Kombinationstherapie der rheumatoiden Arthritis: Update 2001[1]

Zusammenfassung

Für mehrere basistherapeutische Kombinationen ist ihre Überlegenheit gegenüber einfacheren Therapieschemata wie die Monotherapie nun aufgrund neuer Publikationen gut belegt. Dies gilt für die Dreifachkombination Methotrexat + Sulfasalazin + Hydroxychloroquin, die bei einem unausgewählten Krankengut ohne Selektion spezifischer Prognosemerkmale in einem dynamischen, den klinischen Anforderungen nahekommenden Design getestet wurde (Calgüneri 1999; Möttönen 1999); ferner gilt dies für die inzwischen bei MTX-Versagern getestete Kombination von Methotrexat + Leflunomid gegen mono-Methotrexat (Kremer 2000) und die Kombination von MTX mit TNFα-blockierenden Substanzen, die ebenfalls nach ungenügendem Ansprechen auf eine vorherige Monotherapie mit MTX ausführlich untersucht wurden. Darüber hinaus gibt es mehrere klinisch bewährte gegenseitige Kombinationen von Methotrexat, Azathioprin, Chloroquinderivaten, Sulfasalazin und Ciclosporin. Die meisten Studien mit starrem Design zeigen jedoch keine eindeutigen Vorteile der jeweiligen Kombination gegenüber den Einzelsubstanzen, was z. T. durch die erheblichen methodischen Schwierigkeiten erklärt werden kann. Dies gilt auch für die viel versprechende Zweifachkombination von intramuskulärem Gold mit Chloroquin oder mit Methotrexat sowie für die bei therapierefraktärer rheumatoider Arthritis eingesetzte Dreifachkombination von Methotrexat oder von Cyclophosphamid mit Azathioprin plus Chloroquinderivat. Diese Dreifachkombinationen werden in therapierefraktären schwerst verlaufenden Einzelfällen eingesetzt, obwohl ihre Überlegenheit gegenüber einfacheren Therapieschemata studienmäßig noch nicht mit der gewünschten Klarheit belegt ist.

Combination Therapy for Rheumatoid Arthritis: Update 2001

The advantages of several DMARD combinations have been clearly demonstrated in recent well-controlled studies. The triple combination of methotrexate + sulfasalazine + hydroxychloroquine has been proved superior in groups of patients not selected for certain disease patterns or prognostic factors, if compared to less complex DMARD regimens (Calgüneri 1999; Möttönen 1999). Furthermore, in patients not sufficiently responding to methotrexate alone, the combinations of that DMARD with leflunomide (Kremer 2000) or with TNFα-blocking agents yielded surprising improvements and even remissions (Weinblatt 1999, Kremer 2000, Maini 1998, Lipsky 1999 and 2000). In addition, several mutual combinations of methotrexate, azathioprine, chloroquine derivatives, sulfasalazine and ciclosporine have been used in studies giving valuable clinical results. Most clinical studies with a stringent design, however, were unable to exhibit clear advantages of combinations if compared with DMARDs used in monotherapy. This obstacle may in part be explained by the difficulties inherited in rigid study designs and does not entirely exclude the value of such combinations. This applies, for instance, to the combination of intramuscular gold with chloroquine derivatives or with methotrexate and to the triple combination of methotrexate or cyclophosphamide with azathioprine and with a chloroquine derivative. These triple combinations are still used in refractory rheumatoid arthritis although studies reported give only hints regarding superiority.

Literatur

• 1 Rheumatologische Kerndokumentation in den BMG-geförderten Rheumazentren im Jahr 1998. Berlin; Deutsches Rheuma-Forschungszentrum Berlin, Forschungsbereich Epidemiologie. Epi-Report No 13 Nov. 2000
• 2 Rau R. Einführung „Kombinationstherapie”.  Z Rheumatol. 1998;  57 17-19
• 3 Felson D T, Anderson J J, Meenan R F. The efficacy and toxicity of combination therapy in rheumatoid arthritis.  Arthritis Rheum. 1994;  37 1487-1491
• 4 Calgüneri M, Pay S, Caliskaner Z, Apras S, et al. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis.  Clin Exp Rheumatol. 1999;  17 699-704
• 5 Möttönen T, Hannonen P, Leirisalo-Rep O M, Nissilä M et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial.  The Lancet. 1999;  353 1568-1573
• 6 Möttönen T, Paimela L, Ahonen J, Helve T et al. Outcome of patients with early rheumatoid arthritis treated according to „sawtooth” strategy.  Arthritis and Rheumatism. 1996;  39 996-1005
• 7 Hamilton J, McInnes I B, Thomson E A, Hunter J, Porter D, Madhok R, Capell H A. A 48 week randomised study of gold versus methotrexate in the treatment of rheumatoid arthritis.  Rheumatol. 2000;  39 46
• 8 Munro R, Hampson R, McEntegart A, Thomson E A, Madhok R, Capell H. Improved functional outcome in patients with rheumatoid arthritis treated with intramuscular gold: results of a fife year prospective study.  Ann Rheum Dis. 1998;  57 88-93
• 9 Hernandez Garcia C, Jover J A, Morado I C, Banares A. Gold salts and methotrexate in daily pactice. Short-term safety and efficacy in rheumatoid arthritis.  Arthritis Rheum. 1992;  40 S51
• 10 Menninger H, Herborn G, Sander O, Blechschmidt J, Rau R. A 36 Month Comparative Trial of Methotrexate and Gold Sodium Thiomalate in the Treatment of Early Active and Erosive Rheumatoid Arthritis.  Brit J Rheumatol. 1998;  37 1060-1068
• 11 Sander O, Herborn G, Rau R. Effects on the radiological course of rheumatoid arthritis of parenteral gold treatment that was stopped due to side effects - 6 years of results of a prospective study.  Z Rheumatol. 1997;  56 37
• 12 Elkayam O, Yaron M, Zhukovsky G, Segal R, Caspi D. Toxicity profile of dual methotrexate combinations with gold, hydroxychloroquine, sulphasalazine and minocycline in rheumatoid arthritis patients.  Rheumatology International. 1997;  17 49-53
• 13 Sievers K, Hurri L. Combined therapy of rheumatoid arthritis with gold and chloroquine.  Act Rheum Scand. 1963;  9 48-55
• 14 Singleton P L, Cervantes AG. Concomitant gold and hydroxychloroquine therapy for second remission of rheumatoid arthritis. Bangkok, Thailand; Meeting of the Southeast Asia and Pacific Area Against Rheumatism 1984
• 15 Scott D L, Dawes P T, Tunn E, Fowler P D, Schadforth M F, Fisher J, Clarke S, Collins M, Jones P, Popert A J, Bacon P A. Combination therapy with gold and hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo-controlled study.  Br J Rheumatol. 1989;  28 128-133
• 16 Porter D R, Capell H A, Hunter J. Combination therapy in rheumatoid arthritis - No benefit of addition of hydroxychloroquine to patients with suboptimal response to intramuscular gold therapy.  J Rheumatol. 1993;  20 645-649
• 17 Lehman A J, Lacaille D, Nair B, Stein H B, Klinkhoff A V, Esdaile J M. Intramuscular gold and methotrexate combination therapy in rheumatoid arthritis.  Arthritis Rheum. 1998;  41 S59
• 18 Rau R, Schleusser B, Herborn G, Karger T. Longterm combination therapy of refractory and destructive rheumatoid arthritis with methotrexate (MTX) and intramuscular gold or other disease modifying antirheumatic drugs compared to MTX monotherapy.  J Rheumatol. 1998;  25 1485-1492
• 19 Rau R. Combination DMARD treatment with parenteral gold and methotrexate.  Clin Exp Rheumatol. 1999;  17 S83-90
• 20 Krause D. Combination therapy of methotrexate and parenteral gold.  Z Rheumatol. 1997;  56 5
• 21 Krause D. Langzeitkombinationstherapie der chronischen Polyarthritis: Methotrexat und parenterales Gold.  Z Rheumatol. 1998;  57 37-40
• 22 Weinblatt M E, Reda D, Henderson W, Giobbie-Hurder A, Williams D, Diani A, Dosca S. Sulfasalazine treatment of rheumatoid arthritis: a metaanalysis of 15 randomized trials.  J Rheumatol. 1999;  26 2123-2130
• 23 Muir A, Pullar T. Combined Sodium Aurothiomalate (GST) and Sulphasalazine (SASP) in patients with rheumatoid arthritis who showed a partial response to Sulphasalazine alone. Brit Society for Rheumatol, 13th Annual General Meeting 8 - 10 May, 1996.  Br J Rheum. 1996;  35 434
• 24 Zeidler H K, Kvien T K, Hannonen P, Wollheim F A, Forre O, Geidel H, et al. Progression of joint damage in early active severe rheumatoid arthritis during 18 months of treatment: Comparison of low-dose cyclosporine and parenteral gold.  Brit J Rheumatol. 1998;  37 874-882
• 25 Bendix G, Bjelle A. Adding low-dose Cyclosporine A to parenteral Gold Therapy in Rheumatoid Arthritis: A double-blind plazebo-controlled study.  Br J Rheum. 1996;  35 1142 - 1149
• 26 Weinblatt M, Reda D, Henderson W et al. Sulfasalazine treatment for rheumatoid arthritis: a metaanalysis of 15 randomized trials.  J Rheumatol. 1999;  26 2123 - 2130
• 27 Farr M, Bacon P A. How and when should combination therapy be used? The role of an anchor drug.  Brit J Rheumatol. 1995;  34 100-103
• 28 Haagsma C J, van Riel P L, van de Putte L BA. Combination of methotrexate and sulfasalazine versus methotrexate alone. A randomised open clinical trial in rheumatoid arthritis patients resistant to sulfasalazine therapy.  Brit J Rheumatol. 1994;  33 1049-1055
• 29 Haagsma C J, van Riel P L, de Jong A J, van de Putte L BA. Combination of sulphasalazine and methotrexate versus single components in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial.  Brit J Rheumatol. 1997;  36 1082-1088
• 30 Dougados M, Combe B, Cantagrel A, Goupille P. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components.  Ann Rheum Dis. 1999;  58 220-225
• 31 Boers M , Verhoeven A C, Markusse H M, van de Laar M A, Westhovens R. Randomised comparison of combined step-down prednisolone, methotrexate, and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.  Lancet. 1997;  350 309-318
• 32 O’Dell J R, Haire C E, Erikson N, Drymalski W, Palmer W, Eckhoff P J, Garwood V, Maloley P, Klassen W L, Wees S, Klein H, Moore G F. Treatment of rheumatoid arthritis with Methotrexate alone, Sulfasalazine and Hydroxychloroquine, or a combination of all three medications.  N Engl J Med. 1996;  334 1287-1291
• 33 O’Dell J R, Haire C E, Erikson N, Drymalski W, Palmer W, Maloley P, Klassen L W, Wees S, Moore G F. Efficacy of Triple DMARD Therapy in Patients with RA with Suboptimal Response to Methotrexate.  J Rheumatol. 1996;  23 72-74
• 34 Rojkovich B, Hodinka L, Balint G, Szegedi G et al. Cyclosporine and sulfasalazine combination in the treatment of early rheumatoid arthritis.  Scand J Rheumatol. 1999;  28 216-221
• 35 Nishiya K, Hisakawa N, Tahara  K, Matsumori A. Additive triple DMARD combination therapy of a low dose of sulfhydryl compounds, sulfasalazine and methotrexate in the treatment of rheumatoid arthritis.  Acta Medica Okayama. 1999;  53 275-279
• 36 Wollin D, Menninger H. Kombinationstherapie mit Remissionsinduktoren bei chronischer Polyarthritis: Update 1996.  Z Rheumatol. 1997;  56 114-126
• 37 Menninger H. Kombinationstherapie. In: Rau R (ed) Basistherapie der rheumatoiden Arthritis. Bremen, London, Boston; Uni-Med Verlag 2000: 298-329
• 38 Bensen W, Tugwell P, Roberts R M, Ludwin D, Ross H, Grace E, Gent M. Combination Therapy of Cyclosporine with Methotrexate and Gold in Rheumatoid Arthritis (2 Pilot Studies).  J Rheumatol. 1994;  21 2034-2038
• 39 Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G, McKendry R, Tesser J, Baker P, Wells G. Combination therapy with Cyclosporine and Methotrexate in severe rheumatoid arthritis.  N Engl J Med. 1995;  333 137-141
• 40 Salaffi F, Carotti M, Cervini C. Combination therapy of cyclosporine A with methotrexate or hydroxychloroquine in refractory rheumatoid arthritis.  Scand J Rheumatol. 1996;  25 16-23
• 41 Rau R. Einführung Kombinationstherapie.  Z Rheumatol. 1997;  57 17-49
• 42 Clegg D O. Combination Hydroxychloroquine and Methotrexate in the treatment of rheumatoid arthritis.  Arthritis Rheum. 1993;  36 87
• 43 Ferraz M B, Pinheiro G RC, Helfenstein M, Albuquerque E, Rezende C, Roimicher L, Brandao L, Silva S C, Pinheiro G C, Atra E. Combination Therapy with Methotrexate and Chloroquine in Rheumatoid Arthritis.  Scand J Rheumatol. 1994;  23 231-236
• 44 Tvnarsk¿ K, Gatterová J, Lindusková M, Pelisková Z. Combination therapy with hydroxychloroquine and methotrexate in rheumatoid arthritis.  Z Rheumatol. 1993;  52 292-296
• 45 Seideman P, Albertioni F, Beck O, Eksborg S, Peterson C. Chloroquine reduces the bioavailability of methotrexate in patients with rheumatoid arthritis. A possible mechanism of reduced hepatoxicity.  Arthritis & Rheumatism. 1994;  37 830-833
• 46 McCarty D J, Carrera G F. Treatment of intractable rheumatoid arthritis with combined cyclophosphamide, azathioprine and hydroxychloroquine.  JAMA. 1982;  248 1718-1723
• 47 Csuska M E, Carrera G F, Mc Carty J. Treatment of intractable rheumatoid arthritis: with combined Cyclophosphamide, Azathioprine, and Hydroxychloroquine.  JAMA. 1986;  225 2315-2319
• 48 Tiliakos N A. Low-dose cytotoxic drug combination therapy in intractable rheumatoid arthritis: two years later.  Arthritis Rheum. 1986;  29 C51
• 49 Keyszer G, Keysser C, Keysser M. Efficacy and safety of a combination therapy of methotrexate, chloroquine and cyclophosphamide in patients with refractory rheumatoid arthritis: results of an observational study with matched-pair analysis.  Clin Rheumatol. 1999;  18 145-151
• 50 Biro J A, Segal A M, Mackenzie A H, Mazanec D J, Wilke W S. The combination of methotrexate (MTX) and azathioprine (AZA) for resistant rheumatoid arthritis (RA).  Arthritis Rheum. 1987;  30 48
• 51 Wilke W S, Sherrer Y R, Clough J D. Combination chemotherapy for severe rheumatoid arthritis.  Intern Med Specialist. 1989;  10 59-76
• 52 Willkens R F, Urowitz M B, Stablein D M, McKendry R JR et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical study.  Arthritis and Rheumatism. 1992;  35 849-856
• 53 Willkens R F, Sharp J T, Stablein D, Marks C, Wortmann R. Comparison of Azathioprine, Methotrexate, and the combination of the two in the treatment of rheumatoid arthritis: A forty-eight-week controlled clinical trial with radiologic outcome assessment.  Arthritis Rheum. 1995;  38 1799-1806
• 54 McCarty D J. Letter to the editor.  Arthritis Rheum. 1996;  39 1436
• 55 Schneider B, Hartmann F, Klek M, Menninger H. Bei prognostisch ungünstigen Verlaufsformen einer chronischen Polyarthritis (CP) ist die Dreifachkombination von Methotrexat (MTX), Azathioprin (AZA) und Chloroquin (CQ) wirksam und verträglich.  Z Rheumatol. 1997;  56 S.33
• 56 Kahan A, Menkes C J. The use of antimalarials in combination with other disease modifying agents in rheumatoid arthritis - the French experience.  Lupus. 1996;  5 S45-49
• 57 Porter D R, Capell H A, Hunter J. Combination therapy in rheumatoid arthritis - No benefit of addition of hydroxychloroquine to patients with a suboptimal response to intramuscular gold therapy.  J Rheumatol. 1993;  20 645-649
• 58 Sievers K, Hurri L. Combined therapy of rheumatoid arthritis with gold and chloroquine.  Act Rheum Scand. 1963;  9 48-55
• 59 Scott D L, Dawes P T, Tunn E, Fowler P D, Schadforth M F, Fisher J, Clarke S, Collins M, Jones P, Popert A J, Bacon P A. Combination therapy with gold and hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo-controlled study.  Br J Rheumatol. 1989;  28 128-133
• 60 Csuska M E, Carrera G F, Mc Carty J. Treatment of intractable rheumatoid arthritis: with combined Cyclophosphamide, Azathioprine, and Hydroxychloroquine.  JAMA. 1986;  225 2315-2319
• 61 McCarty J, Carrera G F. Intractable rheumatoid arthritis: Treatment with combined Cyclophosphamide, Azathioprine, and Hydroxychloroquine.  JAMA. 1992;  248 1718-1723
• 62 Tiliakos N A. Low-dose cytotoxic drug combination therapy in intractable rheumatoid arthritis: two years later.  Arthritis Rheum. 1986;  29 C51
• 63 Biro J A, Segal A M, Mackenzie A H, Mazanec D J, Wilke W S. The combination of methotrexate (MTX) and azathioprine (AZA) for resistant rheumatoid arthritis (RA).  Arthritis Rheum. 1987;  30 48
• 64 Duncan M R, Capell H A. The use of antimalarials in combination with other disease modifying agents in RA - the British experience.  Lupus. 1996;  5 S50-58
• 65 Daller D, Menninger H. Kombinationstherapie mit Remissionsinduktoren bei chronischer Polyarthritis: Stand der klinischen Forschung.  Akt Rheumatol. 1995;  20 113-123
• 66 Blanke R. Persönl. Mitteilung der Bayer Vital GmbH. 2000
• 67 Jeurissen M EC, Boerbooms A MTh, van de Putte LB A, Doesburg W H, et al. Methotrexate versus azathioprine in the treatment of rheumatoid arthritis. A forty-eight-week randomized, double-blind trial.  Arthritis and Rheumatism. 1991;  34 961-972
• 68 Smolen J S, Kalden J R, Scott D L, Rozman B, Kvien T K, Larsen  A et al. Efficacy and safety of leflunomide compared with placebo and sulfasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial.  Lancet. 1999;  353 259-266
• 69 Rückermann K, Fairbanks L D, Carrey E A, Hawrylowicz C M, Richards D F, Kirschbaum B et al. Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans.  J Bio Chem. 1998;  273 21 682-21 691
• 70 Mroczkowski P J, Weinblatt M E, Kremer J M. Methotrexate and Leflunomide Combination Therapy for Patients with Active Rheumatoid Arthritis.  Clin Exp Rheumatol. 1999;  17 S66-68
• 71 Weinblatt M E, Kremer J M, Coblyn J S, Maier A L, et al. Pharmacokinetics, Safety, and Efficacy of Combination Treatment with Methotrexate and Leflunomide in Patients with Active Rheumatoid Arthritis.  Arthritis & Rheumatism,. 1999;  42 1322-1328
• 72 Kremer J M, Caldwell J R, Cannon G W, Genovese M. The Combination of Leflunomide (LEF) and Methotrexate (MTX) in Patients with Active Rheumatoid Arthritis (RA) Who are Failing on MTX Treatment Alone: A Double-Blind Placebo (PBC) Controlled Study.  Arthritis & Rheumatism. 2000;  43 S224
• 73 . Aventis Pharma . Wichtige Information zur Arzneimittelsicherheit.  Leflunomid (Arava®) Schwerwiegende und ernste Leberfunktionsstörungen. Firmenmitteilung. 2001; 
• 74 Empfehlungen der Deutschen Gesellschaft für Rheumatologie zur Therapie mit Tumornekrosefaktor-hemmenden Substanzen (2000).  Z Rheumatol. 2000;  59 291-292
• 75 Smolen J S, Breedveld F C, Burmester G R, Combe B et al. Consensus statement on the initiation and continuation of tumour necrosis factor blocking therapies in rheumatoid arthritis.  Ann Rheum Dis . 2000;  59 504-505
• 76 Moreland L W, Schiff M H, Baumgartner S W, Tindall E A et al. Etanercept Therapy in Rheumatoid Arthritis. A Randomized, Controlled Trial.  Annals of Internal Medicine. 1999;  130 478-486
• 77 Finck B, Martin R, Fleischmann R, Moreland L, Schiff M. A Phase III Trial of Etanercept vs Methotrexate (MTX) in Early Rheumatoid Arthritis (Enbrel® ERA Trial).  Arthritis & Rheumatism. 1999;  42 S117
• 78 Lovell D J, Giannini E H, Lange M, Burge D, Finck B K. Safety and Efficacy of Enbrel® (Etanercept) in the Extended Treatment of Polyarticular-Course JRA.  Arthritis & Rheumatism. 1999;  42 S117
• 79 Weinblatt M E, Kremer J M, Bankhurst A D, Bulpitt K J et al. A Trial of Etanercept, a Recombinant Tumor Necrosis Factor Receptor:Fc Fusion Protein, in Patients with Rheumatoid Arthritis Receiving Methotrexate.  N Engl J Med. 1999 a;  340 253-259
• 80 Weinblatt M E, Kremer J M, Lange M, Burge D J. Long-Term Safety and Efficacy of Combination Therapy with Methotrexate (MTX) and Etanercept (Enbrel®).  Arthritis & Rheumatism. 2000;  42 S401
• 81 Kremer J M, Weinblatt M E, Fleischmann R M, Bankhurst A D. Etanercept (Enbrel®) in Addition to Methotrexate (MTX) in Rheumatoid Arthritis (RA): Long-Term Observations.  Arthritis & Rheumatism. 2000;  43 S270
• 82 Elliott M J, Maini R N, Feldmann M et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis.  Lancet. 1994;  344 1105-1110
• 83 Maini R N, Breedveld F C, Kalden J R, Smolen J S et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly Methotrexate in rheumatoid arthritis.  Arthritis & Rheumatism. 1998;  41 1552-1563
• 84 Lipsky P, van der Heijde D, StClair D W, Smolen J et al. 102-Wk Clinical and Radiologic Results From the ATTRACT Trial:a 2 Year, Randomized, Controlled, Phase 3 Trial of Infliximab (Remicade®) in Pts with Active RA Despite MTX.  Arthritis & Rheumatism. 2000;  43 S269
• 85 Maini R, van der Heijde D, Smolen J, Kalden J et al. Week 102 Clinical and Radiologic Results From the ATTRACT Trial: A Two Year, Randomized, Controlled Phase III Trial of Infliximab in Patients with Active RA Despite MTX.  Ann Rheum Dis. 2001;  60 Suppl 1
• 86 Lipsky P, Clair W St, Furst D, Breedveld F, Smolen J, Kalden J R et al. 54-Week Clinical and Radiographic Results from the ATTRACT Trial: A phase III Study of Infliximab (Remicade™) in Patients with Active RA Despite Methotrexate.  Arthritis & Rheumatism. 1999;  42 S 401
• 87 Schattenkirchner M, Krüger K, Sander O, Rau R et al. Efficacy and tolerability of weekly subcutaneous injections of the fully human anti-TNF-Antibody D2E7 in patients with rheumatoid arthritis - results of a phase I study.  Arthritis Rheum. 1998;  41 S57
• 88 Rau R, Sander O, den Broeder A et al. Long-term efficacy and tolerability of multiple doses of the fully human anti-TNF antibody D2E7 in patients with rheumatoid arthritis.  Arthritis Rheum. 1998;  41 S55
• 89 Rau R, Herborn G, Sander O et al. Long-term treatment with the fully human anti-TNF-antibody D2E7 slows radiographic disease progression in rheumatoid arthritis.  Arthritis Rheum. 1999 a;  42 S400
• 90 Rau R, Simianer S, Weier R, Kroot E J, van Riel P LCM et al. Effective combination of the fully human anti-TNF-antibody and methotrexate in active rheumatoid arthritis.  Ann Rheum Dis. 1999 b;  58 217
• 91 Rau R, Herborn G, Sander O, van de Putte L BA et al. Long-term treatment with the fully human anti-TNF-antibody D2E7 slows radiographic disease progression in rheumatoid arthritis.  Arthritis. Rheum. 1999 c;  42 S400
• 92 Sokka T, Möttönen T, Hannonen P. Disease-modifying anti-rheumatic drug use according to the „sawtooth” treatment strategy improves the functional outcome in rheumatoid arthritis: results of a long-term follow-up study with review of the literature.  Rheumatology. 2000;  39 34-42

1 Der Artikel basiert auf einem Vortrag, der während der 29. Tagung der Deutschen Gesellschaft für Rheumatologie (Aachen, 13. - 16. September 2000) auf einem Satellitensymposium gehalten wurde („Nicht alles, was glänzt, ist Gold: Goldtherapie - aktueller denn je”; Vorsitz: R. Rau und H. Menninger).