RPH Prof B Walters, KEMH, RPH Dr D Graham, KEMH Supervisor: Dr M McComish, HOD, Internal Medicine RPH Case • 33 year old, born in Zambia, in Australia for last 5 years • G4P3, 30+5 • 1/52 Hx: sore throat, malaise, headache, intermittent fevers, myalgias Case • O/E • tachycardia HR 150/min, • tachypnoea , RR 25/min • High fever • other nad Temp chart Case Ix • WCC 8.2 → 16.6, neutrophilia • CRP 53 → 220 • abnormal LFTs: • bilirubin 35, ALT 106, GGT 68 • No improvement despite Abs Ix between 26/07/2008 – 12/08/2008 summary • • • • • • • • • • B/C MSU Faeces Malaria screening Throat swab TB: urine, B/C, sputum BM aspirate CXR, TSS ECHO, TOE Amniocentesis Abdominal U/S x9 x3 x4 x4 x3 x5, x2, x2 x1 x1,x1, x1 x1 mild splenomegaly Ix between 26/07/2008 – 12/08/2008 summary • Serology for • Mycoplasma, legionella, influenza • Brucella, Bordetella, arbovirus, leptospira • Q fever, recettsial, schistosomiasis • parvovirus • Toxoplasmosis, EBV, CMV, Hepatitis A,B,C, HIV • Cryptococcal • Serum ACE Ix between 26/07/2008 – 12/08/2008 summary • Auto-immune screening ENA, ANA, p/c-ANCA, Antiphospholipid antibodies, beta-2-glycoprotein NEGATIVE • Rheumatoid factor NEGATIVE Case progress • • • • Admission to ASCU Remaining febrile Physical exam nad first 3 days left elbow arthritis • Improvement after 2 days • Right ankle arthralgia • Improvement after 2 days • Right hip pain • Improvement after 3 days Remaining febrile …and then on Friday, 8/8/8, not only was it the start of the Olympics, but also the beginning of the end of wandering in medical darkness… Australia 14 gold 15 silver 17 bronze ferritin 102.000ug/L Onehundredandtwo thousand iron 24, transferrin 16, Satt 75% Adult-onset Still’s Disease (AOSD) Sir George Frederick Still (1868-1941) The father of British paediatrics. formerly known as WisslerFanconi Syndrome Progress Delivery of a healthy infant at term Patient remains well after 9 months, low dose steroids No flare QUESTIONS AOSD • Systemic inflammatory condition of unknown aetiology • 1-10 cases/million in European and Japanese publications, no mention of black-African cases • George Still- 1897 described series of juvenile idiopathic arthritis • Patient > 16 years of age • Female>male DDx • Infective • Autoimmune • Malignant • No Dx • AOSD DDx, infection • • • • • • • • • Amebic liver abscess Brucellosis Chronic active hepatitis Cytomegalovirus Dental abscesses Discitis Gonococcal arthritis Herpes simplex encephalitis Infectious mononeucleosis • • • • • • • • • Kala azar Kikuchi's disease Lyme disease Pyelonephritis Rheumatic fever Sinusitis Typhoid fever Whipple's disease Malaria DDx autoimmune • Allergic granulomatous • Angiitis • Antiphospholipid syndrome • Granulomatous hepatitis • Hypersensitivity vasculitis • Inflammatory bowel disease • Pan-aortitis • Reiters syndrome • Sarcoidosis DDx, malignancy • Atrial myxoma • Aleukemic leukemia • Colon carcinoma • Kaposi's sarcoma • Lung cancer • Multiple myeloma • Sarcoma Diagnostic criteria • Typical presentation • Yamaguchi – J Rheumatol 1992;19:424-430 • Fautrel – Best Practice and Research Clinical Rheumatology;2008;22(5):773-792 • 5 others • Cush et al – ArthritisRheum;1987;30:186-194 • Goldman et al - South Med J;1980;73:555-563 • Calabro et al – J Rheumatol;1986;13;827-828 • Kahn et al - Les maladies systè systèmiques.Paris,Flammarion;1991;231miques.Paris,Flammarion;1991;231-238 • Reginato - Semin Arthritis Rheum;1987;17:39-57 AOS Triad typical • fever • rash • evanescent • salmon-pink • maculopapular • prox limbs and trunk • arthritis/arthralgias • knees, wrists and ankles • symmetric • may progress to ankylosis AOSD • Cardinal symptoms • Spiking fever • Evanescent salmonpink maculo-papular rash • Arthritis • Neutrophilia • Other symptoms • • • • • • • • Sore throat pharyngitis myalgia Lymphadenopathy Splenomegaly abnormal LFTs pleuritis pericarditis AOS – Yamaguchi classification criteria Yamaguchi M; J Rheum; 1992; 19:3, 424-430 Fautrel criteria • Major criteria • Spiking fever > 39 °C • Arthralgia • Transient erythema • Pharyngitis • PMN > 80% • Glycosylated ferritin > 20% • Minor criteria • Maculo-papular rash • Leukocytes > 10.000/mm3 To make Dx: 4 or more major; 3 major + 2 minor criteria AOSD • Yamaguchi criteria • sens 96.2%, spec 92.1% • Fautrel criteria • sens 80.6%, spec 98.5% AOSD - course Three patterns • Self limited • 1 disease episode- median duration 9 months • Intermittent • recurrent flares with complete remission between • Chronic articular• dominated by arthritis (1/3 of patients) Cush JJ; Arthritis Rheum. 1987 Feb; 30(2):18630(2):186-94 AOSD- treatment • Empirical • NSAIDS- response rate ≈ 12% • Steroids- response rate ≈ 76% • Disease modifying agents • methotrexate, infliximab (monoclonal antiTNF α Ab), anti-IL6 & IL1 Abs Wouters JM; Q J Med.1986 Nov; 61(235):1055-65 Pathogenesis • High levels of • IL 1 beta, IL-6, IL-18, TNF alpha, interferon gamma • IL-6, IL-18 • Fever, rash, LFTs abnormal, raised CRP • IL-18 part of IL1 family • Raised ferritin AOSD and pregnancy • relapsing postpartum possible if Dx prior to pregnancy • First onset in 2nd and 3rd trimester • Most commonly; also 1rst trimester • Relationship to immune changes in pregnancy unknown Le Loet J Rheumatol.1993 Jul; 20(7):1158-61 Pan VL Obstet Gynecol. 2003 May; 101(5Pt2):1112-6 Mok My J Rheumatol. 2004 Nov; 31(11):2307-9 Cytokines in AOSD vs pregnancy IFN gamma Th1 Th2 ratio PREGNANCY ↓ ↓ ↑ ↓ RA ↑ ↑ ↓ ↑ AS ↓ ↓ ↑ ↓ AOSD ↑ ↑ ↓ ↑ RA – rheumatoid arthritis, gets better in pregnancy, worse post-partum AS – ankylosing spondylitis, remains the same in pregnancy or worse AOSD – adult onset Still’s – should behave like RA and get better and not appear in pregnancy, therefore: in regards to immuno - (patho) - physiology LIKELY TO BE NO RELATIONSHIP M Østensen, F Fö Förger, JL Neslon, A Schumacher, G Hebisch, PM Villiger; Ann Rheum Dis 2005; 64: 839839844, Pregnancy in patients with rheumatic disease: antianti-inflammatory cytokines increase in pregnancy and decrease potpot-partum Genetics of AOSD • HLA Bw35 • Milder self-limiting form • found in JRA • HLA-Dw3 – polyarticular • Dw7+Dw11 = Tmo,DRw5,DRw8 pauciarticular • HLA-Cw4 • Unremitting, chronic erosive arthritis • R Terkeltaub et al; Arthritis and Rheumatism;1981;24(12):1469-1472 Timing of Dx • 3 weeks until diagnosis and initiation of Rx • Nil deterioration in patient nor fetus Thanks to everybody involved Elevated ferritin • Acute phase reactant • elevation in AOSD disproportionate to inflammatory state • >1500ug/L • • • • • • • • • • HHC alcoholic liver disease haemochromatosis inflammatory conditions neoplasim repeated blood transfusion iron overload autoimmune disease renal failure weight loss ACE • Non-specific • False positive ACE found in a group of people developing arthritis • Sarcoid • 75% of patients dx have ↑ serum ACE • abnormal CXR • Extra-pulmonary manifestions • Skin – • rash maculopapular on face • nodular on trunk and extremities • Loefgren syndrome • Leucopaenia • thrombocytopaenia • eosinophilia • hypercalcaemia DD insertion/deletion polymorphism in intron 16 of the ACE gene > ↑ in serum ACE • ?association with systemic juvenile rheumatoid arthritis – and therefore possibly also associated with AOSD • Genetic studies in our patient are pending