Transcript AOSDposter3.6.09

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.