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The Seamstress With Sore Joints: Adult Onset Still’s Disease Maureen Dubreuil MD, Eugene Kissin MD Department of Internal Medicine, Boston Medical Center Boston, Massachusetts 02118 A 45-year-old Asian female presented in March 2008 due to joint pain and swelling. -Two months prior to presentation she developed pain in her wrists and ankles, worst at 2AM, and associated with swelling - Pain improved slightly with naproxen, but this was stopped due to itching ROS: Faint rash over arms and legs a few weeks prior, decreased appetite, episodic diaphoresis and chills PMH: None significant SH: Emigrated to US from Vietnam ten years ago. Work as a seamstress. Lives with husband and children in an urban area. No smoking, alcohol or drugs FH: No known autoimmune disease Diagnosis Epidemiology WBC PMNs Adult Onset Still’s Disease (AOSD) is an inflammatory disease of unclear etiology that is diagnosed by the presence of five or more clinical features, as presented by Yamaguchi and colleagues.1 AOSD is a rare disease, with new cases in 0.16 persons per 100,000 in a French study.7 16,800/μl 90% Hematocrit MCV Platelets 32% 88 FL 464,000/μl ESR CRP 58 mm/hr 35 ANA Negative Rheumatoid factor Negative Anti-CCP Negative Serum chemistries Normal BUN 3.9 Creatinine ALT 28 AST 82 Alkaline Phos 75 Total bilirubin 0.5 Hepatitis B/C serologies Gonorrhea PCR SSA/SSB RPR Negative Negative Negative Negative Ferritin 0.8 Chlamydia PCR Negative 37,469 ng/mL Imaging Studies General: Mild discomfort HEENT, lymphatic, pulmonary, cardiovascular and abdominal exams: All normal SAMPLE Musculoskeletal: -Swelling of right wrist extensor tendons and pain with resisted extension - Fifteen degree flexion contracture of the right elbow with boggy synovium at the radiohumeral joint, and tenderness with palpation and movement -Trace effusion of the right knee -Swelling and tenderness inferoposterior to the right lateral malleolus and inferoposterior to the left medial malleolus Skin: Sub-centimeter salmon-pink macules over the extremities A Frequency (%) Fever over 38C lasting one week or longer Typically quotidian or double-quotidian 94-100 Joint pain lasting two weeks or longer Typically polyarticular 68-100 Rash Typically salmon-colored and evanescent 51-94 Abnormal white blood cell count Or other hematologic problems 62-93 Minor AOSD Criteria Frequency (%) Sore throat 35-92 Lymphadenopathy or splenomegaly 15-81(J) Abnormal liver function tests or hepatomegaly 40-65 (J) Absence of rheumatoid arthritis 93 Age of onset: Median 25 years of age, with a bimodal peak and 15-25 years and 36-46 years of age. B Figure 1. (A) Wrist X-rays of a patient with AOSD showing nonerosive narrowing of the carpometacarpal and intercarpal joints with bony ankylosis. (B) Cervical spine X-ray showing facet joint narrowing and ankylosis. Radiographs courtesy of Dr. Burton Sack. Patient Course The diagnosis of Adult Onset Still’s Disease was made on clinical and laboratory criteria. -Initial treatment with NSAIDs was stopped due to a pruritic rash -Prednisone 50 mg daily was started, with gradual improvement. Prednisone was gradually tapered, then self-discontinued by the patient. -She developed a rash on stopping prednisone, so she was maintained on prednisone 5 mg daily, and later switched to methotrexate. -Arthralgias and rash resolved, and she has returned to work. Other clinical features Frequency (%) Pleuritis 40 Pericarditis 30 Weight loss 100 Dermatographism 92 The etiology remains unknown, and is thought to be due to an environmental trigger, such as an infection, in combination with a genetic susceptibility. Proposed triggers include viruses and bacterial infections. The pathway leading to clinical disease has yet to be fully elucidated, but is thought to involved altered cytokine production. Altered Cytokine Production IL-1 is produced by activated macrophages, and is involved in the TH1 (cell-mediated) immune response. - IL-1 levels are elevated in some patients with AOSD,8 and are markedly reduced in patients who improved when treated with an IL-1β receptor antagonist . - IL-18 is a member of the IL-1 cytokine family and is also elevated in patients with AOSD; levels correlate with liver dysfunction and elevated ferritin.9,10 Frequencies as reported by Singh et. al,3 except dermatographism, reported by Mehrpoor et. al.4 Common laboratory findings Frequency (%) ESR elevated 99 Ferritin elevated Ferritin over 5 times normal value Glycosylated ferritin under 20% 67 40 78 WBC over 10,000/mm3 92 WBC over 15,000/mm3 88 Neutrophils over 80 percent 88 Anemia (Hgb less than10g/dL) 68 Platelets over 400,000/mm3 62 Serum Albumin less than 3.5 g/dl 81 Elevated liver enzymes (any) 73 IL-6 is produced by macrophages and lymphocytes, and induces acute phase reactants. - IL-6 levels are elevated in serum of AOSD patients.14 Disease Course/Prognosis AOSD may be limited to a single episode, or may follow a more chronic course. Several prognostic factors have been identified.11 40 35 92 Negative RF 93 Frequencies as reported by Effthimou et. al,2 except ferritin/glycosylated ferritin reported by Fautrel et. al.5 Imaging Studies Xrays Wrist Non-erosive narrowing of carpometacarpal and intercarpal joints with bony ankylosis Ankles Tarsal ankylosis, same characteristics as wrist Photograph by E. Kissin Figure 2. Serum ferritin (ng/ml) level over time. Arrow indicates initiation of treatment with prednisone. 20 15 10 0 Self-Limited Episodic Chronic Figure 3. Frequency of AOSD patients with self-limited, episodic and chronic disease course, as reported by Pouchot et. al.11 Poor prognosis was associated with: - Chronic disease course (longer time to remission and Need for systemic glucocorticoids for >2 years) - Polyarthritis early in illness - Arthritis of the shoulders of hips References 1. 2. 3. 4. 5. The rash typically affects the proximal limbs and trunk, but spares the face and distal limbs, and is often associated or more pronounced with fever. 25 Findings reported by Medsger et. al.6 Differential Diagnosis Figure 1. Evanescent, salmon-pink maculopapular rash over the leg of a woman with Adult Onset Still’s Disease. 30 5 Negative ANA Infectious Non-Infectious Gonococcal arthritis Reactive arthritis Meningococcemia Rheumatologic 6. 7. 8. 9. Parvovirus SLE 10. EBV Rheumatoid arthritis 11. Disseminated lyme disease Seronegative arthritis 12. 13. Primary HIV Hepatitis B 14. 15. Macrophage Activating Syndrome/ Reactive Hemophagocytic Syndrome (MAS/RHS) MAS/RHS is a severe complication of AOSD due to dysregulation of macrophages in bone marrow and other reticuloendothelial tissues.12 Diagnosis is made in a patient with active AOSD and: - Cytopenia of two cell lines - Bone marrow biopsy showing hematophagocytosis by macrophages Pathophysiology Frequencies as reported by Effthimou et. al.2 Physical exam: Vitals: Temp , HR , BP , RR , sat %, weight 130 lbs Major AOSD Criteria (at least two) Gender distribution: typically affects women slightly more than men (60%women), particularly at older ages Frequency (%) Case Presentation Laboratory Studies Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, Kashiwazaki S, Tanimoto K, Matsumoto Y, Ota T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992;19(3):424-30. Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis. 2006;65(5):564-72. Singh S, Samant R, Joshi VR. Adult onset Still's disease: a study of 14 cases. Clin Rheumatol. 2008;27(1):35-9. Mehrpoor G, Owlia MB, Soleimani H, Ayatollahi J. Adult-onset Still's disease: a report of 28 cases and review of the literature. Mod Rheumatol. 2008;18(5):480-5. Fautrel B, Le Moël G, Saint-Marcoux B, Taupin P, Vignes S, Rozenberg S, KoegerAC, Meyer O, Guillevin L, Piette JC, Bourgeois P. Diagnostic value of ferritin and glycosylated ferritin in adult onset Still'sdisease.J Rheumatol. 2001;28(2):322-9. Medsger TA Jr, Christy WC. Carpal arthritis with ankylosis in late onset Still's disease. Arthritis Rheum. 1976;19(2):232-42. Magadur-Joly G, Billaud E, Barrier JH, Pennec YL, Masson C, Renou P, Prost A. Epidemiology of adult Still's disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis. 1995 Jul;54(7):587-90. Kötter I, Wacker A, Koch S, Henes J, Richter C, Engel A, Günaydin I, Kanz L. Anakinra in patients with treatment-resistant adult-onset Still's disease: four case reports with serial cytokine measurements and a review of the literature.Semin Arthritis Rheum. 2007;37(3):189-97. Choi JH, Suh CH, Lee YM, Suh YJ, Lee SK, Kim SS, Nahm DH, Park HS. Serum cytokine profiles in patients with adult onset Still's disease. J Rheumatol. 2003;30(11):2422-7. Chen DY, Lan JL, Lin FJ, Hsieh TY. Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still's disease. J Rheumatol. 2004;31(11):2189-98. Pouchot J, Sampalis JS, Beaudet F, Carette S, Décary F, Salusinsky-Sternbach M, Hill RO, Gutkowski A, Harth M, Myhal D, et al. Adult Still's disease: manifestations, disease course, and outcome in 62 patients. Medicine (Baltimore). 1991;70(2):118-36. Fukaya S, Yasuda S, Hashimoto T, Oku K, Kataoka H, Horita T, Atsumi T, Koike T. Clinical features of haemophagocytic syndrome in patients with systemic autoimmune diseases: analysis of 30 cases. Rheumatology (Oxford). 2008;47(11):1686-91. Lequerré T, Quartier P, Rosellini D, Alaoui F, De Bandt M, Mejjad O, Kone-Paut I, Michel M, Dernis E, Khellaf M, Limal N, Job-Deslandre C, Fautrel B, Le Loët X, Sibilia J; Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis. 2008;67(3):302-8. Matsumoto K, Nagashima T, Takatori S, Kawahara Y, Yagi M, Iwamoto M, Okazaki H, Minota S. Glucocorticoid and cyclosporine refractory adult onset Still's disease successfully treated with tocilizumab. Clin Rheumatol. 2009;28(4):485-7. Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 2008;371(9617):998-1006. Clinical features: fever, rash, hepatosplenomegaly and delerium Laboratory features: cytopenias, coagulopathy and elevated ESR Triggers: infections or medications Treatment: cyclosporine, cyclophosphamide and steroids, in addition to typical AOSD therapy (see below) Incidence: Estimated at 8% of AOSD patients; more common in AOSD than other autoimmune diseases Treatment Treatment of AOSD remains largely empiric as there have not been large trials due to the rarity of the disease. NSAIDs are first line therapy, but approximately 80% of patients require additional treatment. - Ibuprofen 800 mg orally four times daily - Naproxen 500 mg orally twice daily Glucocorticoids - Prednisone 0.5 to 1.0 mg/kg daily Disease-modifying antirheumatic drugs (DMARDs) Typically used in patients with episodic or chronic disease course to prevent complications from arthritis, or as glucocorticoid-sparing agents. - Methotrexate - Cyclosporine - Chloroquine/hydroxychloroquine - Cyclophosphamide Biologics are used in approximately 15% of patients who do not respond to other therapy. TNF inhibitors have been successful in some cases, but IL-1β and IL-6 antagonists show the most promising results. - Anakinra (IL-1β receptor antagonist) Case series of 4 patients who failed DMARDs and other biologic therapy, but who had rapid clinical and biochemical improvement with anakinra.8 Similar results were shown numerous other case reports. A retrospective study in France found 11 of 15 AOSD patients achieved ACR50% improvement in symptoms with anakinra treatment.13 Randomized controlled studies have not yet been performed. - Tocilizumab (IL-6 receptor antibody) Effective in a case report of a Japanese woman with refractory AOSD.14 A prospective, randomized Japanese trial found 80% of systemic-onset juvenile idiopathic arthritis subjects (a pediatric equivalent to AOSD), had a marked improvement in symptoms and CRP values, as compared to 15% of those given placebo.15 Randomized controlled studies in AOSD have not yet been performed.