Immunsuppression und Immunmodulation beim Sjögren-Syndrom - Was ist bewiesen? Lindert sie die Sicca-Symptome?

Zusammenfassung

Das Sjögren-Syndrom (SS) ist eine chronische Autoimmunerkrankung, die durch lymphoplasmazelluläre Infiltration und Verlust des sekretorischen Epithels der exokrinen Drüsen charakterisiert ist (wobei besonders Speichel- und Tränendrüsen befallen sind) und zu Mund- und Augentrockenheit führt. Die Symptome des SS sind chronisch und manchmal verheerend mit schweren Einbußen der Lebensqualität. Obwohl das SS als klassische Autoimmunkrankheit gilt, werden Immunsuppressiva als wichtigster Bestandteil der Therapie von Autoimmunerkrankungen selten eingesetzt. Cholinergika wie Pilocarpin und Cevimeline sind die Stützen der gegenwärtigen Therapie des SS, während orales Interferon und topisches Ciclosporin als Augentropfen eine mildernde Wirkung auszuüben scheinen. Im Gegensatz dazu haben andere Immunsuppressiva wie Methotrexat, Azathioprin oder Anti-TNF-α die Symptome des mit dieser Erkrankung verbundenen Sicca-Komplexes nicht gelindert. Der Einsatz von Kortikosteroiden, Cyclophosphamid und Nucleosid-Analoga ist für den extraglandulären Befall des SS reserviert.

Abstract

Sjögren’s syndrome (SS), is a chronic autoimmune disorder, characterized by lymphocytic infiltration and destruction of the exocrine glands (mainly the salivary and the lacrimal glands) resulting in dry mouth and eyes. The symptoms of SS are chronic and sometimes devastating, compromising the quality of life at a major extent. Although SS is considered a classical autoimmune disorder, evidence for the use of immunosuppressive agents, the mainstay of therapy of diseases of autoimmune origin, is scarce. Cholinergic agents, such as pilocarpine and cevimeline are the cornerstone of current therapy of SS, while oral interferon and ciclosporine ocular drops seem to be of some benefit. In contrast, other immunosuppressive substances, such as methotrexate, azathioprine or anti-TNF agents, did not alleviate the sicca features associated with the disease. Corticosteroids, cyclophosphamide and nucleoside analogues are reserved for life threatening severe extraglandular manifestations of SS.

Schlüsselwörter

Sjögren-Syndrom (SS) - Autoimmunerkrankung - Immunsuppression - Immunmodulation

Key words

Sjögren’s Syndrome (SS) - autoimmune disease - immunosuppression - immunomodulation

Literatur

• 1 Kassan S S, Moutsopoulos H M. Clinical manifestations and early diagnosis of Sjögren syndrome.  Arch Intern Med. 2004;  164 1275-1284
• 2 Vivino F B, Al-Hashimi I, Khan Z. et al . Pilocarpine tablets for the treatment of dry mouth and dry eye Symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92 - 01 Study Group.  Arch Intern Med. 1999;  159 174-181
• 3 Tsifetaki N, Kitsos G, Paschides C A. et al . Oral pilocarpine for the treatment of ocular Symptoms in patients with Sjögren’s syndrome: a randomized 12 week controlled study.  Ann Rheum Dis. 2003;  62 1204-1207
• 4 Porter S R, Scully C, Hegarty A M. An update of the etiology and management of xerostomia.  Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;  97 28-46
• 5 Fife R S, Chase W F, Dore R K. et al . Cevimeline for the treatment of xerostomia in patients with Sjögren syndrome: a randomized trial.  Arch Intern Med. 2002;  162 1293-1300
• 6 Petrone D, Condemi J J, Fife R. et al . A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren’s syndrome patients with xerostomia and keratoconjunctivitis sicca.  Arthritis Rheum. 2002;  46 748-754
• 7 Ono M, Takamura E, Shinozaki K. et al . Therapeutic effect of cevimeline on dry eye in patients with Sjögren’s syndrome: a randomized, double-blind clinical study.  Am J Ophthalmol. 2004;  138 6-17
• 8 Takagi Y, Kimura Y, Nakamura T. Cevimeline gargle for the treatment of xerostomia in patients with Sjögren’s syndrome.  Ann Rheum Dis. 2004;  63 749
• 9 Valtysdottir S T, Wide L, Hallgren R. Low serum dehydroepiandrosterone sulfate in women with primary Sjögren’s syndrome as an isolated sign of impaired HPA axis function.  J Rheumatol. 2001;  28 1259-1265
• 10 Pillemer S R, Brennan M T, Sankar V. et al . Pilot clinical trial of dehydroepiandrosterone (DHEA) versus placebo for Sjögren’s syndrome.  Arthritis Rheum. 2004;  51 601-604
• 11 Skopouli F N, Fox P C, Galanopoulou V. et al . T cell subpopulations in the labial minor salivary gland histopathologic lesion of Sjögren’s syndrome.  J Rheumatol. 1991;  18 210-214
• 12 Drosos A A, Skopouli F N, Costopoulos J S. et al . Ciclosporin A (CyA) in primary Sjögren’s syndrome: a double blind study.  Ann Rheum Dis. 1986;  45 732-735
• 13 Sall K, Stevenson Ö D, Mundorf T K. et al . Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group.  Ophthalmology. 2000;  107 631-639
• 14 Boumba D, Skopouli F N, Moutsopoulos H M. Cytokine mRNA expression in the labial salivary gland tissues from patients with primary Sjögren’s syndrome.  Br J Rheumatol. 1995;  34 326-333
• 15 Skopouli F N, Jagiello P, Tsifetaki N. et al . Methotrexate in primary Sjögren’s syndrome.  Clin Exp Rheumatol. 1996;  14 555-558
• 16 Price E J, Rigby S P, Clancy U. et al . A double blind placebo controlled trial of azathioprine in the treatment of primary Sjögren’s syndrome.  J Rheumatol. 1998;  25 896-899
• 17 Zandbelt M M, van den Hoogen F H, de Wilde P C. et al . Reversibility of histological and immunohistological abnormalities in sublabial salivary gland biopsy specimens following treatment with corticosteroids in Sjögren’s syndrome.  Arm Rheum Dis. 2001;  60 511-513
• 18 Fox P C, Datiles M, Atkinson J C. et al . Prednisone and piroxicam for treatment of primary Sjögren’s syndrome.  Clin Exp Rheumatol. 1993;  11 149-156
• 19 Linardaki G, Moutsopoulos H M. The uncertain role of immunosuppressive agents in Sjögren’s syndrome.  Cleve Clin J Med. 1997;  64 523-526
• 20 Tishler M, Yaron I, Shirazi I. et al . Salivary and serum soluble interleukin-2 receptor in primary Sjögren’s syndrome.  Arch Oral Biol. 1999;  44 305-308
• 21 Manoussakis M N, Moutsopoulos H M. Antimalarials in Sjögren’s syndrome - the Greek experience.  Lupus. 1996;  5 (suppl 1) 28-30
• 22 ter B org EJ, Haanen H C, Haas F J. et al . Treatment of primary Sjögren’s syndrome with D-penicillamine: a pilot study.  Neth J Med. 2002;  60 402-406
• 23 Steinfeld S D, Demols P, Salmon I. et al . Infliximab in patients with primary Sjögren’s syndrome: a pilot study.  Arthritis Rheum. 2001;  44 2371-2375
• 24 Steinfeld S D, Demols P, Appelboom T. Infliximab in primary Sjögren’s syndrome: one-year followup.  Arthritis Rheum. 2002;  46 3301-3303
• 25 Steinfeld S, Cogan E, King L S. et al . Abnormal distribution of aquaporin-5 water channel protein in salivary glands from Sjögren’s syndrome patients.  Lab Invest. 2001;  81 143-148
• 26 Mariette X, Ravaud P, Steinfeld S. et al . Inefficacy of infliximab in primary Sjögren’s syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren’s Syndrome (TRIPSS).  Arthritis Rheum. 2004;  50 1270-1276
• 27 Zandbelt M M, de Wilde P, van Damme P. et al . Etanercept in the treatment of patients with primary Sjögren’s syndrome: a pilot study.  J Rheumatol. 2004;  31 96-101
• 28 Ferraccioli G F, Salaffi F, De Vita S. et al . Interferon α-2 (IFN α 2) increases lacrimal and salivary function in Sjögren’s syndrome patients. Preliminary results of an open pilot trial versus OH-chloroquine.  Clin Exp Rheumatol. 1996;  14 367-371
• 29 Unoki H, Moriyama A, Tabaru A. et al . Development of Sjögren’s syndrome during treatment with recombinant human interferon-α-2 b for chronic hepatitis C.  J Gastroenterol. 1996;  31 723-727
• 30 Shiozawa S, Morimoto I, Tanaka Y. et al . A preliminary study on the interferon-α treatment for xerostomia of Sjögren’s syndrome.  Br J Rheumatol. 1993;  32 52-54
• 31 Shiozawa S, Tanaka Y, Shiozawa K. Single-blinded controlled trial of low-dose oral IFN-α for the treatment of xerostomia in patients with Sjögren’s syndrome.  J Interferon CytokineRes. 1998;  18 255-262
• 32 Cummins M J, Papas A, Kammer G M. et al . Treatment of primary Sjögren’s syndrome with low-dose human interferon alfa administered by the oromucosal route: combined phase III results.  Arthritis Rheum. 2003;  49 585-593
• 33 Smith J K, Siddiqui A A, Modica L A. et al . Interferon-α upregulates gene expression of aquaporin-5 in human parotid glands.  J Interferon Cytokine Res. 1999;  19 929-935
• 34 Steinfeld S D, Demols P, Van Vooren J P. et al .Zidovudine in primary Sjögren’s syndrome. Oxford; Rheumatology 1999 38: 814-817
• 35 Moutsopoulos H M, Kordossis T. Sjögren’s syndrome revisited: autoimmune epithelitis.  Br J Rheumatol. 1996;  35 204-206
• 36 Moutsopoulos H M, Balow J E, Lawley T J. et al . Immune complex glomerulonephritis in sicca syndrome.  Am J Med. 1978;  64 955-960
• 37 Skopouli F N, Dafni U, loannidis J P. et al . Clinical evolution, and morbidity and mortality of primary Sjögren’s syndrome.  Semin Arthritis Rheum. 2000;  29 296-304
• 38 Somer B G, Tsai D E, Downs L. et al . Improvement in Sjögren’s syndrome following therapy with rituximab for marginal zone lymphoma.  Arthritis Rheum. 2003;  49 394-398
• 39 Voulgarelis M, Giannouli S, Anagnostou D. et al .Combined therapy with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjögren’s syndrome-associated B-cell aggressive non-Hodgkin’s lymphomas. Oxford; Rheumatology 2004 43: 1050-1053
• 40 Voulgarelis M, Petroutsos G, Moutsopoulos H M. et al . 2-chloro-2’-deoxyadenosine in the treatment of Sjögren’s syndrome-associated B cell lymphoproliferation.  Arthritis Rheum. 2002;  46 2248-2249
• 41 Hayashi Y, Ishimaru N, Arakaki R. et al . Effective treatment of a mouse model of Sjögren’s syndrome with eyedrop administration of anti-CD4 monoclonal antibody.  Arthritis Rheum. 2004;  50 2903-2910
• 42 Triantafyllopoulou A, Tapinos N, Moutsopoulos H M. Evidence for coxsackievirus infection in primary Sjögren’s syndrome.  Arthritis Rheum. 2004;  50 2897-2902