CSS/EGPA is a challenging disease to diagnose and treat. Every patient presents differently, some are ANCA negative, some are ANCA positive, any organ system can be affected, and achieving and maintaining remission can also be a challenge. The CSSA is fortunate to have an outstanding and dedicated Medical Advisory Board willing to consult with physicians on difficult cases when time permits. Please do not hesitate to contact them.
In addition, the Vasculitis Clinical Research Consortium, an integrated group of academic medical centers, patient support organizations, and clinical research resources, has a section just for treating physicians to refer a patient for clinical care, refer a patient for research and to request medical advice.
This section will contain articles written by the world's leading experts in CSS/EGPA as well as news of upcoming physician events related to CSS/EGPA.
EGPA: early diagnosis is better
By Christian Pagnoux, MD MPH MSc
May 2013 Mount Sinai Hospital Division of Rheumatology – Vasculitis clinic
60 Murray Street Room 2-220 Toronto, ON, M5T 3L9, Canada
Phone: 416-586-4800 ext. 8549
Article in PDF format
As compared with initial descriptions of eosinophilic granulomatosis and polyangiitis (EGPA) showing poor survival, patient outcomes have dramatically improved over the past 2 decades. At 1 and 5 years post-diagnosis, survival rates now exceed 90% and 85%, respectively [1-3]. Besides advances in the therapeutic management of EGPA, better awareness and recognition of this rare condition have clearly contributed to improved survival. Delayed diagnosis and initiation of appropriate treatments can indeed negatively affect overall prognosis and outcomes.
However, it should be acknowledged that the diagnosis of EGPA often remains challenging and in some cases can be confirmed only during the course of the disease. EGPA is a rare disease with an incidence of about 1 to 2 per million people and a prevalence of about 10 to 15 per million [4-6]. Hence, most physicians will not likely see more than a couple of EGPA cases during their career.
Diagnostic criteria to help with early diagnosis are lacking. The 1990 American College of Rheumatology criteria included the most typical “full-blown” disease characteristics and aimed at classifying patients with already diagnosed and proven vasculitis into a disease category. The Chapel Hill nomenclature are useful to define EGPA among the medical community but cannot be used for diagnosis. More importantly, we lack a good biologic or radiologic test to detect early EGPA or confirm the diagnosis. Anti-neutrophil cytoplasm antibodies (ANCA) are present in only 30% to 40% of EGPA patients at diagnosis and/or during disease flare (mainly antimyeloperoxidase perinuclear ANCA) [1, 7-9]. Increased blood eosinophil count can suggest disease but is lacking in specificity in that it can be observed in other conditions as well, including simple allergy. Serum level of immunoglobulin E (IgE) is also usually elevated, but this sign lacks specificity even more so than blood eosinophilia. Biopsy of an affected tissue thus remains the gold standard to support the diagnosis; it may show vasculitis, i.e. inflammation of the blood vessel wall, mainly with eosinophils, with other more subtle but inconstant features such as fibrinoid necrosis or granulomas. However, biopsies can be invasive and, depending on the organ, can cause moderate but irreversible damage such as persistent localized numbness after a peripheral nerve biopsy. In addition, biopsies do not always show typical histologic features, depending on the organ and because vasculitis lesions are segmental (i.e., have a patchy distribution along blood vessels).
Hence, physicians should think earlier than later of the possibility of EGPA in several clinical settings described below and must not hesitate to refer patients to a vasculitis center for evaluation and further investigation if needed. As described by Lanham et al., in the early 1980s, EGPA may be divided into and progress in 3 stages : asthma and/or recurrent nasal polyposis (stage 1), which indeed corresponds more to a background condition than EGPA if not a prerequisite to 3 development of blood and tissue eosinophilia (stage 2), then EGPA with its vasculitis manifestations (stage 3). Early identification of these pre-EGPA stages may help prevent severe complications of EGPA and promote faster remission. However, not all patients will show progression through these 3 stages, and one should not over- or prematurely diagnose EGPA. Eosinophilic allergic asthma with nasal polyposis is indeed more frequent than EGPA, and EGPA will not develop in most patients with allergic asthma .
The most frequent clinical settings that should alert physicians (and patients) to the possibility of EGPA are relatively easy to identify and remember.
- Asthma, especially late-onset asthma (i.e., starting in adulthood), that gradually worsens and becomes refractory to usual antiasthma drugs, with increased eosinophilia on white blood cell count. In most of these cases, allergic asthma or allergic bronchopulmonary aspergillosis is diagnosed, but early stages of EGPA can present in this way.
- Recurrent bronchitides and/or “pneumoniae” in a patient with background asthma, especially late-onset asthma, with increased eosinophilia on white blood cell count. In most of these cases, “simple” infection, allergic bronchopulmonary aspergillosis or eosinophilic pneumonia is diagnosed, but early stages of EGPA can present in this way.
- Worsening, lingering and/or recurrent sino-nasal polyposis and/or sinusitis, especially if associated with (late-onset) asthma, with increased eosinophilia on white blood cell count. These manifestations are not sufficient for a diagnosis of EGPA because of no vasculitis, but early stages of EGPA can present in this way.
- Recurrent skin rash (any type) or hives with increased eosinophilia on white blood cell count. In most of these cases, simple allergy or chronic urticaria is diagnosed, but early 4 stages of EGPA can present in this way and many different types of skin lesions can occur in EGPA (Figures 1 to 4).
- In a patient with asthma and/or sino-nasal polyposis, any symptoms of systemic vasculitis, including skin purpuric rash, numbness, tingling or weakness in hands or feet (mononeuritis multiplex), scleritis (or episcleritis), or renal disease (microscopic hematuria being the first manifestation of glomerulonephritis). Other possible and/or more severe manifestations, such as coronary arteritis or gut perforations due to inflammation and occlusion of the small vessels of the bowels, are rare features of EGPA that are more easily considered related to vasculitis (EGPA or another type of vasculitis).
- In a patient with asthma and/or sino-nasal polyposis, any new or worsening general or constitutional symptoms, including fever, joint pain, diffuse muscle pain, major involuntary weight loss, chest pain, palpitations or abdominal pain. These symptoms are not specific but may be the first signs of a vasculitis, including EGPA.
In such cases, it is wise to control blood cell count, including eosinophil count; check some inflammatory signs such as level of C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR); and perhaps order an ANCA screening test as well as other investigations according to the clinical presentation (e.g., chest X-ray or CT with respiratory symptoms; CT scan of sinuses with ear nose, and throat manifestations [Figure 5]; electromyography of peripheral nerve conduction with numbness; electrocardiography and cardiac imaging). Biopsies of skin lesions are easy to perform but may show non-specific leucocytoclastic vasculitis. The sensitivity of sinus biopsy is low (<50%). Other biopsies, such as peripheral nerve or lung lesion, may be considered depending on the clinical presentation and after review of all obtained results, which may be sufficient to consider the diagnosis of EGPA highly probable for starting the appropriate treatment.
As with other vasculitides, such as giant cell arteritis, starting systemic corticosteroid treatment early, which remains the cornerstone of EGPA treatment, should not be considered a mistake, at least after all the appropriate diagnostic investigations have been realized (especially to rule out parasitic infections that can cause blood eosinophilia). Corticosteroids alone may still be insufficient to prevent more severe vasculitis complications, such as those listed in the original 1996 five factor score (i.e., cardiomyopathy or central nervous system, severe gastrointestinal or renal involvement [creatinine level > 140 µmol/l or proteinuria > 1 g/24 hr) . Physicians should remain alert to such severe complications and follow patients closely for early detection. Conversely, corticosteroid treatment should not be prolonged in the absence of a clear diagnosis. The diagnosis of EGPA should not be made too easily (and erroneously) for the (rare) patients with allergic asthma who depend on systemic corticosteroids for asthma control but who never had any other (vasculitis) manifestations, simply because they are corticosteroid-dependent. A corticosteroid-sparing agent can still be considered for such patients with intractable asthma. Of note, the discontinuation of corticosteroids in these patients with intractable asthma, sometimes after a successful trial with other anti-asthma drugs such as a leukotriene receptor antagonist, may unmask vasculitis manifestations (i.e., a “forme fruste” of EGPA) [13-15].
Studies may eventually identify more specific and sensitive biologic markers that will help in the early diagnosis of EGPA and in differentiating EGPA from mimicking diseases such as common allergic asthma, allergic bronchopulmonary aspergillosis, eosinophilic pneumonia or primary hypereosinophilic syndrome. Several potential biologic candidates have been investigated and 6 include eotaxin-3 (CCL26), interleukin 5 (IL-5), IL-25, eosinophil cationic protein, and thymus and activation-regulated chemokine (TARC or CCL17) but with relatively disappointing results or that need to be validated in a larger number of patients with EGPA or mimicking conditions [16-19]. Because EGPA is a rare disease, achieving reliable and reproducible results will take some time. Until then, effort must continue to improve awareness of this condition, systematize the diagnostic approach and investigations, optimize treatments for severe manifestations, reduce cumulative corticosteroid exposure and limit treatment-related side effects.
1 CT Scan.jpg
2 necrotic ulcer copy.jpg
3 nodule copy.jpg
4 urticarial copy.jpg
5 macular leg copy.jpg
Figure 1: CT scan of sinuses showing bilateral maxillary and sphenoidal sinusitis and nasal polyps in a patient with EGPA diagnosed after she presented some vasculitis manifestations (lung infiltrates and nodules with eosinophilic vasculitis on lung biopsy).
Figures 2 to 5: Possible lesion types in EGPA: purpuric and ulcero-necrotic lesions on both legs (2), diffuse erysipelas-like rash with subcutaneous nodules (circle) on one leg (3), pseudo-urticarial hive-like (itchy) lesions on one arm (4), and macular erythematous and purpuric rash on one leg (5) from 4 different patients.
1. Comarmond, C., et al., Eosinophilic granulomatosis with polyangiitis (Churg-Strauss):
clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis
Study Group cohort. Arthritis Rheum, 2013. 65(1): p. 270-81.
2. Pagnoux, C., Churg-Strauss syndrome: evolving concepts. Discov Med, 2010. 9(46): p. 243-52.
3. Moosig, F., et al., A vasculitis centre based management strategy leads to improved outcome in eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA): monocentric experiences in 150 patients. Ann Rheum Dis, 2013. 72(6): p. 1011-7.
4. Mohammad, A.J., et al., Prevalence of Wegener's granulomatosis, microscopic polyangiitis, polyarteritis nodosa and Churg-Strauss syndrome within a defined population in southern Sweden. Rheumatology (Oxford), 2007. 46(8): p. 1329-37.
5. Pagnoux, C. and L. Guillevin, Churg-Strauss syndrome: evidence for disease subtypes? Curr Opin Rheumatol, 2010. 22(1): p. 21-8.
6. Vaglio, A., C. Buzio, and J. Zwerina, Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): state of the art. Allergy, 2013. 68(3): p. 261-73.
7. Sinico, R.A., et al., Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum, 2005. 52(9): p. 2926-35.
8. Keogh, K.A. and U. Specks, Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med, 2003. 115(4): p. 284-90.
9. Baldini, C., et al., [Churg-Strauss syndrome: outcome and long-term follow-up of 38 patients from a single Italian centre]. Reumatismo, 2009. 61(2): p. 118-24.
10. Lanham, J.G., et al., Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore), 1984. 63(2): p. 65-81.
11. Harrold, L.R., et al., Incidence of Churg-Strauss syndrome in asthma drug users: a population-based perspective. J Rheumatol, 2005. 32(6): p. 1076-80.
12. Guillevin, L., et al., Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore), 1996. 75(1): p. 17-28.
13. Wechsler, M. and J.M. Drazen, Churg-Strauss syndrome. Lancet, 1999. 353(9168): p. 1970-1.
14. Wechsler, M.E., et al., Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest, 2000. 117(3): p. 708-13.
15. Wechsler, M.E., et al., Churg-strauss syndrome in patients treated with omalizumab. Chest, 2009. 136(2): p. 507-18.
16. Khoury, P., et al., Serum biomarkers are similar in Churg-Strauss syndrome and hypereosinophilic syndrome. Allergy, 2012. 67(9): p. 1149-56.
17. Polzer, K., et al., Eotaxin-3 is involved in Churg-Strauss syndrome--a serum marker closely correlating with disease activity. Rheumatology (Oxford), 2008. 47(6): p. 804-8.
18. Zwerina, J., et al., Eotaxin-3 in Churg-Strauss syndrome: a clinical and immunogenetic study. Rheumatology (Oxford), 2011. 50(10): p. 1823-7.
19. Hellmich, B., E. Csernok, and W.L. Gross, Proinflammatory cytokines and autoimmunity in Churg-Strauss syndrome. Ann N Y Acad Sci, 2005. 1051: p. 121-31.
Figures 1 to 4: Possible lesion types in EGPA: purpuric and ulcero-necrotic lesions on both legs (1), diffuse erysipelas-like rash with subcutaneous nodules (circle) on one leg (2), pseudourticarial hive-like (itchy) lesions on one arm (3), and macular erythematous and purpuric rash on one leg (4) from 4 different patients.
Figures 5: CT scan of sinuses showing bilateral maxillary and sphenoidal sinusitis and nasal polyps in a patient with EGPA diagnosed after she presented some vasculitis manifestations (lung infiltrates and nodules with eosinophilic vasculitis on lung biopsy).
The following article was written by Dr. Christian Pagnoux, who is one of the world's leading researchers into this rare disease.
Churg-Strauss Syndrome: Evolving Concepts
by Christian Pagnoux
Permission given from Dr Pagnoux & Discovery Medicine
What’s new in Churg-Strauss research?
The next article was written by Dr. David Jayne, a consultant with the Vasculitis and Lupus Service at Addenbrooke’s Hospital in Cambridge, UK. Dr. Jayne is a noted vasculitis researcher who has a special interest in CSS
What’s new in Churg-Strauss research?
The treatment of Churg-Strauss syndrome (CSS) has been modelled on that of more common vasculitis syndromes such as Wegener’s granulomatosis (WG) or microscopic polyarteritis (MPA). However, the French Collaborative Research Group have a good tradition of studying CSS on its own and have completed the largest trials in CSS so far (www.vascularite.com). They have recently looked at the role of the ANCA blood test in 112 new CSS patients and found ANCA in 38%[Sable-Fourtassou, 2005 #11]. This is somewhat lower than previous studies, but of more importance they found that the patients with ANCA were more likely to have kidney and nerve involvement and were less likely to have involvement of the heart or a fever. This suggests that ANCA may be useful in dividing CSS into two subgroups and different treatment approaches may be required.
In Cambridge, we have been impressed by the improvements seen in some of our vasculitis patients with Rituximab (Mabthera in Europe, Rituxan in the US). Rituximab is a monoclonal antibody that has been designed to remove a type of white blood cell, the B cell, from the body. After rituximab treatment, B cells become undetectable in the blood for around six months. It appears that B cells are an important player in vasculitis and without B cells around, vasculitis tends to subside. Fortunately we can cope without B cells reasonably well and this treatment may well be safer than current immunesuppressive drugs. Six CSS patients with disease that has proved difficult to control with the usual drugs have been treated with rituximab in Cambridge. Results in the first two patients were promising and have been published[Koukoulaki, 2006 #155]. These patients continue to do well although have required further courses of rituximab. We have also been encouraged by the results in the next four patients but it is too early to make any firm conclusions. It would appear that this success is similar to that seen with rituximab in WG and MPA and underlines the importance of bigger studies in CSS. The Mayo Clinic in the USA have started such a study and we hope that a European study may start soon as well.
Another drug that has attracted interest is Mepolizumab. Like rituximab, mepolizumab is also an antibody targeted treatment. Mepolizumab aims to neutralise a messenger in the immune system called IL-5 which is released by a subset of white blood cells, T cells, and stimulates eosinophils, the cell type closely involved in CSS. It has been effective in a related condition called hyper eosinophilic syndrome (HES), there are no results in CSS yet but we know that IL-5 levels are high in active CSS and fall when the CSS comes under control and there are good reasons for thinking that reducing IL-5 activity may help control CSS.
Other ongoing research in vasculitis and CSS is the study of gene expression in circulating blood cells. Newer scientific techniques allow the activity of almost 30,000 genes to be studied. The resulting patterns of expression, whether a gene or group of genes are more or less active than other genes, can be compared to other information such as the activity of vasculitis or the type of drugs a patient is on. This technique has been effective in other areas of medicine to predict the course of a disease and to predict how patients will respond to a particular drug. Patterns unique to vasculitis patients have now been described and we hope to find a CSS pattern and relate this to what is happening to our CSS patients in the future.
Workshops and CMEs
The Sixteenth International Vasculitis & ANCA Workshop
will take place April 14-17, 2013,
at the"Institut des Cordeliers" in Paris.
This International Vasculitis and ANCA Workshop will provide the opportunity to meet physicians involved in vasculitis care, exchange opinions and discuss new projects. The major aspects of the vasculitis field will be explored, taking into consideration and comparing the points of view of clinicians and basic researchers, and physicians and patients.
Cleveland Clinic Center for Continuing Education CME website series: New Directions in
Small Vessel Vasculitis -
ANCA, Target Organs,
Treatment, and Beyond
From the website “…This webcast series and online Cleveland Clinic Journal of Medicine supplement, "New Directions in Small Vessel Vasculitis — ANCA, Target Organs, Treatment, and Beyond," present in-depth reviews and discussions of our current understanding of the clinical features, diagnostic methodology, monitoring, and treatment of patients with small-vessel vasculitis. The goal of the webcast series and journal supplement is to improve the knowledge, comprehension, and skills of practitioners. The series and supplement offer detailed analyses of the following:
Small vessel vasculitis: Clinical features and diagnosis.
Impact of vasculitis on individual organ systems.
Patient safety issues in vasculitis.
Treatment of vasculitis – conventional immunosuppressive agents and biologic therapies.”
The Cleveland Clinic is also offering a live CME course on May 1, 2013 entitled: Large Vessel Vasculitis, Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome), and Other Unique Vasculitides
This Symposium is directed towards rheumatologists and rheumatology allied health practitioners, vascular physicians, neurologists, pulmonologists, allergists, hepatologists, ophthalmologists, and associated allied health practitioners interested in vasculitis.
In addition, The Cleveland Clinic offers a series of webcasts relevant to CSS/EGPA for CME credit:
Initial Presentation and Diagnosis of Small Vessel Vasculitis
Monitoring Patients with
OKTOBERFEST-SATELLITE ERA/EDTA CME COURSE “FOREFRONTS IN ANCA VASCULITIS”
Department of Nephrology, University of Munich, Germany.
: CME course covering the pathogenesis of ANCA-associated vasculitis and pauci-immune glomerulonephritis, renal pathology and biomarkers of ANCA vasculitis, assessment or disease activity, and therapy and patient management. Case examples will illustrate common and less frequent clinical scenarios.
The event will take place in Munich, Germany on September 28, 2013.
CanVasc of Canada offers many services to treating physicians and CSS patients. Medical centers and physicians across Canada with expertise in vasculitis have been identified and are part of this initiative. Among its several other aims, important ones are to help conduct studies on vasculitis, provide support and educational material on vasculitides for physicians and other health care providers and, eventually, optimize the therapeutic management of patients with these rare diseases. There are CanVasc reviews of recent articles for physicians to keep up the pace with scientific publications, downloadable vasculitis presentations (PowerPoint/pdf files) as well as a section entitled Tools for Physicians.
Groupe Francais d’Etude des Vascularities (French Vasculitis Study Group)
The Referral Center Group I, Rare Systemic Diseases and Autoimmune Diseases, Necrotizing Vasculitides and Systemic Sclerosis coordinates and manages the care of patients with vasculitis in France, in cooperation with the other centers comprising Group I. There is alsodetailed information about the FVSG including how to become a member.
The European Vasculitis Center (EUVAS) The European Vasculitis Society evolved from the European Vasculitis Study Group and was established on 15 May 2011. The website contains information on Disease Scoring, ANCA testing, publications, and recommendations for management of vasculitis.
APFED has a listing of Online Videos for CMEs.