DOI: https://doi.org/10.4414/smw.2011.13189
Many guidelines for treating rheumatoid arthritis patients are available, including US and European guidelines. This document, based on evidence and expert opinion, but without any formal and systematic process or review of the literature, presents what is regarded as current practice by the representatives of the Swiss university hospitals. Those recommendations are intended as a pragmatic help for Swiss practitioners to improve standard care in Switzerland.
Rheumatoid arthritis (RA) is an immune mediated, chronic and progressive inflammatory joint disease [1] with auto-immune phenomena such as rheumatoid factor (RF) and antibodies against citrullinated cyclic peptides (anti-CCP-antibodies, ACPA), clinically characterised by the symmetric involvement of multiple small and large peripheral joints. RA is the most prevalent inflammatory joint disease in developed countries, affecting up to 1% of the entire population. RA may lead to bone erosions and cartilage destruction resulting in loss of joint function, severe handicap and work disability.
There are a few variables which help to predict aggressive disease course and guide therapy: Presence of RF, CCP auto-antibodies, high CRP/ESR, early bony erosions and extra-articular manifestations [2, 3]. Importantly, RA should never be regarded as trivial, and an early and adapted therapy has to be started as soon as possible. Every patient presenting with arthritis of more than one joint and lasting for more than 6 weeks should be evaluated by a rheumatologist for possible RA. The recent revision of the ACR/EULAR classification criteria presented at ACR 2009 acknowledges this need [4].
There is currently no cure for RA, and the vast majority of patients will have to be treated for the rest of their lives and with well-defined objectives. With the broad variety of treatment options, the aim is early and complete remission, which means the absence of swollen and tender joints, morning stiffness and fatigue, as well as clinical and laboratory signs of systemic inflammation. Furthermore, the structural integrity of joints has to be monitored in order to prevent any (progression of) structural damage, and thus to prevent handicap and work disability.
The best validated tool for disease activity monitoring is the disease activity score (DAS). The DAS28 score includes the number of tender or swollen joints (out of 28 defined joints), acute phase reactants and a general health evaluation by the patient [5]. Despite limitations, this composite index is the international assessment tool used for clinical studies, and also to prospectively monitor disease with the aim to adjust treatment intensity [6–8]. The structural joint status is monitored by conventional X rays on a yearly basis. Joint ultrasonography is an ideal bed-side method to detect early structural changes, and this rapidly expanding technique will certainly become a standard. The Swiss Society for Rheumatology (SGR/SSR) provides a user-friendly web-based tool for longitudinal monitoring and documentation of all necessary disease parameters (http://scqm.ch). This disease assessment should be completed on a regular basis, with annual radiographic analyses and patient-centred assessments of functional status and quality of life by standardised measures, such as the health assessment questionnaire of disability (HAQ-DI) or SF-36.
Patients with diagnosed RA should be started with a disease-modifying anti-rheumatic drug (DMARD) therapy as early as possible. Methotrexate (MTX) is the gold standard drug for mildly to highly active disease activity. The use of subcutaneous administration, starting with (at least) 10 mg per week and combined with folate substitution (5–10 mg per week) to minimise side effects is recommended. MTX dose should be increased by up to 25–30 mg per week within 2 to 3 months depending on efficacy and tolerability.
Monotherapy with other DMARDs such as anti-malarials, sulfasalazine and leflunomide is recommended for patients with low disease activity and a lack of bad prognostic markers. Combinations of MTX with other conventional DMARD have been tested in several clinical trials, and were shown to provide some increased efficacy without potentiating toxicity [9, 10]. Systemic or intra-articular gluco-corticoids may be used to rapidly induce remission but the daily dose should not exceed 5 mg if given over prolonged periods (> a few weeks).
Ongoing stringent monitoring of RA disease activity and progression, as recommended above, allows appropriate adaptation of DMARD and biologics treatment. The authors of this consensus agree that if low disease activity or remission (defined for practical purposes as at least a DAS28 ≤3.2) has not been achieved within 3 months with the initial conventional DMARD therapy, that the use of a biologic agent is recommended as the likelihood of reaching a low disease activity status, after initial failure of MTX, using subsequent conventional DMARDs is low [11].
At present, TNF blocking agents are the 1st choice for biologic treatment when conventional DMARD therapy has failed to induce disease remission. This recommendation is based on the good clinical experience with anti-TNF-therapy, their demonstrated strong efficacy, their rapid onset of action and the known benefit–risk profile with over a million patients treated up to date and more than a decade of experience with the use of the three TNF-blocking agents currently licensed for the Swiss market.
Prior to the initiation of any anti-TNFα therapy, a systematic workup has to be performed to exclude the various contra-indications to such treatment. The current recommendations in regard to this topic released by the Swiss Society of Rheumatology are available online ( http://www.rheuma-net.ch/richtlinien ).
The choice of the anti-TNF agent used is primarily based on the individual patient characteristics (such as compliance, preference for long dosing interval with intravenous administration or preference for self-subcutaneous administration, venous access) and the availability of the appropriate infrastructure for intravenous infusions. The authors believe there is currently no efficacy or safety data to suggest an overwhelming advantage of one agent over the others.
Whenever possible, it is strongly recommended to use any TNF-blocking agent in combination with MTX, as combination of both agents was superior to monotherapy with either one of these substances in all clinical trials, in terms of clinical response, physical function and radiographic progression [6, 12]. In the case of MTX intolerance, reduction of the MTX dose or use of an alternative DMARD such as leflunomide is recommended. Biologics, such as monotherapy, should only be considered when traditional DMARDs are contraindicated. Monotherapies were not shown to have superior efficacy compared to MTX, except tocilizumab, a humanised monoclonal antibody against the interleukin 6-receptor which was more effective in monotherapy than MTX alone. However, this study did not include a combination arm, and for the moment tocilizumab should also be used whenever possible in association with MTX [13].
The disease course of patients on an anti-TNF therapy is not linear. Thus, disease activity has to be tightly monitored with treatment modification in case of a lack of/or insufficient efficacy, or a secondary loss of response, while some treatment de-escalations may be considered in the case of persisting remission.
Insufficient response or secondary loss of response:
If remission is not reached or is lost after an initial favourable response, modification or intensification of therapy is mandatory. In the setting of a significant clinical response, such as a good EULAR response, but in the absence of remission, treatment optimisation with a dose increase of the conventional DMARD and/or the addition of another DMARD, as well as short-term gluco-corticoids are reasonable options for the authors, even if no formal trials support these suggestions.
In the absence of a response, or if a tentative optimisation fails, the anti-TNF agent should be stopped and an alternative biologic agent should be used; either an alternative anti-TNF agent or a biologic agent with a different mode of action such as rituximab, abatacept or tocilizumab. Efficacy, in this difficult-to-treat TNF-resistant population, has been demonstrated for all of these agents in randomised controlled trials [14–16]. Whether changing to a second TNF blocker or to a biologic with a different mechanism of action is the better option has not been evaluated in head-to-head trials [17–24]. The preference for currently available treatment strategies in this setting still varies from centre to centre.
In case of remission, even if the optimal therapeutic strategy remains unknown, all centres agree that gluco-corticoids should be tapered first and discontinued whenever possible. The authors agree that the dosage of either the biologic or the conventional DMARD should not be modified for at least 6 months of persisting remission. Thereafter, treatment intervals of biologics are prolonged and biologics are finally stopped with ongoing DMARD therapy.
Drug-free remission:
The ultimate goal of treatment would be an ongoing drug-free remission. Based on the results of the BEst study, it appears possible to discontinue anti-TNF therapy as well as concomitant DMARD in a small percentage of patients [25]. However, these patients were treated very early and very aggressively (combination of infliximab and MTX). The data led to the hypothesis that there exists a “window of opportunity” (i.e., an, as yet, undefined time slot in early RA) when it is possible to eradicate all disease processes and achieve a “re-set” of inflammatory and autoimmune phenomena. In such cases, it remains even more crucial to tightly monitor the patients for any signs of reactivation or structural damage progression, with prompt resumption of therapy if needed.
1 Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–61.
2 Vastesaeger N, Xu S, Aletaha D, St Clair EW, Smolen JS. A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology (Oxford). 2009;48:1114–21.
3 da Mota LM, Laurindo IM, de Carvalho JF, dos Santos-Neto LL. Prognostic evaluation of early rheumatoid arthritis. Swiss Med Wkly. 2010;140:w13100. doi: 10.4414/smw.2010.13100.
4 Aletaha D, Neogi T, Silman A, et al. The American College of Rheumatology / European League Against Rheumatism Classification and Diagnostic Criteria for Rheumatoid Arthritis. Ann Rheum Dis 2010;69:1580–8.
5 Prevoo ML, van ’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:44–8.
6 Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363:675–81.
7 Haraoui B. Assessment and management of rheumatoid arthritis. J Rheumatol Suppl. 2009;82:2–10.
8 van der Heijde D, Klareskog L, Boers M, Landewe R, Codreanu C, Bolosiu HD, et al. Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis. 2005;64:1582–7.
9 Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997;350:309–18.
10 Mottonen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet. 1999;353:1568–73.
11 van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YPM, van Zeben D, Kerstens PJSM, et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum. Published Online First: 2007/02/09. doi:10.1136/ard.2006.066662
12 Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26–37.
13 Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010 Jan;69(1):88–96.
14 Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54:2793–806.
15 Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114–23.
16 Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516–23.
17 Smolen JS, Kay J, Doyle MK, Landewe R, Matteson EL, Wollenhaupt J, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet. 2009;374:210–21.
18 Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;11(Suppl 1):S1. Epub 2009 Apr 6.
19 Finckh A, Ciurea A, Brulhart L, Kyburz D, Moller B, Dehler S, et al. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum. 2007;56:1417–23.
20 Buch MH, Bingham SJ, Bejarano V, Bryer D, White J, Reece R, et al. Therapy of patients with rheumatoid arthritis: outcome of infliximab failures switched to etanercept. Arthritis Rheum. 2007;57:448–53.
21 Hyrich KL, Lunt M, Dixon WG, Watson KD, Symmons DP. Effects of switching between anti-TNF therapies on HAQ response in patients who do not respond to their first anti-TNF drug. Rheumatology (Oxford). 2008;47:1000–5.
22 Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ. Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum. 2007;56:13–20.
23 Karlsson JA, Kristensen LE, Kapetanovic MC, Gulfe A, Saxne T, Geborek P. Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology (Oxford). 2008;47:507–13.
24 Finckh A, Ciurea A, Brulhart L, Moller B, Walker UA, Courvoisier D, et al. Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent? Ann Rheum Dis. 2010;69:387–93.
25 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005;52:3381–90.
This work was supported by an unrestricted grant from Essex Chemie AG.