Churg Strauss Syndrome

Jun-Ki Park, 4/12/11

History

Definition

Epidemiology

Clinical symptoms / Classification

Pathophysiology

Treatment

History

“Allergic granulomatosis, allergic angiitis, and periarteritis nodosa”

In 1951, Jacob Churg and Lotte Strauss at Mount Sinai Hospital first described the syndrome in 13 patients who had

asthma, eosinophilia, granulomatous inflammation,

necrotizing systemic vasculitis, and necrotizing GN.

Definition

“Eosinophil-rich and granlomatous inflammation involving respiratory tract and necrotizing vasculitis affecting small-

to medium-sized vessels and associated with asthma and eosinophila”

(Chapel Hill Consensus Conference Definition)

Classified under “ANCA associated vasculitis”

Epidemiology

Incidence 1.3 -

6.8 cases per 1000 000/yr

Prevalence 10.7 -

13 per 1000 000

Mean age of disease onset ~38y

No sexual predominance

Clinical presentation3 stages:

1. Severe asthma, frequently accompanied by sinusitis

2. Blood eosinophilia and eosinophilic infiltration of tissues (similar to HES)

3. Onset of systemic vasculitis and sometimes granulomatous disease, usually several years after onset of asthma

It’s likely that the three clinical stages of CSS are immunologically distinct.

Renato et al. Best P&R Clin Rheum 2009

Prognosis

Initially uniformly fatal, with 50% of untreated patients dying within 3 months of the onset of vasculitis.

Since widespread use of systemic glucocorticoids prognosis improved dramatically; survival rate of > 70% at 5 yrs

Most deaths result from complications of the vasculitic phase of

the disease: - Cardiomyopathy (HF/MI)-

CNS involovement (Cerebral hemorrhage)-

Renal failure (Cr>1.6 mg/dL, proteinuria >1 g/day)-

GI involvement (GI bleeding) -

Status asthmaticus

Prognosis

Initially uniformly fatal, with 50% of untreated patients dying within 3 months of the onset of vasculitis.

Since widespread use of systemic glucocorticoids prognosis improved dramatically; survival rate of > 70% at 5 yrs

Most deaths result from complications of the vasculitic phase of

the disease: - Cardiomyopathy (HF/MI)-

CNS involovement (Cerebral hemorrhage)-

Renal failure (Cr>1.6 mg/dL, proteinuria >1 g/day)-

GI involvement (GI bleeding)

-

Status asthmaticus

“Five Factor Score”

“Five Factor Score”One large series reported the following 5-year mortality figures. (342 pts; 260 PAN, 82 CSS)

12% when 0 FFS present

26% when 1 FFS present

46% when 3 or more FFS present

Guillevin et al. Br J Rheumatology1996

Pathology

Histopathology may vary with the phase of disease.

Eosinophilic phase: tissue infiltration by eosinophils may be present without overt vasculitis.

Vasculitic phase: nondestructive infiltration of vessel walls, necrotizing vasculitis.

Most common renal finding is necrotizing crescentic glomerulonephritis, but eosinophilic interstitial nephritis, mesangial glomerulonephritis, and FSGS are also seen.

Pathophysiology

Cytokine pattern in CSS is characterized by the release of Th2 cytokines (IL4, IL5, IL13; typical for HES), combined with the release of Th1 cytokines (IFN-γ

and TNF-α; typical for WG).

CSS combines features of hypereosinphilic disorder and a vasculititc/granulomatous disease, not only clinically but also immunologically.

Hellmich et al. Ann. N.Y. Acad. Sci. 2005

Pathophysiology –

IL5

IL5 induces terminal differentiation of eosinophil precursors.

IL5 prolongs the survival of mature eosinophils and delays apoptosis of eos.

IL5 promotes adhesion of eosinophils to vascular endothelium and CCR3 dependent migration of eos from vasculature.

IL5

PBMCs of patients with CSS cultured with T cell-specific stimuli compared with PBMCs from healthy controls.

Production of IL 5 analyzed w/ cytometric bead arrays before and after stimulation w/ anti- CD3 and anti-CD28-antibodies for 24h.

Hellmich et al. Ann. N.Y. Acad. Sci. 2005

ANCA in CSS

2 studies on large cohorts of patients have found that ANCAs were present in only 38% of patient, predominantly MPO / P-ANCA.

CSS is associated with not only vasculitis, but also with eosinophil-rich granulomatous inflammation. Animal models for MPA are not directly transferable to CSS.

Unclear, whether ANCAs have a direct pathogenic role in CSS or whether they are a response to control the autoantigen.

Sinico et al. Arthritis Rheum 2005 / Sable-Fourtassou et al. Ann Intern Med 2005

Renato et al. Best P&R Clin Rheum 2009

ANCA in CSS

Genetics

Both HLA-DRB1*07 and HLA-DRB4 more prevalent among patients with CSS and HLA-DRB4 correlated with the number of vasculitic manifestations (study of 48 patients and 350 healthy controls)

Genotyping identified three single nucleotide polymorphisms relating to the interleukin IL10 gene. The IL-10 -3575/-1082/-

592 TAC haplotype was strongly associated with CSS (OR=2.16) and negatively associated with WG. (study of 103 patients with CSS)

Vaglio et al. Arthritis Rheum. 2007 / Wieczorek et al. Arthritis Rheum. 2008

Treatment –

Glucocorticoids (CSS w/ FFS 0)

Ribi et al. Arthritis & Rheumatism 2008

Treatment -

Glucocorticoids

Prednisone 0.5 to 1.5 mg/kg per day, higher dose used for pts with more severe vasculitis (GN, resp. failure, cardiac involvement, neuropathy)

For acute multiorgan disease, IV solumedrol 1g 3days.

Majority achieve remission w/ glucocorticoids alone

Treatment –

Cyclophophamide

Results of prospective trials have demonstrated that patients with severe manifestations benefited from CYC in addition to GC.

However the potential infectious and neoplastic complications of this treatment make optimization of therapeutic regimens necessary.

Treatment –

Cyclophophamide

Cohen et al. Arthritis Rheum. 2007

Treatment –

Cyclophophamide

Cohen et al. Arthritis Rheum. 2007

Treatment –

Cyclophophamide

Cohen et al. Arthritis Rheum. 2007

Treatment –

Azathioprine

Typically used after induction of remission with cyclophosphamide

or as a glucocorticoid-sparing agent in

patients requiring long-term treatment with prednisone

at doses greater than 15 mg per day

Target dose of 2 mg/kg

Treatment –

Azathioprine

Ribi et al. Arthritis & Rheumatism 2008

Other Therapies

Anti-IgE

therapy: Omalizumab, used in refractory asthma, case report successful use in refractory CSS. Omalizumab

may have a pro-apoptotic effect on eosinophils. (Pabst et al. Thorax.2008)

Anti-IL 5 Ab: Mepolizumab, humanized monoclonal antibody to IL-5, appears to have GC sparing effect in pts w/ HES. Case reports of CSS refractory to prednisone and CYC, responding to IV mepolizumab. (Rosenwasser

et al. J Allergy Clin

Immunol. 2010)

MMF: Case reports described successful use of mycophenolate

mofetil

plus oral glucocorticoids

to treat a patient with CSS manifested by asthma, chronic rhinosinusitis, cutaneous

vasculitis, and a positive ANCA (pANCA/MPO-Ab) (Assaf

et al. Br J Dermatol. 2004)

Interferon alpha : Case series of 7 pts with refractory CSS received interferon-alpha for induction of remission. All 7 pts entered remission after 3 months of treatment. (Metzler et al. Clin

Exp Rheumatol. 2008)

IVIG: Case series showing improvement in disease contol

in pts with refractory disease after addition of high-dose IVIG. (Tsurikisawa

et al. Ann Allergy Asthma Immunol. 2004)

Hydroxyurea: Case report (used in HES) found to be beneficial as a glucocorticoid-sparing agent, relatively few side effects (Lee et al. J Allergy Clin Immunol. 2009)

Rituximab:

Case reports, however found to cause immediate and severe bronchospasm

in 2 pts with ANCA-negative CSS. (Saech

et al. Ann Rheum Dis. 2010)

Thank You!