TREATMENT OF CHURG-STRAUSS SYNDROME WITH AN INHALED CORTICOSTEROID AFTER ORAL STEROIDS DISCONTINUATION DUE TO SIDE EFFECTS

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1 JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2008, 59, Suppl 6, E. SWIETLIK 1, A. DOBOSZYNSKA 1, 2 TREATMENT OF CHURG-STRAUSS SYNDROME WITH AN INHALED CORTICOSTEROID AFTER ORAL STEROIDS DISCONTINUATION DUE TO SIDE EFFECTS 1 Department of Internal and Pulmonary Medicine, Miedzyleski Hospital, Warsaw, Poland; 2 Department of Clinical Nursing, Warsaw Medical University, Warsaw, Poland Churg-Strauss syndrome is characterized by a history of asthma, peripheral blood and tissue eosinophilia, with a predilection to the lungs. In this article we present a case of a 35 years old patient admitted to the hospital as a case of severe asthma apparently complicated by bilateral pneumonia. After a transient improvement on antibiotics, the respiratory symptoms recurred one month later in an exacerbated form. The diagnosis of Churg - Strauss syndrome was established on a clinical basis and a long-term therapy with oral corticosteroids and cyclophosphamide was introduced. The treatment must have been withdrawn after a year, because of a whole range of adverse effects, even though there was a severe recurrence of symptoms during the therapy. A regimen of the inhaled corticosteroid ciclesonide was then started, which entirely prevented the recurrence of respiratory symptoms over a twoyear follow-up period. Key words: Churg-Strauss syndrome, ciclesonide, corticosteroids, respiratory symptoms INTRODUCTION The Churg-Strauss syndrome, anti-neutrophil cytoplasmatic antibodies (ANCA)-associated vasculitides is a rare disease with poorly understood pathogenesis. It is characterized by a history of asthma, peripheral blood and tissue eosinophilia, with a particular predilection to the lungs, in the context of a multisystem disorder manifested by skin involvement, mesenteric ischemia, peripheral neuropathy, and myocarditis. Frequent occurrence of ANCA and granulomatous changes in vessels and in extravascular sides justify grouping the

2 690 Churg-Strauss syndrome with Wegener s granulomatosis and microscopic polyangiitis, which renders these conditions difficult to differentiate. CASE REPORT The study was performed according to the standards set by the Helsinki Declaration of 1975 regarding the Human Research and was approved by an institutional Ethics Committee. Informed consent was obtained from the patient described in this article. We would like to present a case of a 35 year-old patient with severe asthma, referred to the hospital with the symptoms of status asthmaticus. On admission, the patient was in a severe distress. Physical examination suggested bilateral pneumonia, confirmed by chest X-ray, and a blood gas analysis showed features of respiratory failure. The patient was successfully treated with three antibiotics and oxygen. On subsequent hospitalization, one month later, due also to asthma exacerbation he had been presented with fever, cough, dyspnea, myalgia, and the symptoms of sinusitis. Chest CT revealed profuse pulmonary infiltrates (Fig. 1) and a peripheral blood smear showed eosinophilia of 50%. A history of severe asthma and peripheral blood eosinophilia made us suspect the Churg-Strauss syndrome. Further investigations revealed negative tests for both panca and canca and granulomas in the bronchi, which could correspond to Wegener s granulomatosis. The therapy with oral steroids was introduced, with the resolution of symptoms. After 10 months of oral steroid use, the patient again developed dyspnea, fever, marked obstruction, hypoxemia, disseminated patchy infiltrates seen on chest X-ray, and sinusitis with nasal polyps (Fig. 2). Ultimately, the diagnosis of Churg Strauss syndrome was established on the clinical basis and cyclophosphamide was added to the corticosteroids. Clinical improvement in the patient s general health and normalization of laboratory tests were achieved. The patient was followed for 2 years and over that time symptoms and lesions to the lungs did not recur. Cyclophosphamide was discontinued after 12 months Fig. 1. Profuse pulmonary infiltrates in a patient with the Churg-Strauss syndrome.

3 of use. It was decided to withdraw oral steroids because of the whole range of adverse symptoms: significant weight gain, striae of the skin on abdomen (Fig 3), aseptic necrosis of both femoral heads (Fig. 4), and diabetes mellitus. To prevent disease recurrence, a new regimen with ciclesonide 2 x 320 µg was introduced. The patient remained in good health with no symptoms. Subsequent laboratory findings showed eosinophilia of 6%, which was the lowest in his disease course. 691 DISCUSSION In 1951, Churg and Strauss described 13 patients who presented with severe asthma, fever, pulmonary infiltrations, skin lesions, elevated peripheral-blood eosinophilic count, cardiac failure, renal damage, and peripheral neuropathy. In the described cases, asthma was the primary manifestation of the disease which Fig. 2. Nasal polyps in a patient with the Churg- Strauss syndrome. Fig. 3. Striae in the abdominal skin in a patient with the Churg-Strauss syndrome.

4 692 Fig. 4. Aseptic necrosis of both femoral heads due to steroid use. increased in the severity and progressed toward a systemic disorder. The characteristic constellation of symptoms was consequently term the Churg- Strauss syndrome (1). To diagnose the Churg-Strauss syndrome at least four of the following six features should be present: history of asthma, eosinophilia greater than 10%, mononeuropathy, migratory or transient pulmonary opacities, paranasal sinus abnormalities, and extravascular eosinophils in biopsy (2). The etiology of the disease remains unknown, although it has been reported that leukotriene receptor antagonists may trigger the disease development. The central features of the disease are the presence of late onset asthma and peripheral eosinophilia. The lungs and the skin are the most commonly involved organs, but the heart, the gastrointestinal tract, and central nervous system may also be affected. The severity of the disease may be assessed using a five factors score developed by the French Vasculitis Study Group (4). The presence of each factor is given 1 point. The score of 1 or greater requires combined treatment with corticosteroids and cyclophosphamide, as patients with such a score were shown to have a greater early mortality when treated only with corticosteroids (5). Recommendations concerning the duration of treatment remain controversial. The treatment with corticosteroids should be tapered off as the symptoms improve and cyclophosphamide should be used only to induce remission, which may be sustained with other less toxic drugs, such as methotrexate or azathiopirine. It is also uncertain when the maintenance therapy should be discontinued, although it seems reasonable to withdraw methotrexate or azathiopirine in the case of the overall absence of symptoms of active disease, especially in ANCA-negative patients with no history of relapses. As some patients are not challenged by conventional treatment or develop permanent treatment morbidities, there is an urgent need for new less toxic therapeutic strategies. Biologic therapies that emerge from a better understanding of etiopathology of the disorder give hope for the patient-tailored treatment. Among novel agents there are Rituximab, Infliximab, Mepolizumab, and intravenous immunoglobulins (7-15).

5 693 Table 1. Anatomic locations and manifestations of Churg-Strauss syndrome, according to Jeong et al. (3). Location Lungs Skin Heart Gastrointestinal tract Central nervous system Kidney Muscles and joints Manifestations Pulmonary vasculitis, pleural effusion, hilar lymphadenopathy Purpura, macular or erythematous rash, urticaria, subcutaneous nodules Acute pericarditis, constrictive pericarditis, cardiac failure, myocardial infarction Eosinophilic gastroenteritis, bleeding Mononeuritis complex Focal segmental glomerulonephritis Myalgia, joint pain Table 2. Five factors score (FFS) developed by the French Vasculitis Study Group, according to Guillevin et al. (4). Signs and Symptoms Renal insufficiency (creatinine level >1.58 mg/dl) Score Proteinuria higher than 1g/dL 1 Gastrointestinal bleeding, perforation, infraction or pancreatitis Central nervous system involvement 1 Cardiomyopathy Table 3. Treatment of the Churg-Strauss syndrome, according to Bosch et al. (6). Disease state Treatment FFS 1 Corticosteroids + Cyclophosphamide Remission induction Grade of A Remission maintenance Treatment Less toxic immunosuppressant FFS=0 Corticosteroids A Low dose corticosteroids if persistent asthma Grade of B C Another important issue is to determine safety and efficacy of well known medications, such as ciclesonide for remission maintenance in the disease localized to the lungs (FFS=0). The use of ciclesonide is not recommended for the Churg- Strauss syndrome and there is no current data for such practice. However, in the case described in this article, a patient with mainly pulmonary manifestations, who discontinued oral steroids due to side effects, responded to

6 694 ciclesonide well. Further investigations are needed to establish whether cyclesonide may replace oral steroids in the long-term control of the Churg- Strauss syndrome with mainly pulmonary manifestations. It is now well known that the future of vasculitis treatment is a patient-tailored therapy, taking into account the disease severity, which means that all patients should be scrupulously evaluated and treated according to clinical manifestations and biological markers. To do so we need to develop precise definitions of the disease stage and activity and to adjust treatment protocols. As for the treatment, there is a hope for new less toxic and more efficacious agents as we are gaining more knowledge about the pathogenesis. It is a matter of future research to strengthen the evidence for new immunosuppressive and biological agents, but also to re-evaluate the current therapeutic options. Conflicts of interest: The authors had no conflicts of interest to declare in relation to this article. REFERENCES 1. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951; 27: Masi AT, Hunder GG, Lie JT et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33: Jeong YJ, Kim KI, Seo IJ et al. Eosinophilic lung diseases: a clinical, radiologic, and pathologic overview. Radiographics 2007; 27: Guillevin L, Lhote F, Gayraud M et al. Prognostic factors in polyarteritis nodosa and Churg- Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 1996; 75: Bourgarit A, Le Toumelin P, Pagnoux C et al. French Vasculitis Study Group. Deaths occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective analysis of causes and factors predictive of mortality based on 595 patients. Medicine (Baltimore) 2005; 84: Bosch X, Guilabert A, Espinosa G, Mirapeix E. Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review. JAMA 2007; 298: Bosch X, Guilabert A, Espinosa G, Mirapeix E. Immunotherapy for antineutrophil cytoplasmic antibody-associated vasculitis: challenging the therapeutic status quo? Trends Immunol 2008; 29: Huugen D, Cohen Tervaert JW, Heeringa P. TNF-alpha bioactivity-inhibiting therapy in ANCAassociated vasculitis: clinical and experimental considerations. Clin J Am Soc Nephrol 2006; 1: Aries PM, Lamprecht P, Gross WL. Biological therapies: new treatment options for ANCAassociated vasculitis? Expert Opin Biol Ther 2007; 7: Pepper RJ, Fabre MA, Pavesio C et al. Rituximab is effective in the treatment of refractory Churg-Strauss syndrome and is associated with diminished T-cell interleukin-5 production. Rheumatology (Oxford) 2008; 47: Langford CA. Small-vessel vasculitis: therapeutic management. Curr Rheumatol Rep 2007; 9:

7 Hot A, Perard L, Coppere B, Simon M, Bouhour F, Ninet J. Marked improvement of Churg- Strauss vasculitis with intravenous gamma globulins during pregnancy. Clin Rheumatol 2007; 26: Taniguchi M, Tsurikisawa N, Higashi N et al. Treatment for Churg-Strauss syndrome: induction of remission and efficacy of intravenous immunoglobulin therapy. Allergol Int 2007; 56: Danieli MG, Cappelli M, Malcangi G, Logullo F, Salvi A, Danieli G. Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome. Ann Rheum Dis 2004; 63: [No authors listed] Mepolizumab: anti-il-5 monoclonal antibody - GlaxoSmithKline, antiinterleukin-5 monoclonal antibody - GlaxoSmithKline, SB Drugs R D. 2008; 9: Received: June 16, Accepted after revision: August 25, Author s address: E. Swietlik, Department of Internal and Pulmonary Medicine, Miedzyleski Hospital, Warsaw, Poland; em_swietlik@wp.pl