Rheumatoid arthritis combination therapy

Darmawan J, Nasution AR, Rasker JJ, Zhao DB, Soorosh GS, Chen SL et al. Sustained clinical and radiological remission in DMARD refractory rheumatoid arthritis treated with step-down bridge combination therapy of five immunosuppressants without corticosteroids in a 6 years observation in Asia - WHO-ILAR COPCORD Stage II Treatment. APLAR J Rheumatol 2007 10 in press. 

Darmawan J, Rasker JJ, Nasution AR, Zhao DB, ChenS-L, Haq SA et al. WHO-ILAR COPCORD Stage II treatment of the autoimmune diseases with step-down bridge combination of five immunosuppressants (SBC-5-IMNs) in therapy of rheumatoid arthritis. Proceedings book of the 12th APLAR Congress of Rheumatology. Kuala Lumpur (Malaysia) 2006. 

Hydroxychloroquine Plaquenil) and chloroquine Ara-len) are 4-aminoquinoline antimalarial drugs that possess modest DMARD activity. They are indicated for the treatment of rheumatoid arthritis and systemic lupus erythematosus their use as antimalarials is detailed in Chapter 53. The onset of action of these drugs is longer than that of other DMARDs, and their side effects are relatively mild. Because of this, these agents show promise as ingredients of combination therapies for rheumatoid arthritis. 

Anakinra (Kineret) is the first antirheumatic agent that acts by blocking the action of IL-1. This drug was recently approved for the treatment of moderately to severely active rheumatoid arthritis in adults who have not responded to therapy with one or more DMARDs. Anakinra may be used alone or in combination with DMARDs other than the TNF antagonists. Clinical trials have shown anakinra to be more effective than placebo, either alone or in conjunction with methotrexate. 

The most recent treatment paradigm calls for earher, more aggressive treatment of rheumatoid arthritis. DMARDs are frequently employed along with NSAIDs in the initial treatment of the disease. The COX-2 inhibitors are often used because they are less likely to cause serious GI toxicity than are the nonspecihc COX inhibitors. The usual DMARD of choice for patients with mild rheumatoid arthritis is hydroxychloroquine or sulfasalazine methotrexate is used for those with moderate to serious disease. Other DMARDs are used if these agents are poorly tolerated or do not produce suf-hcient response. Combination therapy of methotrexate and another agent is also used to treat disease that is not responsive to individual DMARDs. 

In a 1998 study, approximately half of North American rheumatologists treated moderately aggressive rheumatoid arthritis with combination therapy, and the use of drug combinations is probably much higher now. Combinations of DMARDs can be designed rationally on the basis of complementary mechanisms of action, nonoverlapping pharmacokinetics, and nonoverlapping toxicities. 

While it might be anticipated that combination therapy might result in more toxicity, this is often not the case. Combination therapy for patients not responding adequately to monotherapy is becoming the rule in the treatment of rheumatoid arthritis. 

Gerards AH et al Cyclosporine A monotherapy versus cyclosporine A and methotrexate combination therapy in patients with early rheumatoid arthritis A double blind randomised placebo controlled trial. Ann Rheum Dis 2003 62 291. [PMID 12634224]... 

In general, these drugs are more toxic and are usually reserved for patients who have not responded to more traditional DMARDs such as methotrexate. Drugs with immunosuppressant activity may also be used in combination with more traditional DMARDs to provide optimal benefits in certain patients. Combination drug therapy in rheumatoid arthritis is addressed in the next section. 

Garrood T, Scott DL. Combination therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis. BioDrugs. 2001 15 543-561. 

Gossec L, Dougados M. Combination therapy in early rheumatoid arthritis. C/zw Exp Rheumatol. 2003 ... 

Levamisole was first synthesized for the treatment of parasitic infections. Later studies suggested that it increases the magnitude of delayed hypersensitivity or T cell-mediated immunity in humans. In immunodeficiency associated with Hodgkin s disease, levamisole has been noted to increase the number of T cells in vitro and to enhance skin test reactivity. Levamisole has also been widely tested in rheumatoid arthritis and found to have some efficacy. However, it has induced severe agranulocytosis (mainly in HLA-B27-positive patients), which required discontinuation of its use. The drug may also potentiate the action of fluorouracil (5-FU) in adjuvant therapy of colorectal cancer, and this combination has been approved for clinical use in the treatment of Dukes class C colorectal cancer after surgery. Its use in these cases reduces recurrences, and the mechanism... 

Morgan, A. W., Hale, G., Waldmann, H., Emery, P., and Isaacs, J. D. (1997). Combination of anti-cytokine and anti-T cell therapy for rheumatoid arthritis A pilot study. Br. J. Rheumatol. 36 (Suppl 1), S 188. 

Corticosteroids have a range of activity. They have potent antiinflammatory and immunosuppressive activity. Many synthetic drugs are available as corticosteroids. In appropriate doses, these are used as replacement therapy in adrenal insufficiency. The topical application of corticosteroids is safer when compared with systemic use. Corticosteroids should be used in smaller doses for the shortest duration of time. A high dose may be used for life-threatening syndromes or diseases. A tapering pattern of withdrawal should be followed to avoid complications of sudden withdrawal. Systemic therapy is indicated in a variety of conditions. These are administered by intraarticular injections with aseptic conditions for rheumatoid arthritis and osteoarthritis. In skin diseases, such as eczema, contact dermatitis, and psoriasis, corticosteroids are used topically. In some cases, steroids are combined with antimicrobial substances such as neomycin. 

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(8) 1485-92. 

Cyclosporine is an important drug in preventing rejection after kidney, hver, heart and other organ transplantation (Haberal et al., 2004). Cyclosporine usually is combined with other immunosuppressives especially glucocorticoids and either azathioprine or mycophenolate mofedl and sirolimus (Krensky et al., 2005). In renal alio transplants it has improved graft acceptance in most clinics to 95 percent. In addition to its use in transplantation cyclosporine is used for the treatment of a number of autoimmune diseases. In autoimmune diseases, as might be anticipated, cyclosporine is most effective in those which are T cell mediated. These include several forms of psoriasis, rheumatoid arthritis refractive to all other therapy, uveitis, nephrotic syndrome and type I diabetes mellitus. 

Gastrointestinal. Patients taking continuous steroid, especially in combination with a nonsteroidal antiinflammatory drug (NSAID), have an excess incidence of peptic ulcer and haemorrhage of about 1-2%. It is plainly unreasonable to seek to protect all such patients by routine prophylactic antiulcer therapy, i.e. to treat 98 patients unnecessarily in order to help two. But such therapy (proton pump inhibitor, histamine H -receptor blocker, sucralfate) is appropriate when ulcer is particularly likely, e.g. a patient with rheumatoid arthritis taking an NSAID, or for patients with a history of peptic ulcer disease. There is increased incidence of pancreatitis. 

Blanco R, Martinez-Taboada VM, Gonzalez-Gay MA, Armona J, Fernandez-Sueiro JL, Gonzalez-Vela MC, Rodriguez-Valverde V. Acute febrile toxic reaction in patients with refractory rheumatoid arthritis who are receiving combined therapy with methotrexate and azathioprine. Arthritis Rheum 1996 39(6) 1016-20. 

Leflunomide has anti-inflammatory, immunosuppressive, and virustatic effects. Its efficacy has been demonstrated in patients with rheumatoid arthritis and psoriatic arthritis and other conditions in randomized, double-blind, placebo-controlled trials and other studies (8-32), and it was approved for treatment of adult rheumatoid arthritis in August 1998 (Table 1) (33). In three large phase III trials (US301, n = 482 MN301, n = 358 MN302, n = 999), leflunomide was as effective and well tolerated as methotrexate and sulfasalazine and superior to placebo (34). These data were confirmed by a meta-analysis (35,36). Leflunomide is therefore indicated for patients with rheumatoid arthritis who have failed first-line disease modifying anti-rheumatic drug therapy on the basis of efficacy, safety, and costs (36). It is effective as monotherapy and in combination with methotrexate or infliximab (6). 

Kiely PD, Johnson DM. Infliximab and leflunomide combination therapy in rheumatoid arthritis an open-label study. Rheumatology (Oxford) 2002 41(6) 631-7. 

Godinho F, Godfrin B, El Mahon S, Navaux F, Zabraniecki L, Cantagrel A. Safety of leflnnomide plus infliximab combination therapy in rheumatoid arthritis. Clin Exp Rheumatol 2004 22(3) 328-30. 

Kremer J, Genovese M, Cannon GW, Caldwell J, Cush 1, Furst DE, Luggen M, Keystone E, Bathon 1, Kavanaugh A, Ruderman E, Coleman P, Curtis D, Kopp E, Kantor S, Weisman M, Waltuck J, Lindsley HB, Markenson J, Crawford B, Fernando I, Simpson K, Strand V. Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy open-label extension of a randomized, double-blind, placebo controlled trial. J Rheumatol 2004 31(8) 1521-31. 

Sibilia J. Combinaison de traitements de fond dans la poly-arthrite rhumatoide. [Combination therapy for rheumatoid arthritis.] Ann Med Interne (Paris) 2CX)2 153(l) 41-52. 

Menninger H. Combination therapy for rheumatoid arthritis update 2001. Aktuel Rheumatol 2001 26 146-58. 

Jaffe lA. Combination therapy of rheumatoid arthritis— rationale and overview. J Rheumatol Suppl 1990 25 24—7. 

Sheldon P, Wood JK. Remission of arthritis and radiological improvement after combination therapy for non-Hodgkin s lymphoma in a patient with rheumatoid arthritis undergoing treatment with D-penicillamine. Ann Rheum Dis 1985 44(8) 556-8. 

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