Editorial
Triple therapy in rheumatoid arthritis
Triple terapia en la artritis reumatoide
Lydia Abásolo Alcázar
Unidad de Gestión Clínica (UGC) de Reumatología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
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Its prevalence varies little between countries, being 0.5% in our country.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The disease is associated with severe morbidity, impaired functional capacity and disability, decreased quality of life, loss of independence and increased mortality.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the last 20 years, the management of patients with RA has changed dramatically and RA therapies now focus on remission or at least a reduction in the inflammatory activity in order to reduce or prevent joint damage and disability. This has been prompted by several reasons: early therapy, dose optimization, use of combination therapies and the emergence of new forms of treatment. According to the study of Welsing et al.,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> the disease has a better prognosis in recent decades, and this may reflect earlier diagnosis and a proper treatment more than a change in the disease characteristics.</p><p id="par0015" class="elsevierStylePara elsevierViewall">All these advances in the management of RA have provided rheumatologists today with a wide therapeutic arsenal and many published recommendations and guidelines that aim to aid the physician in making decisions. Within these recommendations, perhaps the use of triple therapy in combination therapy is less characterized and its use is less widespread. The guidelines of the American College of Rheumatology (ACR) 2012<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and the Canadian Rheumatology Association<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> 2012 recommend the use of combination therapy with disease modifying antirheumatic drugs (DMARDs), including triple therapy in patients with early RA, with moderate or severe disease activity and poor prognostic factors associated. Combination therapy should also be considered in patients who have an inadequate response to monotherapy. The EULAR 2013<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> recommendations are less explicit in the use of combined therapy and triple therapy. They report that in patients that have not received prior DMARD, that the use of monotherapy or combination therapy is justified. If the goal of treatment is not achieved with the first DMARD strategy, in the absence of poor prognostic factors, the clinician should consider switching to another DMARD strategy.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the 1990s the first studies in the literature showing the benefit of triple therapy versus monotherapy, particularly methotrexate, sulfasalazine and hydroxychloroquine (HCQ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ) appeared. In the study by Möttönen et al.,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> the efficacy and tolerability of the combination of MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ and low-dose prednisone was compared to monotherapy, with or without oral prednisone in RA patients with early and active disease. Combination therapy was significantly better and was no more dangerous than monotherapy in remission induction. O_Dell<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> shows that, in patients with established RA, combination therapy with MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ was more effective than MTX alone or MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ, with no differences in the percentage of adverse events. Katchamart et al. published<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> in 2009, a systematic review with a meta-analysis of the efficacy and toxicity of MTX monotherapy versus MTX combined with traditional DMARDs. With regard to triple therapy, they conclude that the combination of MTX, SSZ, and HCQ shows improved effectiveness/toxicity than MTX alone (hazard ratio 0.3, 95% <span class="elsevierStyleSmallCaps">CI</span> 0.14–0.65).</p><p id="par0025" class="elsevierStylePara elsevierViewall">Recently, a study by de Jong et al.,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> also evaluated the effect of corticosteroids in different treatment groups. It compared, in patients with early RA, the clinical efficacy of triple therapy with classic DMARDs (MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HQC) and a regimen (oral or intramuscular) of corticosteroids compared to treatment with MTX monotherapy and an oral steroid regimen. Clinical improvement with fewer escalations is quickly reached and maintained with triple therapy so. No significant differences in radiographic progression serious adverse events were found. In any case, the proportion of patients with medication adjustments due to adverse events was significantly higher in those taking triple therapy versus monotherapy.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Since the year 2012 there have been several published studies of triple therapy combinations where biological agents were included. Van Vollenhoven et al.,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> published a clinical trial that compared the addition of an anti-TNF (infliximab<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX) agent to MTX with the addition of sulfasalazine plus hydroxychloroquine in patients with early RA who had not responded to MTX (MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ). The proportion of patients with good clinical response at 18 and 24 months of treatment was similar in both treatment groups. At 24 months, radiographic disease progression was significantly higher in patients receiving triple therapy than in those receiving biological treatment (mean 7.23 versus 4, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009). However, improved radiographic results after 24 months must be weighed against the lack of a convincing clinical difference at 24 months with substantially higher costs in the group with biological drugs. Similar clinical outcomes were seen by O_Dell et al.,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> in 2013 for patients with established and active RA despite treatment with MTX, showing that the clinical benefit was similar in the triple therapy group (MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ) to that seen in the etanercept plus MTX group. Moreland et al.,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> in 2013 compared in early RA, and with disease activity, the following strategies. Etanercept<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX versus immediate triple therapy (MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ) or triple step therapy. After 102 weeks, all 3 strategies were more effective than MTX monotherapy before starting step-up therapy, but slower in reaching clinical objectives than the initial combinations. With regard to radiological progression, the group assigned to receive MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>etanercept had a smaller increase in radiological Sharp scores compared with those receiving triple therapy (0.64 vs 1.69<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.047). There were no differences across treatment groups in the number of serious adverse events. Under the “real life” conditions, decision making in patients with RA is certainly more complex than in clinical trials. No selection of patients exists and treatment must be performed in an outpatient basis in an environment of rising health care demands and limited time available. Furthermore, in clinical practice, there are many factors that influence the choice of treatment for a specific patient with RA. This is the result of a decision process which usually influences the activity of the disease itself and certain physician and patient characteristics. Thus, the current tendencies in light of new knowledge on the management of RA, prior treatment and the reason for its suspension, consideration of comorbidities, age, disability and patients’ concomitant medications, or patient preferences and treatment adherence, and certain economic factors, are influencing the decision process of the rheumatologist. This leads the rheumatologist, in many cases, to use combinations of treatment regimens, that although have efficacy and safety profiles that are not analyzed in the scientific literature, are based on clinical experience in order to shuffle the different options available. For example data from our hospital shows that, in 2012, 35% of patients were taking combination therapy and 5% had triple therapy. The most used combinations were MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ, MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>leflunomide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>biological agent, MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>biological agent and leflunomide<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ. The follow-up visits of patients with RA, which occupied about 50% of all subsequent visits, aimed to maximize the number of remissions of the disease, and to minimize the impact of adverse events, which are a major cause of treatment failure and morbidity. We should not forget this aspect and, in this sense, it is important to note that although the level of evidence is low, in contrast to the main benefits of combination treatments in general, it seems that combination therapy may result in more suspensions<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15–17</span></a> than monotherapy due to toxicity. Many questions remain on the risks of different combinations strategies through a range of adverse effects, from the relatively minor to serious and potentially deadly problems. In summary, we can say that triple therapy is an appropriate option for the management of our patients. Specifically, the combination of MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ has been shown to be more effective than monotherapy and some combination therapies in treating RA. It also appears that the combination of MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SLZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ is not inferior to some MTX combination therapies with biological agents, although it appears from recent studies that there is less radiographic progression with biologicals, but no clinical consequences. Based on current scientific data, triple therapy and combination therapy with DMARDs, in our view, should be more explicitly included in any clinical treatment guideline of RA. In our view, it is necessary to develop observational studies based on clinical practice, to adequately assess the efficacy and safety of different regimens of treatment combinations used by rheumatologists.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Abásolo Alcázar L. Triple terapia en la artritis reumatoide. Reumatol Clin. 2014;10:275–277.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The prevalence of rheumatoid arthritis in the general population of Spain" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 12 | 1 | 13 |
| 2024 October | 214 | 42 | 256 |
| 2024 September | 207 | 22 | 229 |
| 2024 August | 245 | 42 | 287 |
| 2024 July | 196 | 26 | 222 |
| 2024 June | 161 | 40 | 201 |
| 2024 May | 192 | 48 | 240 |
| 2024 April | 190 | 37 | 227 |
| 2024 March | 174 | 35 | 209 |
| 2024 February | 125 | 22 | 147 |
| 2024 January | 133 | 23 | 156 |
| 2023 December | 121 | 28 | 149 |
| 2023 November | 140 | 32 | 172 |
| 2023 October | 191 | 39 | 230 |
| 2023 September | 99 | 32 | 131 |
| 2023 August | 114 | 24 | 138 |
| 2023 July | 118 | 25 | 143 |
| 2023 June | 131 | 24 | 155 |
| 2023 May | 126 | 24 | 150 |
| 2023 April | 97 | 15 | 112 |
| 2023 March | 134 | 42 | 176 |
| 2023 February | 107 | 30 | 137 |
| 2023 January | 121 | 27 | 148 |
| 2022 December | 115 | 43 | 158 |
| 2022 November | 149 | 36 | 185 |
| 2022 October | 116 | 44 | 160 |
| 2022 September | 91 | 46 | 137 |
| 2022 August | 80 | 39 | 119 |
| 2022 July | 91 | 49 | 140 |
| 2022 June | 83 | 33 | 116 |
| 2022 May | 106 | 45 | 151 |
| 2022 April | 123 | 41 | 164 |
| 2022 March | 106 | 54 | 160 |
| 2022 February | 97 | 23 | 120 |
| 2022 January | 67 | 44 | 111 |
| 2021 December | 57 | 44 | 101 |
| 2021 November | 65 | 44 | 109 |
| 2021 October | 65 | 48 | 113 |
| 2021 September | 56 | 39 | 95 |
| 2021 August | 56 | 40 | 96 |
| 2021 July | 45 | 34 | 79 |
| 2021 June | 42 | 37 | 79 |
| 2021 May | 54 | 37 | 91 |
| 2021 April | 147 | 71 | 218 |
| 2021 March | 136 | 27 | 163 |
| 2021 February | 75 | 20 | 95 |
| 2021 January | 63 | 11 | 74 |
| 2020 December | 57 | 25 | 82 |
| 2020 November | 49 | 21 | 70 |
| 2020 October | 53 | 9 | 62 |
| 2020 September | 57 | 43 | 100 |
| 2020 August | 31 | 17 | 48 |
| 2020 July | 28 | 18 | 46 |
| 2020 June | 46 | 22 | 68 |
| 2020 May | 30 | 11 | 41 |
| 2020 April | 18 | 22 | 40 |
| 2020 March | 17 | 9 | 26 |
| 2020 February | 1 | 0 | 1 |
| 2018 May | 4 | 0 | 4 |
| 2018 April | 42 | 3 | 45 |
| 2018 March | 65 | 7 | 72 |
| 2018 February | 32 | 5 | 37 |
| 2018 January | 50 | 6 | 56 |
| 2017 December | 44 | 6 | 50 |
| 2017 November | 50 | 9 | 59 |
| 2017 October | 57 | 12 | 69 |
| 2017 September | 47 | 14 | 61 |
| 2017 August | 41 | 14 | 55 |
| 2017 July | 57 | 14 | 71 |
| 2017 June | 58 | 23 | 81 |
| 2017 May | 73 | 23 | 96 |
| 2017 April | 52 | 12 | 64 |
| 2017 March | 45 | 26 | 71 |
| 2017 February | 97 | 11 | 108 |
| 2017 January | 68 | 16 | 84 |
| 2016 December | 97 | 20 | 117 |
| 2016 November | 83 | 20 | 103 |
| 2016 October | 134 | 15 | 149 |
| 2016 September | 120 | 11 | 131 |
| 2016 August | 70 | 14 | 84 |
| 2016 July | 51 | 10 | 61 |
| 2015 December | 1 | 0 | 1 |
| 2015 November | 1 | 0 | 1 |
| 2015 September | 1 | 0 | 1 |
| 2015 August | 2 | 0 | 2 |
| 2015 July | 28 | 9 | 37 |
| 2015 June | 38 | 10 | 48 |
| 2015 May | 99 | 27 | 126 |
| 2015 April | 55 | 19 | 74 |
| 2015 March | 44 | 12 | 56 |
| 2015 February | 58 | 13 | 71 |
| 2015 January | 67 | 22 | 89 |
| 2014 December | 58 | 12 | 70 |
| 2014 November | 59 | 10 | 69 |
| 2014 October | 70 | 31 | 101 |
| 2014 September | 30 | 14 | 44 |
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