Editorial
Glucocorticoids for rheumatoid arthritis in the era of targeted therapies
Glucocorticoides para artritis reumatoide en la era de las terapias dirigidas
Maarten Boers
Epidemiology & Biostatistics, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, Netherlands
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"figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2046 "Ancho" => 1558 "Tamanyo" => 144115 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Systematic review of combination of TNF inhibitors and methotrexate (aTNF<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX) compared to traditional combination therapy in rheumatoid arthritis. Forest plots show mean (95%CI) difference per trial, and weighted mean difference (random effects model) over all trials. Only traditional combinations (DMARD comb) that contain glucocorticoids (GC, light blue) are as good as aTNF<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX, other combinations (dark blue) are not. Middle blue rhomboid: overall estimate. DAS28: Disease activity Score-28 joints; SvdH (erosion): Sharp van der Heijde radiographic damage erosion subscore; Double: MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>sulfasalazine; Triple: Double<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>hydroxychloroquine. GC: glucocorticoids; iv: intravenous. Trial references: APPEAL,<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> BeSt (T is trial arm 3, with COBRA; D is trial arm 2, with Double)<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>; IMPROVED<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>; LARA<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>; RACAT<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a>; TEAR<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a>; IDEA<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a>; SWEFOT.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Background/Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Glucocorticoids (GC) constitute one of the cornerstones of therapy for rheumatoid arthritis (RA), and are likely the most frequently prescribed chronic therapy after methotrexate. Both in surveys (QUEST-RA) and in trials about half of RA patients are on chronic GC therapy, with considerable variation between countries.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It was expected that the introduction of targeted therapies such as the biologics would lead to reductions in GC use, but this has not really materialized.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">GC are associated with many adverse events, and treatment guidelines always stress that GC use must be as brief as possible, and at the lowest possible dose. So there is a discrepancy between ‘the real world’ and the guidelines (and pharma marketing).</p><p id="par0015" class="elsevierStylePara elsevierViewall">The purpose of this viewpoint is to provide a realistic perspective on the current state of the art regarding the balance of benefit and harm of GC in RA, and to compare disease-modifying strategies that include GC with strategies that include biologics and synthetic targeted agents. It is not a systematic review, although the reader is pointed to other reviews for reference.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Notes on scope and definitions</span><p id="par0020" class="elsevierStylePara elsevierViewall">Low dose GC therapy is defined as 7.5<span class="elsevierStyleHsp" style=""></span>mg/d of prednisolone equivalent or less, and intermediate dose as >7.5 and ≤30<span class="elsevierStyleHsp" style=""></span>mg/d.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Most studies on GC have employed doses between 5 and 10<span class="elsevierStyleHsp" style=""></span>mg/d. Some have started with a high dose (30–60<span class="elsevierStyleHsp" style=""></span>mg/d) rapidly ‘stepping down’ to low dose, and some have looked at ‘bridging strategies’ where intermediate doses were given for the initial months, either as oral therapy or as repeated intramuscular injections. Intravenous pulse therapy has rarely been studied and falls outside the scope of this viewpoint.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Disease-modifying antirheumatic drugs (DMARDs) are those drugs that are able to alter the course of disease, and this is usually translated to mean that the drug is able to slow or halt the progression of joint damage as assessed on radiographs of hands and forefeet. Traditional DMARDs such as methotrexate (MTX), sulfasalazine, and hydroxychloroquine were also called ‘slow-acting’ and distinguished from GC because the latter act rapidly. Until quite recently, GC were not regarded as DMARD because of a wrongly held belief that GC did not slow progression of damage. Despite quite convincing evidence to the contrary (dating back to the early 1960-ies!),<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> this belief is tenacious, and many review articles on the treatment of RA still distinguish between ‘traditional DMARDs’ and GC. Newer DMARDs are often called ‘Targeted therapies’ and include targeted biologicals (‘bDMARDs’) and targeted synthetic agents (‘tsDMARDs’; currently only Janus kinase-inhibitors).</p><p id="par0030" class="elsevierStylePara elsevierViewall">‘Treat to target’ (T2T) is an ill-defined concept: both the specified target and the treatment protocol varies widely; most research in treat-to-target is in early RA.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Regarding outcome measurement, In RA trials ACR (American College of Rheumatology) response (suite: 20-50-70)<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and DAS28 (Disease Activity Score-28 joints),<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> including EULAR response<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> are most commonly used. Although both perform admirably in distinguishing active from placebo, and also weak from strong drug treatment, they work best in the setting of moderate to severe disease activity. Both are suboptimal in the setting of low disease activity or remission.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Evidence for benefit of treat-to-target and combination therapy in early disease</span><p id="par0040" class="elsevierStylePara elsevierViewall">A systematic review on T2T published in 2017 included 16 studies.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Only 6 of these compared T2T with usual care (usually MTX monotherapy), providing some evidence that T2T is better, via earlier achievement of desired state. The 10 other trials compared different strategies against each other.</p><p id="par0045" class="elsevierStylePara elsevierViewall">There is a substantial body of evidence for the benefit of GC in early RA, but much less for established RA; this is discussed below. This contrasts with the evidence for most other therapies, where the focus is on established RA. Also, most GC trials describe a treatment strategy where GC combined with other DMARDs is compared to DMARDs alone. For non-GC traditional DMARDs there is usually evidence for both combination therapy and monotherapy. For the biologics and tsDMARDs, the most frequently studied combination is that with MTX.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In registration (phase 3) trials of new DMARDs, most frequently patients with an insufficient response to MTX are randomized to additional placebo or the new DMARD. This is technically also a combination study, but it supplies little information on the true value of the combination because patients have already shown insufficient response (or failure) on MTX.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">For non-GC DMARD strategies mostly initial combo vs MTX monotherapy studies have been performed. Recent and older reviews collected very limited evidence that initial combo is better: most trials were negative, except for some evidence to suggest a benefit of ‘triple therapy’ (MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>SSZ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>HCQ) over MTX monotherapy.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In the course of their development, all targeted agents have been studied in early RA (MTX naïve patients), where MTX monotherapy was compared with the combination, sometimes also with a third arm (targeted agent monotherapy).</p><p id="par0065" class="elsevierStylePara elsevierViewall">A recent review<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> summarized the results as follows: for disease activity a combination works better than MTX monotherapy; the new agent as monotherapy is only marginally better than MTX monotherapy, with the possible exception of tofacitinib monotherapy. More specifically, MTX + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab); and tofacitinib monotherapy resulted in an ACR50 response range of 56–67%, compared to 41% for MTX monotherapy. For damage, several MTX-biologic combinations (adalimumab, etanercept, certolizumab, or infliximab) were statistically superior to MTX monotherapy, but in all treatment groups the estimated mean 1-y change was less than the minimal clinically important difference (5 units on the Sharp van der Heijde score<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>). Since this review, similar evidence for baricitinib has been published.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Evidence for GC-DMARD strategies</span><p id="par0070" class="elsevierStylePara elsevierViewall">As stated above, most evidence for the efficacy of GC is in early RA. However, this is about to change as the GLORIA trial has recently closed inclusion and will present results in 2021. It is a large (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>452) pragmatic trial running in 7 European countries that compares the addition of 5<span class="elsevierStyleHsp" style=""></span>mg/d prednisolone or placebo to standard of care therapy in RA patients aged 65+.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Also, a withdrawal study presented at last year's American College of Rheumatology meeting showed that patients in low disease activity on tocilizumab plus low-dose GC were worse off if they tapered the GC, indicating continued efficacy beyond that of tocilizumab.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The older literature is already conclusive on the efficacy of GC; effective in this review is shorthand for improvement on signs and symptoms AND slowing of damage progression; effects are consistent, as summarized in Cochrane reviews.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,17,18</span></a> As designer of COBRA, the first step-down trial, this schedule has a special place in my heart.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Since its publication, its evidence has been replicated (BeSt trial<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,21</span></a>) and the schedule has been shown to be effective in lower dose modifications,<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,23</span></a> as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>. However, more simple schedules are also effective<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24–26</span></a>. The benefits of early GC also extend to less starts of expensive biologic therapy,<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,26</span></a> and counteraction of the systemic inflammatory effects that may include glucose intolerance, lipid disorders, mood disturbance and weight loss.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,27,28</span></a> Finally, GC co-therapy reduces the chance of hypersensitivity reactions to other antirheumatic drugs.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In Amsterdam an interesting experiment studied glucose metabolism during a week of 60 or 30<span class="elsevierStyleHsp" style=""></span>mg/d prednisolone in early untreated RA.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> These patients subsequently went on in the COBRA-light trial.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> 41 patients were given 60 or 30<span class="elsevierStyleHsp" style=""></span>mg/d. At baseline 23 patients had impaired glucose tolerance, and 3 had unrecognized diabetes type 2! The extent of glucose intolerance correlated with disease activity. After 1 week of either 30 or 60<span class="elsevierStyleHsp" style=""></span>mg/d prednisolone, the mean glucose tolerance was unchanged. However, 7 patients with initially impaired tolerance progressed to diabetes mellitus, whereas 9 regressed to normal! Even in these early patients, progression to diabetes was more likely with longer symptom duration (36 v 16 weeks).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">So how does combination therapy that includes GC compare with biologic therapy? Quite well, actually. The most well-known example is the BeSt trial where infliximab plus high dose methotrexate was indistinguishable from traditional COBRA therapy (treatment schedule, see <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) in efficacy.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> A recent review confirmed this with other GC schedules and biologics (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> These results strongly suggest biologics should not be started in early RA before a combination that includes GC has been tried.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Harm</span><p id="par0085" class="elsevierStylePara elsevierViewall">Most concern with GC in RA is not whether they work, but the ‘certainty’ that the harm outweighs any benefit. The number of observational studies that ‘prove’ this point increases every day, but in this (and many other) setting observational studies can never overcome the strong confounding by indication.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30–32</span></a> This occurs because patients with poor prognosis are not only more likely to receive these agents, and poor prognosis RA is itself associated with many of the adverse events that are traditionally associated with GC. A recent example of this, only presented in abstract is a study from the CATCH cohort, that looked at 1689 early RA patients<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>: 59% received GC within the first 3 months (30% oral). These patients were older, less likely to be employed, had shorter disease duration, were more often rheumatoid factor or anti-citrullinated protein antibody positive, and were worse in all indicators of disease activity, and in physical disability scores. They had a worse course in the first year including more biologic starts.</p><p id="par0090" class="elsevierStylePara elsevierViewall">In contrast, the experience from randomized trials (where by definition GC therapy is not associated with RA prognosis) consistently contradicts that low-dose GC (≤7.5<span class="elsevierStyleHsp" style=""></span>mg prednisolone equivalent/d) given for extended periods is associated with excessive harm. However such evidence has proved hard to publish: a systematic review is still languishing in abstract form.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> However, a published case in point is our series on the long-term effects seen in the COBRA cohort: evidence for prolonged protection against damage,<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> and no signs of excessive harm<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> or increased mortality.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> It is certain that GC can cause serious harm, but it is highly likely that such harm is mostly seen in conditions where GC are given for long periods in high doses. Such conditions include complicated lupus and vasculitis, but most are non-rheumatologic, such as lymphoma.</p><p id="par0095" class="elsevierStylePara elsevierViewall">In conclusion, it is time we dropped our strange reservations against the inclusion of GC in our treatment armamentarium, as a ‘normal’ drug, with pro's and con's like any other treatment. This includes getting rid of our collective self-denial, where guidelines (‘short-term’, ‘taper as rapidly as possible’<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>) are completely at odds with daily practice (about 50% of our RA patients on long-term GC therapy), but also optimal attention to effective preventive measures (screening and treating comorbidity, bone protection). Finally, more public funding and research effort must be spent on acquiring more knowledge about this essential agent.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Background/Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Notes on scope and definitions" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Evidence for benefit of treat-to-target and combination therapy in early disease" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Evidence for GC-DMARD strategies" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Harm" ] 5 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1990 "Ancho" => 2056 "Tamanyo" => 184341 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Variations on the COBRA schedule. Based on: COBRA: Boers et al.,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> COBRA-light: den Uyl et al.,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and COBRA-slim: Verschueren et al.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Graudal et al.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> with permission." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2046 "Ancho" => 1558 "Tamanyo" => 144115 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Systematic review of combination of TNF inhibitors and methotrexate (aTNF<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX) compared to traditional combination therapy in rheumatoid arthritis. Forest plots show mean (95%CI) difference per trial, and weighted mean difference (random effects model) over all trials. Only traditional combinations (DMARD comb) that contain glucocorticoids (GC, light blue) are as good as aTNF<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX, other combinations (dark blue) are not. Middle blue rhomboid: overall estimate. DAS28: Disease activity Score-28 joints; SvdH (erosion): Sharp van der Heijde radiographic damage erosion subscore; Double: MTX<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>sulfasalazine; Triple: Double<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>hydroxychloroquine. GC: glucocorticoids; iv: intravenous. Trial references: APPEAL,<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> BeSt (T is trial arm 3, with COBRA; D is trial arm 2, with Double)<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>; IMPROVED<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>; LARA<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>; RACAT<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a>; TEAR<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a>; IDEA<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a>; SWEFOT.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "QUEST-RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 3 | 2 | 5 |
| 2024 October | 44 | 33 | 77 |
| 2024 September | 51 | 16 | 67 |
| 2024 August | 69 | 39 | 108 |
| 2024 July | 48 | 30 | 78 |
| 2024 June | 50 | 46 | 96 |
| 2024 May | 54 | 49 | 103 |
| 2024 April | 49 | 26 | 75 |
| 2024 March | 34 | 34 | 68 |
| 2024 February | 46 | 31 | 77 |
| 2024 January | 36 | 18 | 54 |
| 2023 December | 27 | 24 | 51 |
| 2023 November | 46 | 36 | 82 |
| 2023 October | 87 | 27 | 114 |
| 2023 September | 94 | 32 | 126 |
| 2023 August | 28 | 14 | 42 |
| 2023 July | 33 | 22 | 55 |
| 2023 June | 61 | 26 | 87 |
| 2023 May | 54 | 28 | 82 |
| 2023 April | 53 | 6 | 59 |
| 2023 March | 83 | 24 | 107 |
| 2023 February | 82 | 29 | 111 |
| 2023 January | 44 | 14 | 58 |
| 2022 December | 74 | 25 | 99 |
| 2022 November | 66 | 27 | 93 |
| 2022 October | 87 | 39 | 126 |
| 2022 September | 44 | 20 | 64 |
| 2022 August | 41 | 43 | 84 |
| 2022 July | 54 | 44 | 98 |
| 2022 June | 42 | 52 | 94 |
| 2022 May | 54 | 37 | 91 |
| 2022 April | 59 | 37 | 96 |
| 2022 March | 49 | 38 | 87 |
| 2022 February | 35 | 32 | 67 |
| 2022 January | 61 | 24 | 85 |
| 2021 December | 40 | 50 | 90 |
| 2021 November | 64 | 49 | 113 |
| 2021 October | 58 | 46 | 104 |
| 2021 September | 43 | 49 | 92 |
| 2021 August | 44 | 35 | 79 |
| 2021 July | 42 | 29 | 71 |
| 2021 June | 44 | 30 | 74 |
| 2021 May | 47 | 44 | 91 |
| 2021 April | 97 | 100 | 197 |
| 2021 March | 52 | 34 | 86 |
| 2021 February | 33 | 17 | 50 |
| 2021 January | 32 | 25 | 57 |
| 2020 December | 24 | 15 | 39 |
| 2020 November | 26 | 15 | 41 |
| 2020 October | 14 | 9 | 23 |
| 2020 September | 26 | 18 | 44 |
| 2020 August | 22 | 23 | 45 |
| 2020 July | 12 | 9 | 21 |
| 2020 June | 11 | 7 | 18 |
| 2020 May | 18 | 16 | 34 |
| 2020 January | 1 | 0 | 1 |
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