Evidence for early disease-modifying drugs in rheumatoid arthritis
Arthritis Res Ther volume 6, Article number: 15 (2003)
Some research evidence supports early aggressive treatment of rheumatoid arthritis (RA) using combination therapy with two or more disease modifying anti-rheumatic drugs (DMARDs) plus steroids, or even DMARDs plus an anti-TNF. By contrast, conservatively delayed DMARD monotherapy, given after non-steroidal anti-inflammatory drugs have failed, has been criticised. However, recent long-term studies highlight the complexities in evaluating whether to abandon pyramidal treatment in favour of early DMARDs. Although patients given early DMARD therapy show short-term benefits, longer-term results show no prolonged clinical advantages from early DMARDs. By 5 years patients receiving early DMARDs had similar disease activity and comparable health assessment questionnaire scores to patients who received DMARDs later in their disease course. X-ray progression was persistent and virtually identical in both groups. These negative findings do not invalidate the case for early DMARD therapy, as it is gives sustained reductions in disease activity in the early years of treatment without excessive risks from adverse effects. However, early DMARDs alone do not adequately control RA in the longer term. This may require starting with very aggressive therapy or treating patients more aggressively after early DMARD therapy has been initiated.
The optimal treatment for early rheumatoid arthritis (RA) remains the subject of intense debate. There are many options. There is some support for aggressive treatment by immediately starting combination therapy with two or more disease-modifying antirheumatic drugs (DMARDs) plus steroids, or even with DMARDs plus antitumour necrosis factor (anti-TNF). The most conservative alternative involves initially using nonsteroidal anti-inflammatory drugs (NSAIDs), only starting DMARD monotherapy if this proves insufficient. The value of this latter therapeutic pyramid has been questioned for many years . Current opinion favours early DMARD therapy . A recent report by Verstappen and colleagues  focused attention on the complexities in evaluating whether to abandon the pyramidal approach to treatment and to focus on starting DMARDs early.
Observational studies provide an opportunity to explore the benefits of early DMARDs. The Norfolk Arthritis Register, a large observational study in early arthritis, enrols cases of early polyarthritis from one area of England. A recent report from the register evaluated DMARD therapy in 353 consecutive RA patients followed for 5 years . As patients with mild arthritis inevitably have good outcomes without DMARDs, statistical adjustment was essential to control for disease severity. Although patients who received DMARDs had more radiographic progression, this was related to their high initial disease severity. After adjusting for baseline severity, early DMARD therapy in severe RA gave the most beneficial outcomes at 5 years.
Evidence from randomised controlled trials (RCTs) supports these observational findings. Early treatment with sulphasalazine reduces disease activity and X-ray progression over 12 months compared with persisting with NSAIDs alone . As a relatively potent DMARD, sulphasalazine is also more effective than a 'weaker' DMARD such as hydroxychloroquine in limiting the X-ray progression in early RA . Benefits from early DMARD therapy extend over 5 years. Borg and colleagues  compared early treatment with a weak DMARD (auranofin) against a wait-and-see policy in 137 patients with early RA. After 2 years there was convincing evidence favouring early DMARD therapy. A subsequent review of 75 of these patients after 5 years  showed continuing benefits from early DMARD therapy on clinical and radiological outcomes. A comparable study  evaluated 104 of 119 patients who had participated in a 9-month RCT of hydroxychloroquine versus placebo in early RA. Three years after the study ended, early DMARD therapy still resulted in less pain and disability.
The report by Verstappen and colleagues  shows that the situation is very complex. The report outlined 5-year follow-up results from an earlier trial involving 238 patients with recently diagnosed RA. The minority of cases had been randomised to pyramid treatment, receiving NSAIDs for at least 12 months and waiting an average of 14 months before starting DMARDs. The majority were randomised to receive early DMARDs. Five-year results in 44 patients given pyramid treatment and in 145 patients given early DMARDs, however, showed no prolonged clinical advantages from early DMARDs. In the first 12 months there had been many advantages from early DMARDs; most clinical variables showed better responses. These benefits were reported in an initial paper , which provided strong support for early DMARD therapy. Nevertheless, the benefits of early DMARDs became less obvious with time. By 5 years patients receiving early DMARDs had similar disease activity and comparable health assessment questionnaire scores with patients who received DMARDs later in their disease course. X-ray progression was persistent and virtually identical in both groups.
Such negative results do not weaken the case for early DMARD therapy. Patients receiving early DMARDs benefited from sustained reductions in disease activity in the early years of treatment without excessive risks from adverse effects. However, early DMARDs alone do not adequately control RA in the longer term. Two alternative strategies may be needed. First, starting with more aggressive therapy and, second, treating patients more aggressively after early DMARD therapy has been initiated.
More aggressive initial therapy may involve adding low-dose steroids, using combination DMARDs and the early use of biologics. The early use of low-dose steroids is very controversial. Two RCTs have addressed this question. The Arthritis Research Council steroid study  showed that adding low-dose steroids to DMARDs reduced the subsequent X-ray progression. van Everdingen and colleagues  enrolled 81 patients with early active RA who had not been treated with DMARDs. Patients received 10 mg/day oral prednisone or placebo. After 6 months sulphasalazine could be prescribed as rescue medication. Radiological scores after 6 months showed significantly less progression with prednisone compared with placebo without major side effects from steroids.
Although such benefits from low-dose steroids meant that some experts believe they should become standard treatment , other experts disagree . The issue is made more complex by the potential role of high-dose step-down steroid therapy used in combination studies (discussed later). Interestingly, an analysis of the cost-effectiveness of low-dose steroids in RA concluded that their use was economically favourable .
The next question is whether to use one DMARD or several DMARDs in early RA. The COBRA (Combinatietherapie Bij Reumatoide Artritis) study  compared sulphasalazine monotherapy with the combination of sulphasalazine, methotrexate and prednisolone (tapered from 60 mg/day to 7.5 mg/day over 9 months and then stopped) in 155 patients with early RA. By 6 months 72% of patients on combination therapy had ACR-20 responses compared with 49% of patients on monotherapy, and median X-ray damage had increased by 1 Sharp unit with combined therapy and by 4 Sharp units with monotherapy. Five years later the benefits of combination therapy on joint damage persisted . After adjusting for treatment and disease activity during follow-up, the between-group difference in radiological progression (3.7 points/year) still favoured combination therapy. Economic analysis also showed that the COBRA study was cost-effective .
Another RCT, the FIN-RACo (Finnish Rheumatoid Arthritis Combination) trial, also favoured combination therapy in early RA . It compared combination therapy (sulphasalazine, methotrexate, hydroxychloroquine and prednisolone) with DMARD monotherapy (with or without prednisolone) in 199 patients over 2 years. At 12 months, 24 of 97 patients achieved remission with combination therapy but only 11 of 98 patients achieved remission with monotherapy. Remission remained more frequent with combination therapy at 2 years. Subsequent analyses found that delaying DMARD therapy by only a few months decreased the ability of the monotherapy to induce remission . The benefits of combination therapy were unaffected by delay.
Not all trials of early combination DMARDs are positive. Haagsma and colleagues  found that combination therapy was no more effective than monotherapy with sulphasalazine or methotrexate in 105 patients with early RA. Dougados and colleagues  also found no benefit from combining methotrexate and sulphasalazine in 205 patients with active RA. A 5-year review of these cases also showed no benefits from combination DMARDs . RCTs with cyclosporin as part of a DMARD combination in early RA have also given equivocal  or negative  results, although these latter studies were relatively small.
The final approach to early aggressive treatment is to use biologics. The only published evidence for biologics is from the early RA trial of etanercept, which showed that this biologic is more effective than methotrexate over 2 years in reducing X-ray progression and in controlling symptoms . More impressive results are likely from combining anti-TNF therapy with methotrexate. Unpublished data from a RCT combining infliximab with methotrexate, presented at the European League Against Rheumatism congress (the ASPIRE [Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset] trial), strongly suggests this will be the case. Preliminary data from the ASPIRE trial indicate that patients treated with infliximab plus methotrexate had no X-ray progression and had markedly less disability than patients receiving methotrexate monotherapy.
There is similar unpublished data with other anti-TNF drugs. The implication is that excellent short-term outcomes can be achieved by treating all early RA patients with a combination of methotrexate and anti-TNF. However, before introducing such a policy in routine practice, several questions need to be addressed. The short-term benefits of combination therapy with biologics may not last and, as with the report from Verstappen and colleagues , initial good results may not give long-term benefits. Another problem is that many patients with early RA may not need aggressive treatment. Observational studies and RCTs in early RA invariably identify cohorts of patients with mild disease that respond well to NSAIDs alone. The blanket use of DMARD/biologic combinations would expose such mild cases to prolonged courses of highly active drugs. An added difficulty is the high cost of biologics, which may mean that their widespread use cannot be economically justified.
An alternative assessment of the results reported by Verstappen and colleagues  is that early DMARDs are useful in the short term, but that in the medium term more aggressive treatment is needed in some patients. There is a relative dearth of information on this issue, although one RCT (Tight Control of Rheumatoid Arthritis, C Grigor and colleagues) presented at The British Society for Rheumatology meeting, 2003, and not yet published suggests that adding DMARDs sequentially to obtain tight control of RA is practical and effective. It seems most logical to treat some patients with early RA with NSAIDs alone, to treat some patients with DMARD monotherapy, to treat some patients with DMARD combination therapy and to treat some patients with DMARDs and biologics. Although treating all patients with DMARDs and biologics may seem better than other choices over 12–24 months, the gradual addition of drugs in an organised manner over 5 years may be equally clinically effective and will be substantially more cost-effective. Providing answers to such complex questions will take many years, and it is likely to remain an area of research endeavour for the foreseeable future.
= antitumour necrosis factor
= Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset
= Combinatietherapie Bij Reumatoide Artritis
= disease modifying antirheumatic drug
= Finnish Rheumatoid Arthritis Combination
= nonsteroidal anti-inflammatory drug
= rheumatoid arthritis
= randomised controlled trial.
Wilske KR, Healey LA: Remodeling the pyramid: a concept whose time has come. J Rheumatol. 1989, 16: 565-567.
Quinn MA, Conaghan PG, Emery P: The therapeutic approach of early intervention for rheumatoid arthritis: what is the evidence?. Rheumatology. 2001, 40: 1211-1220. 10.1093/rheumatology/40.11.1211.
Verstappen SM, Jacobs JW, Bijlsma JW, Heurkens A, van Booma-Frankfort C, Borg EJ, Hofman DM, van der Veen MJ: Utrecht Arthritis Cohort Study Group. Five-year followup of rheumatoid arthritis patients after early treatment with disease-modifying antirheumatic drugs versus treatment according to the pyramid approach in the first year. Arthritis Rheum. 2003, 48: 1797-1807. 10.1002/art.11170.
Bukhari MA, Wiles NJ, Lunt M, Harrison BJ, Scott DG, Symmons DP, Silman AJ: Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study. Arthritis Rheum. 2003, 48: 46-53. 10.1002/art.10727.
Choy EH, Scott DL, Kingsley GH, Williams P, Wojtulewski J, Papasavvas G, Henderson E, Macfarlane D, Erhardt C, Young A, Plant MJ, Panayi GS: Treating rheumatoid arthritis early with disease modifying drugs reduces joint damage: a randomised double blind trial of sulphasalazine vs diclofenac sodium. Clin Exp Rheumatol. 2002, 20: 351-358.
van der Heijde DM, van Riel PL, Nuver-Zwart IH, Gribnau FW, vad de Putte LB: Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet. 1989, 1: 1036-1038. 10.1016/S0140-6736(89)92442-2.
Borg G, Allander E, Berg E, Brodin U, From A, Trang L: Auranofin treatment in early rheumatoid arthritis may postpone early retirement. Results from a 2-year double blind trial. J Rheumatol. 1991, 18: 1015-1020.
Egsmose C, Lund B, Borg G, Pettersson H, Berg E, Brodin U, Trang L: Patients with early arthritis benefit from early 2nd line therapy: 5 year follow-up of a prospective double blind placebo controlled study. J Rheumatol. 1995, 22: 2208-2213.
Tsakonas E, Fitzgerald AA, Fitzcharles MA, Cividino A, Thorne JC, M'Seffar A, Joseph L, Bombardier C, Esdaile JM: Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a 3 year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study. J Rheumatol. 2000, 27: 623-629.
Van der Heide A, Jacobs JW, Bijlsma JW, Heurkens AH, Booma-Frankfort C, van der Veen MJ, Haanen HC, Hofman DM, van Albada-Kuipers GA, ter Borg EJ, Brus HL, Dinant HJ, Kruize AA, Schenk Y: The effectiveness of early treatment with 'second-line' antirheumatic drugs: a randomized, controlled trial. Ann Intern Med. 1996, 124: 699-707.
Kirwan JR: The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The ARC Low Dose Glucocorticoid Study Group. N Engl J Med. 1995, 333: 142-146. 10.1056/NEJM199507203330302.
van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW: Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med. 2002, 136: 1-12.
Conn DL: Resolved: low-dose prednisone is indicated as a standard treatment in patients with rheumatoid arthritis. Arthritis Rheum. 2001, 45: 462-467. 10.1002/1529-0131(200110)45:5<462::AID-ART366>3.0.CO;2-V.
Saag KG: Resolved: low-dose glucocorticoids are neither safe nor effective for the long-term treatment of rheumatoid arthritis. Arthritis Rheum. 2001, 45: 468-471. 10.1002/1529-0131(200110)45:5<468::AID-ART367>3.0.CO;2-A.
Bae SC, Corzillius M, Kuntz KM, Liang MH: Cost-effectiveness of low dose corticosteroids versus non-steroidal anti-inflammatory drugs and COX-2 specific inhibitors in the long-term treatment of rheumatoid arthritis. Rheumatology. 2003, 42: 46-53. 10.1093/rheumatology/keg029.
Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, van Zeben D, Dijkmans BA, Peeters AJ, Jacobs P, van den Brink HR, Schouten HJ, van der Heijde DM, Boonen A, van der Linden S: Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997, 350: 309-318. 10.1016/S0140-6736(97)01300-7.
Landewe RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, van Denderen JC, Westedt ML, Peeters AJ, Dijkmans BA, Jacobs P, Boonen A, van der Heijde DM, van der Linden S: COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum. 2002, 46: 347-356. 10.1002/art.10083.
Verhoeven AC, Bibo JC, Boers M, Engel GL, van der Linden S: Cost-effectiveness and cost-utility of combination therapy in early rheumatoid arthritis: randomized comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone. COBRA Trial Group. Combinatietherapie Bij Reumatoide Artritis. Br J Rheumatol. 1998, 37: 1102-1109. 10.1093/rheumatology/37.10.1102.
Mottonen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, Laasonen L, Julkunen H, Luukkainen R, Vuori K, Paimela L, Blafield H, Hakala M, Ilva K, Yli-Kerttula U, Puolakka K, Jarvinen P, Hakola M, Piirainen H, Ahonen J, Palvimaki I, Forsberg S, Koota K, Friman C: Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet. 1999, 353: 1568-1573. 10.1016/S0140-6736(98)08513-4.
Mottonen T, Hannonen P, Korpela M, Nissila M, Kautiainen H, Ilonen J, Laasonen L, Kaipiainen-Seppanen O, Franzen P, Helve T, Koski J, Gripenberg-Gahmberg M, Myllykangas-Luosujarvi R, Leirisalo-Repo M, Finnish Rheumatoid Arthritis Combination Therapy Trial Group: Delay to institution of therapy and induction of remission using single-drug or combination-disease-modifying antirheumatic drug therapy in early rheumatoid arthritis. Arthritis Rheum. 2002, 46: 894-898. 10.1002/art.10135.
Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB: Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol. 1997, 36: 1082-1088. 10.1093/rheumatology/36.10.1082.
Dougados M, Combe B, Cantagrel A, Goupille P, Olive P, Schattenkirchner M, Meusser S, Paimela L, Rau R, Zeidler H, Leirisalo-Repo M, Peldan K: 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.
Maillefert JF, Combe B, Goupille P, Cantagrel A, Dougados M: Long term structural effects of combination therapy in patients with early rheumatoid arthritis: five year follow up of a prospective double blind controlled study. Ann Rheum Dis. 2003, 62: 764-766. 10.1136/ard.62.8.764.
van den Borne BE, Landewe RB, Goei The HS, Rietveld JH, Zwinderman AH, Bruyn GA, Breedveld FC, Dijkmans BA: Combination therapy in recent onset rheumatoid arthritis: a randomized double blind trial of the addition of low dose cyclosporine to patients treated with low dose chloroquine. J Rheumatol. 1998, 25: 1493-1498.
Proudman SM, Conaghan PG, Richardson C, Griffiths B, Green MJ, McGonagle D, Wakefield RJ, Reece RJ, Miles S, Adebajo A, Gough A, Helliwell P, Martin M, Huston G, Pease C, Veale DJ, Isaacs J, van der Heijde DM, Emery P: Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone. Arthritis Rheum. 2000, 43: 1809-1819. 10.1002/1529-0131(200008)43:8<1809::AID-ANR17>3.0.CO;2-D.
Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Cannon GW, Spencer-Green G, Finck BK: Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002, 46: 1443-1450. 10.1002/art.10308.
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Scott, D.L. Evidence for early disease-modifying drugs in rheumatoid arthritis. Arthritis Res Ther 6, 15 (2003). https://doi.org/10.1186/ar1030
- Early Rheumatoid Arthritis
- Early Aggressive Treatment