Systemic Arthritis [Fwd: New stills research]

[Guest guest]

Hi,

found a bunch of abstracts with new research on adult onset

Still's Disease, which will be presented at this years' upcoming ACR

Conference. I'll post these five here, for the benefit of those whose

children have Systemic JRA. Still's is the same condition, only this

research is specific to those who had onset as adults.

Take care,

Georgina

----Original Message-----

From: Jay [mailto:timberwolf@...]

Sent: Monday, October 29, 2001 3:57 PM

Stills

Subject: [stillsdisease] New stills research

ROLE OF INTERLEUKIN-18 (IL-18) IN ADULT-ONSET STILL'S DISEASE (aosd):

CONTRIBUTION TO HYPERFERRITINEMIA.

Hisae Ichida, Yasushi Kawaguchi, Michi Tanaka, Kae Takagi, Eiichi

Tanaka, Emi Nishimagi, Akiko Tochimoto, Masayoshi Harigai, Masako Hara,

Naoyuki Kamatani Shinjuku-ku, Tokyo and Musashimurayama-shi, Tokyo,

Japan

We have recently reported that IL-18 levels in Adult-onset Still'

disease (aosd) were significantly higher than those in normal healthy

donors and patients with other inflammatory disorders. We found a

significant correlation between serum IL-18 levels and disease severity,

suggesting that IL-18 might be a specific indicator of the severity of

aosd. In addition, serum ferritin levels in active aosd were markedly

higher than those in patients with inactive aosd or other systemic

inflammatory diseases. We found a significant correlation of serum level

of IL-18 to that of ferritin in patients with aosd. Since the molecular

weights of serum ferritin in aosd differed from those in normal

controls, determined by Western blotting, we suspected that inflammatory

mediators might be involved in ferritin production in this disease. In

the present study, we sought to determine whether IL-18 augments

ferritin production by hepatocytes or monocytes/macrophages. HepG2 were

tested as hepatocytes and THP-1/U937 as monocytes/macrophages in this

study. Cells were cultured in serum-free medium (QBSF-51), with

stimulation by IL-1a, TNF-a, IFN-g and IL-18. We determined the

concentrations of ferritin in culture supernatants by RIA after 24, 48

and 72 hrs. In HepG2 culture, increase in ferritin production was not

observed in supernatant. In U937 culture, ferritin production increased

until 72 hrs without stimulation, but various cytokines had no effect on

ferritin production. In THP-1 culture, ferritin production in

supernatant was observed without stimulation, and was significantly

increased with stimulation by various cytokines including IL-18.

Although IL-18 was initially described as a IFN-g inducing factor

through T cells, we have here for the first time demonstrated that IL-18

can modulate ferritin synthesis in monocytes/macrophages. Our

observations suggest that IL-18 plays a central role in the

immunopathogenesis of aosd not only through induction of IFN-g but also

through activation of inflammatory mediators including ferritin.

-----------------------------

INCREASED PRODUCTION OF CHEMOKINES IN ADULT ONSET STILL'S DISEASE.

Do-June Min, Mi-La Cho, Chong-Hyen Yoon, Young-Il Seo, Wan-Uk Kim,

Jun-Ki Min, Yeon-Sik Hong, Sang-Heon Lee, Sung-Hwan Park, Chul-Soo Cho,

Ho-Youn Kim Seoul, Republic of Korea

Objective: Adult onset Still's disease (aosd) is a systemic inflammatory

disorder characterized by reticuloendothelial system activation and

marked leukocytosis. Chemokines recruit and activate leukocytes with

different specificities, and some chemokines can promote leukocytosis.

We investigated the chemokine expression in patients with aosd.

Methods: C-X-C chemokine (IL-8) and C-C chemokines (RANTES, MIP-1a, and

MCP-1) were measured by ELISA in sera and culture supernatants of

peripheral blood mononuclear cells (PBMC) obtained from aosd patients

and healthy controls. Supernatants were collected from PBMC culture

unstimulated or stimulated with lipopolysaccharide (LPS) for 72 h.

Disease activity was assessed by clinical and laboratory parameters at

the time of blood sampling.

Results: The serum levels of C-X-C and C-C chemokines were significantly

higher in patients with aosd (n=24) than in healthy controls (n= 34)

(p<0.001 for all chemokines).Patients with active systemic features

(n=14) showed higher circulating chemokine levels than those with

inactive disease (n= 10) (p=0.001 for MCP-1 and p<0.05 for the

remainder). The serum ferritin levels strongly correlated with C-C

chemokine levels (MIP-1a, r=0.826, p<0.001; RANTES, r=0.583, p<0.05;

MCP-1, r= 0.415,p<0.05), but not with IL-8 levels. However, there was no

correlation between chemokine levels and peripheral blood leukocyte

counts. The chemokine productions by LPS-stimulated PBMC were

significantly augmented in aosd (n= 12) compared to healthy controls (n=

9) (p<0.001 for all chemokines).

Conclusion: Circulating levels of both C-X-C and C-C chemokines are

elevated in aosd, which seems to be related with excessive production of

chemokines by PBMC in response to certain stimuli. Serum C-C chemokine

levels may be a marker of disease activity in aosd.

--------------------------

DRAMATIC IMPROVEMENT OF INTRACTABLE ADULT-ONSET STILL'S DISEASE BY

INTRAVEOUS HUMANIZED ANTI-INTERLEUKIN 6 RECEPTOR ANTIBODY (MRA).

Masahiro Iwamoto, Hiroyuki Nara, Daisuke Hirata, Hitoaki Okazaki, Shogo

Kano, Seiji Minota, Norihiro Nishimoto, Kazuyuki Yoshizaki Tochigi and

Osaka, Japan

It is documented that serum levels of interleukin 6 (IL-6) are markedly

elevated in patients with adult-onset Still's disease (aosd) in active

phase. We experienced a patient with multi-drug-resistant aosd who was

dramatically improved by intravenous humanized anti-IL-6 receptor

antibody (anti-IL-6R Ab), that neutralizes the action of IL-6. A

21-year-old Japanese woman was diagnosed as having aosd two years ago.

Initial treatment with high dose prednisolone was successful. However,

her disease flared up repeatedly when prednisolone was tapered to 10-20

mg/day, which necessitated an increase of prednisolone to at least 30

mg/day. Addition of methotrexate (15 mg/week) or cyclosporine A (240

mg/day) did not give any appreciable beneficial effects. Multiple bone

fractures of thoracic vertebrae and ribs due to prolonged high dose

prednisolone deteriorated her into respiratory failure and she was on a

respirator in ICU.

Anti-IL-6R Ab, which is on a clinical trial for rheumatoid arthritis in

Japan, was instituted intravenously under the approval of the ethical

committee in our hospital. Serum level of CRP decreased from 32 to 1

mg/ml in a week, and dramatic improvement was achieved enabling

successful tapering of prednisolone to 3 mg/day. Thus, anti-IL-6R Ab was

found very efficacious in treating aosd with high

prednisolone-dependency.

----------------------------------

SUCCESSFUL THERAPY WITH INFLIXIMAB IN REFRACTORY ADULT ONSET STILL'S

DISEASE.

Elena Aurrecoechea, Blanco, Senen , Victor M

ez-Taboada, Vicente -Valverde Santander, Cantabria, Spain

Objective: Non steroidal antiinflammatory drugs (NSAIDs) and

corticosteroids (CS) therapy are the initial therapy for Adult Onset

Still's Disease (aosd). In refractory cases or when the dose of

corticosteroid is unacceptably high, other Disease Modifying

Antirheumatic Drugs (DMARDs) have been used with diverging results.

Despite these therapies, a significant proportion of patients respond

poorly following a disabling course. We report two patients with aosd,

refractory to aggressive therapy, treated successfully with Infliximab.

Patients: Two patients with aosd refractory to standard therapy and

severe steroid side effects are described (see Table). They were started

on Infliximab at a dose of 3 mg/kg following the standard schedule

proposed for RA (infusion on weeks 0, 2, 6 and then every 8 weeks).

Results: Shortly after the first infusion both patients experienced a

significant clinical response. The main clinical and laboratory data as

well as the initial response therapy are shown in the table

Conclusion: The rapid and pronounced improvement of our two patients

with Infliximab support the efficacy of TNF-blocking therapy in patients

with aosd refractory to conventional therapy. Prospective controlled

studies are needed to confirm the current anecdotal experience with

TNF-blocking therapy in the treatment of refractory aosd.

Patient 1 Patient 2

Sex/Age Male/28 Female/22

aosd Duration 2 yrs 2 yrs

Previous DMARDs Methotrexate, chloroquine, azathioprine Methrotexate,

chloroquine

Steroid side effects Cushing, acne, myopathy Cushing, hip osteonecrosis

Clinical and lab data previous to infliximab fever, polyarthritis, rash.

ESR 104 mm/1hr (n:<20). CRP 3.3 mg/dl (n:<.5). Ferritin 2827 ng/ml

(n:25-310) polyarthritis, anorexia. ESR 64 mm/1hr. CRP 13.3 mg/dl.

Ferritin 302 ng/ml. 14000 leukocytes/mm3

Clinical and lab data after 2 months of infliximab Asymptomatic. ESR 29

mm/1hr. CRP 4.4 mg/dl. Ferritin 265 ng/ml. Arthralgias. ESR 25 mm/1hr.

CRP 4.3mg/dl. Ferritin 138 ng/ml. 11400 leukocytes/mm3

----------------------------

SUCCESSFUL TREATMENT OF A SMALL COHORT OF PATIENTS WITH ADULT ONSET OF

STILL DISEASE WITH INFLIXIMAB.

Hans G Kraetsch, Christian Antoni, Joachim R Kalden, Bernhard Manger

Erlangen, Bavaria, Germany

In several trials TNF-blocking agents, like infliximab, have been shown

successful in the treatment of rheumatoid arthritis (RA). We tested the

efficacy of infliximab in patients with severe Adult Onset of Still

Disease (aosd).

Methods: In six patients with aosd according to the Yamagushi criteria

treatment with 3 to 5 mg/kg infliximab was started. All patients had a

severe course of disease with high activity and were initially treated

with corticosteroids. One patient had a history of 3 years of aosd with

fever, chills, pleural and pericardial effusions and hepatosplenomegaly

and was treated with methotrexate and azathioprine, but developed

increasing serological signs of inflammation and arthritis of both hips

and peripheral joints. Another patient had a history of 5 years of aosd

with oligoarthritis, recurrent fever and myalgias despite of a therapy

with azathioprine, methotrexate alone and in combination with

cyclosporine A and cyclophosphamide therapy. Also, this patients could

not be treated sufficiently with these therapies. The other four

patients were treated in an earlier stage of disease and did only have

prior steroid therapy. They all had a high disease activity with the

typical symptoms. Reduction of steroid therapy caused a relapse of the

disease in all patients. 3 to 5 mg/kg infliximab was administered at

week 0, 2, and 6, followed by intervals of 6 to 8 weeks depending on the

individual disease activity.

Results: In all patients, fever, arthritis and arthralgias, myalgias,

splenomegaly and the rash resolved within the first courses of

infliximab infusions. All serological parameters like ESR, CRP,

leucocyte counts and ferritine levels returned to normal values. One of

our patients still had severe pain in the left hip. Further

investigations revealed a severe postarthritic osteoarthritis requiring

hip joint replacement. Up to now, our patients are treated between 5 and

28 months. All patients continued to benefit from this therapy with

regard to their clinical symptoms, their joint counts and their

serological disease activity. One of our patients experienced a moderate

infusion reaction during the second infusion. The infusion was

discontinued for one hour and could be resumed after that reaction

without any further problems.

Conclusion: All of our aosd-patients showed an improvement of disease

activity after treatment with infliximab. This suggests a potential

therapeutic benefit of an anti-TNF treatment in aosd.

-------------------------

Visit the International Still's Disease Foundation Website

http://www.stillsdisease.org

Visit the Still's Disease Message Board

http://disc.server.com/Indices/148599.html