1 00:00:15,664 --> 00:00:17,744 Hey, everybody. Welcome back to Palm Peeps. Thanks 2 00:00:17,744 --> 00:00:20,065 for tuning in today. Pumped to be back 3 00:00:20,065 --> 00:00:22,704 with another rapid fire journal club. We're here 4 00:00:22,704 --> 00:00:25,345 with two Palm Peeps experts at this point. 5 00:00:25,345 --> 00:00:27,265 We have Robert Warren joining us. He's a 6 00:00:27,265 --> 00:00:29,744 fellow at Johns Hopkins, currently doing his pulmonary 7 00:00:29,744 --> 00:00:32,189 critical care fellowship. And, actually, about to start 8 00:00:32,189 --> 00:00:34,350 some research into vaping in young adults. You'll 9 00:00:34,350 --> 00:00:35,890 have to let us know what you find. 10 00:00:36,350 --> 00:00:39,009 And Luke Hedrick, who is our rapid fire 11 00:00:39,149 --> 00:00:41,549 journal club editor. He's a Palm Beach pro. 12 00:00:41,549 --> 00:00:42,750 Luke, it's good to see you. How are 13 00:00:42,750 --> 00:00:43,329 you doing? 14 00:00:43,844 --> 00:00:45,284 Hey, David. It's good to see you too. 15 00:00:45,284 --> 00:00:47,844 I'm good. Good. Robert, how are you? I'm 16 00:00:47,844 --> 00:00:49,685 good. I'm good. Alright, guys. Well, what are 17 00:00:49,685 --> 00:00:51,605 we talking about today? Which which article, what 18 00:00:51,605 --> 00:00:53,304 condition, Luca, take us away? 19 00:00:54,085 --> 00:00:56,245 Yeah. So today, we have a pretty interesting 20 00:00:56,245 --> 00:00:58,840 article that Robert brought to us. It was 21 00:00:58,840 --> 00:01:02,219 published in the New England Journal in May. 22 00:01:02,439 --> 00:01:05,079 It's first line treatment of pulmonary sarcoidosis with 23 00:01:05,079 --> 00:01:06,299 prednisone or methotrexate 24 00:01:06,840 --> 00:01:09,159 or the PREDMETH trial. Robert, do you wanna 25 00:01:09,159 --> 00:01:10,599 tell us a little bit about kinda what 26 00:01:10,599 --> 00:01:12,219 made you wanna talk about this? 27 00:01:12,625 --> 00:01:14,625 Yeah. I I brought this trial not just 28 00:01:14,625 --> 00:01:16,305 because it's in the New England Journal and 29 00:01:16,305 --> 00:01:17,984 was presented at ATS, but, 30 00:01:18,305 --> 00:01:20,884 because it's it's not a huge industry sponsored 31 00:01:20,944 --> 00:01:24,244 behemoth. Right? Sarcoidosis is a rare, heterogeneous disease 32 00:01:24,590 --> 00:01:26,909 that has very few randomized controlled trials to 33 00:01:26,909 --> 00:01:30,189 support therapeutic options. And so this trial gives 34 00:01:30,189 --> 00:01:31,790 a wealth of data, but it also presents 35 00:01:31,790 --> 00:01:33,250 unique challenges for interpretation. 36 00:01:35,150 --> 00:01:37,665 Yeah. I love it. I was so excited 37 00:01:37,724 --> 00:01:40,364 to actually see, like, another RCT published in 38 00:01:40,364 --> 00:01:42,525 this space. I feel like there's just such 39 00:01:42,525 --> 00:01:44,305 a a dearth of information, unfortunately. 40 00:01:45,245 --> 00:01:47,405 So, alright, let's get right into it. Is 41 00:01:47,405 --> 00:01:49,239 there any kind of relevant background do you 42 00:01:49,239 --> 00:01:50,920 think we should know or keep in mind 43 00:01:50,920 --> 00:01:52,939 when we start looking at the results here? 44 00:01:54,280 --> 00:01:57,099 Yeah. Absolutely. This was a trial of prednisone 45 00:01:57,560 --> 00:01:58,060 versus 46 00:01:58,679 --> 00:01:59,179 methotrexate. 47 00:01:59,479 --> 00:02:01,179 It's called the PRINT meth trial. 48 00:02:01,765 --> 00:02:02,004 And, 49 00:02:03,444 --> 00:02:03,944 so 50 00:02:04,484 --> 00:02:06,165 to describe a little bit about those two 51 00:02:06,165 --> 00:02:08,405 drugs, right, prednisone is the first line treatment 52 00:02:08,405 --> 00:02:09,064 for sarcoidosis. 53 00:02:09,685 --> 00:02:10,824 We know that it works. 54 00:02:11,284 --> 00:02:13,764 It causes short term improvement in pulmonary function, 55 00:02:13,764 --> 00:02:16,185 decreased symptoms, decreased radiologic abnormalities, 56 00:02:16,485 --> 00:02:18,969 but comes with the whole array of steroid 57 00:02:18,969 --> 00:02:20,889 side effects that we know and love or 58 00:02:20,889 --> 00:02:21,389 hate: 59 00:02:21,689 --> 00:02:24,030 weight gain, sleep problems, hypertension, diabetes, 60 00:02:24,330 --> 00:02:26,569 the whole nine yards. In spite of that, 61 00:02:26,569 --> 00:02:28,250 it hasn't been tested head to head against 62 00:02:28,250 --> 00:02:31,675 any steroid sparing agent, And the sarcoidosis guidelines 63 00:02:31,675 --> 00:02:34,014 note that there's no existing controlled evaluation 64 00:02:34,314 --> 00:02:35,055 of glucocorticoid 65 00:02:35,355 --> 00:02:38,155 treatment efficacy in preventing pulmonary function decline in 66 00:02:38,155 --> 00:02:39,375 severe pulmonary disease. 67 00:02:40,075 --> 00:02:42,395 Methotrexate, on the other hand, it is the 68 00:02:42,395 --> 00:02:44,814 most commonly used steroid sparing agent, 69 00:02:45,539 --> 00:02:47,379 but the evidence for its use is pretty 70 00:02:47,379 --> 00:02:50,099 limited. There's one twenty four patient trial from 71 00:02:50,099 --> 00:02:51,080 the year 2000. 72 00:02:51,620 --> 00:02:53,800 It showed a modest reduction in glucocorticoid 73 00:02:54,180 --> 00:02:54,680 dose. 74 00:02:54,979 --> 00:02:57,639 So overall, the guidelines gave a conditional recommendation 75 00:02:57,780 --> 00:03:00,039 based on very low quality evidence, 76 00:03:01,064 --> 00:03:01,564 and 77 00:03:02,185 --> 00:03:04,504 recommendations for other kinds of immunosuppression are based 78 00:03:04,504 --> 00:03:05,645 on current practice. 79 00:03:06,264 --> 00:03:08,604 So there's a real gap here, and 80 00:03:08,985 --> 00:03:09,965 we need to understand 81 00:03:10,585 --> 00:03:12,985 when and how to use steroid sparing agents 82 00:03:12,985 --> 00:03:13,645 in sarcoidosis. 83 00:03:14,900 --> 00:03:16,500 Yeah. I I I love it. I feel 84 00:03:16,500 --> 00:03:18,819 like the beginning of POM Crit Fellowship was 85 00:03:18,819 --> 00:03:20,740 learning to love steroids and how quickly they 86 00:03:20,740 --> 00:03:22,900 made people feel better. And then the rest 87 00:03:22,900 --> 00:03:24,659 of POM Crit Fellowship has been learning to 88 00:03:24,659 --> 00:03:26,340 hate steroids and, you know, all the terrible 89 00:03:26,340 --> 00:03:27,860 things they do to people after they make 90 00:03:27,860 --> 00:03:28,919 them feel better initially. 91 00:03:29,305 --> 00:03:31,145 One thing too, I guess, that I've always 92 00:03:31,145 --> 00:03:33,625 been taught about methotrexate that it's nice to 93 00:03:33,625 --> 00:03:34,125 see 94 00:03:34,425 --> 00:03:36,425 some data in this paper around is that 95 00:03:36,425 --> 00:03:38,105 it has a slower onset of action. So, 96 00:03:38,105 --> 00:03:39,645 you know, you talked about how quickly, 97 00:03:40,185 --> 00:03:41,965 prednisone makes people feel better. 98 00:03:42,280 --> 00:03:44,120 And I feel like at least before the 99 00:03:44,120 --> 00:03:45,799 trial came out, I don't know that I've 100 00:03:45,799 --> 00:03:48,120 been reaching for methotrexate for first line therapy 101 00:03:48,120 --> 00:03:50,039 just be out of this concern that it 102 00:03:50,039 --> 00:03:51,879 may take too long to start working and 103 00:03:51,879 --> 00:03:54,060 people just kinda need to get better faster. 104 00:03:54,280 --> 00:03:55,799 And so I think it's a really interesting 105 00:03:55,799 --> 00:03:57,639 question to ask about whether that's actually true 106 00:03:57,639 --> 00:03:58,064 or not. 107 00:03:58,544 --> 00:04:00,064 Yeah. And I'll just add one you know, 108 00:04:00,064 --> 00:04:01,585 I love this trial as well. I think 109 00:04:01,585 --> 00:04:03,925 providing guidance in a really common condition 110 00:04:04,224 --> 00:04:06,784 that we all learn how to manage, but 111 00:04:06,784 --> 00:04:09,104 that we all probably learn how to manage 112 00:04:09,104 --> 00:04:10,564 mostly on expert opinion. 113 00:04:11,099 --> 00:04:13,120 I just think in general, methotrexate 114 00:04:13,419 --> 00:04:16,160 is a drug that we as pulmonologists probably 115 00:04:16,459 --> 00:04:18,699 have not been using enough or been as 116 00:04:18,699 --> 00:04:21,019 comfortable with. And there's always reports of it 117 00:04:21,019 --> 00:04:23,500 with methotrexate lung toxicity, which, you know, in 118 00:04:23,500 --> 00:04:25,740 general, multiple literature studies have shown you can 119 00:04:25,740 --> 00:04:27,944 use it without having too much issue with 120 00:04:27,944 --> 00:04:29,865 that. And so any trial that's sort of 121 00:04:29,865 --> 00:04:31,944 saying, Hey, we should have our minds wrapped 122 00:04:31,944 --> 00:04:33,625 around this as an option, I think is 123 00:04:33,625 --> 00:04:35,384 helpful for us in the potent credit community, 124 00:04:35,384 --> 00:04:36,745 because we should really know how to use 125 00:04:36,745 --> 00:04:37,485 this drug. 126 00:04:38,105 --> 00:04:39,084 Yeah, absolutely. 127 00:04:39,750 --> 00:04:41,589 So maybe without any further ado, Robert, do 128 00:04:41,589 --> 00:04:43,029 you wanna tell us a little bit about 129 00:04:43,029 --> 00:04:45,050 what they did, what the study design was? 130 00:04:45,430 --> 00:04:48,329 Yeah. So CREDMETH was an open label, randomized, 131 00:04:48,709 --> 00:04:49,209 noninferiority 132 00:04:49,669 --> 00:04:52,229 trial that was conducted at 17 hospitals in 133 00:04:52,229 --> 00:04:52,810 The Netherlands. 134 00:04:53,944 --> 00:04:56,525 They included pulmonary sarcoid patients 135 00:04:57,384 --> 00:04:59,705 writ large and that this is tough to 136 00:04:59,705 --> 00:05:02,504 define because it's a heterogeneous disease. But they 137 00:05:02,504 --> 00:05:05,085 specified that the patients had to have radiographic 138 00:05:05,709 --> 00:05:08,449 parenchymal abnormality, so not just lymphadenopathy, 139 00:05:09,229 --> 00:05:12,110 but also some marker of impaired lung function. 140 00:05:12,110 --> 00:05:14,689 So that could have been, forced vital capacity 141 00:05:14,750 --> 00:05:18,029 less than 90% or predicted, a DLCO less 142 00:05:18,029 --> 00:05:19,089 than 70%, 143 00:05:19,485 --> 00:05:22,044 or a decrease in either of those in 144 00:05:22,044 --> 00:05:23,504 the preceding twelve months. 145 00:05:25,084 --> 00:05:27,004 And this is sort of to go in 146 00:05:27,004 --> 00:05:28,925 line with it it should be somebody who 147 00:05:28,925 --> 00:05:32,540 needs treatment for sarcoidosis, not somebody who is 148 00:05:32,540 --> 00:05:34,220 mild enough that they are going to go 149 00:05:34,220 --> 00:05:35,120 without treatment. 150 00:05:35,579 --> 00:05:38,060 They also excluded patients who are not treatment 151 00:05:38,060 --> 00:05:41,439 naive, who had received immunosuppression before, or patients 152 00:05:41,579 --> 00:05:42,079 who 153 00:05:42,540 --> 00:05:46,425 had the primary indication for treatment being extrapulmonary, 154 00:05:46,805 --> 00:05:47,785 such as neurosarcoidosis. 155 00:05:49,685 --> 00:05:51,205 The the only thing I'd add here, and 156 00:05:51,205 --> 00:05:53,365 and, Dave, to your point about how if 157 00:05:53,365 --> 00:05:55,525 you ask 10 pulmonologists how to manage sarcoid, 158 00:05:55,525 --> 00:05:57,205 you'll get, like, 11 answers. I don't know 159 00:05:57,205 --> 00:05:59,205 if if you guys' practice is different or 160 00:05:59,205 --> 00:06:01,125 if your experience with this is different, but 161 00:06:01,125 --> 00:06:03,360 I feel like the idea of an indication 162 00:06:03,500 --> 00:06:06,139 to treat for pulmonary sarcoid is also, in 163 00:06:06,139 --> 00:06:07,919 and of itself, like, kind of murky. 164 00:06:08,860 --> 00:06:11,019 You know, the obvious ones are obvious, but 165 00:06:11,019 --> 00:06:13,099 there's a lot of people that I've run 166 00:06:13,099 --> 00:06:15,099 into in fellowship who feel like feel pretty 167 00:06:15,099 --> 00:06:17,524 differently about some of the more moderate, moderately 168 00:06:17,524 --> 00:06:20,644 mildly symptomatic patients and whether steroids are really 169 00:06:20,644 --> 00:06:22,564 beneficial or not just because, you know, so 170 00:06:22,564 --> 00:06:23,544 many of these folks 171 00:06:24,004 --> 00:06:26,805 do get better without treatment over time. And 172 00:06:26,805 --> 00:06:28,644 so I think here, it's just worth kinda 173 00:06:28,644 --> 00:06:30,264 calling out that the 174 00:06:30,740 --> 00:06:33,460 indication for treatment was this quote unquote moderate 175 00:06:33,460 --> 00:06:35,220 or severe symptoms and then a risk of 176 00:06:35,220 --> 00:06:37,620 worsened health or death, which kinda when you 177 00:06:37,620 --> 00:06:39,699 look in a little more detail is mostly 178 00:06:39,699 --> 00:06:42,580 just extensive ILD or pulmonary hypertension, which feels 179 00:06:42,580 --> 00:06:44,100 a little more reasonable to me and a 180 00:06:44,100 --> 00:06:46,665 little less wishy washy. Yeah. I I think 181 00:06:46,665 --> 00:06:48,745 it's a really great point. I I think 182 00:06:48,745 --> 00:06:51,725 multiple things that you learn during pulmonary fellowship, 183 00:06:52,024 --> 00:06:53,725 and then on as a pulmonary attending 184 00:06:54,104 --> 00:06:56,264 are interesting about sarcoid. And you certainly nailed 185 00:06:56,264 --> 00:06:57,865 one of them is that most people don't 186 00:06:57,865 --> 00:07:00,104 need treatment, and especially the people who don't 187 00:07:00,104 --> 00:07:02,270 have pulmonary involvement, we'll have a ton of 188 00:07:02,270 --> 00:07:03,949 these people in your clinic who got a 189 00:07:03,949 --> 00:07:05,490 random CAT scan, had lymphadenopathy, 190 00:07:06,189 --> 00:07:07,009 got a biopsy, 191 00:07:07,389 --> 00:07:09,710 showed sarcoid, but they're otherwise fine. And you're 192 00:07:09,710 --> 00:07:11,949 mostly just watching because this usually is a 193 00:07:11,949 --> 00:07:14,189 process that, thankfully, and a lot of people 194 00:07:14,189 --> 00:07:15,975 burns out and then doesn't cause any other 195 00:07:16,055 --> 00:07:18,214 problems and maybe just left with some chronic 196 00:07:18,214 --> 00:07:18,714 sequelae. 197 00:07:19,014 --> 00:07:20,774 But so this is an interesting thing about 198 00:07:20,774 --> 00:07:22,935 trials in general is that we're gonna answer 199 00:07:22,935 --> 00:07:26,074 this non inferiority question about prednisone or methotrexate, 200 00:07:26,615 --> 00:07:28,535 but it also kind of gives you a 201 00:07:28,535 --> 00:07:30,774 nice guideline of how you should think about 202 00:07:30,774 --> 00:07:32,430 when I wanna treat somebody. You know, this 203 00:07:32,430 --> 00:07:34,350 trial is designed by people who are experts 204 00:07:34,350 --> 00:07:36,029 in the field. We're gonna look at the 205 00:07:36,029 --> 00:07:38,110 data, but they're gonna just look at outcomes 206 00:07:38,110 --> 00:07:40,830 going forward if you started treatment based on 207 00:07:40,830 --> 00:07:41,569 this indication. 208 00:07:42,270 --> 00:07:44,509 It's by no means a trial of these 209 00:07:44,509 --> 00:07:46,404 are the best indications to treat. Right? Like, 210 00:07:46,404 --> 00:07:48,165 we don't have three different options and we 211 00:07:48,165 --> 00:07:49,685 see how people do long term. But I 212 00:07:49,685 --> 00:07:52,004 do think it's a nice window for you 213 00:07:52,004 --> 00:07:53,365 to have going forward to say, hey. This 214 00:07:53,365 --> 00:07:54,884 was a trial for a patient who are 215 00:07:54,884 --> 00:07:57,444 treatment naive of sarcoid, who had some pulmonary 216 00:07:57,444 --> 00:07:59,759 involvement based on these metrics. And when I 217 00:07:59,759 --> 00:08:01,360 have a new patient, maybe I can match 218 00:08:01,360 --> 00:08:02,720 them up and say, would you have fit 219 00:08:02,720 --> 00:08:04,399 in this? Is you a person who should 220 00:08:04,399 --> 00:08:06,100 probably get some upfront immunomodulatory 221 00:08:06,480 --> 00:08:08,800 therapy? Yeah. I love it. Thank you, Dave. 222 00:08:08,800 --> 00:08:10,240 So maybe we talked about who they were 223 00:08:10,240 --> 00:08:11,680 trying to include and who they were trying 224 00:08:11,680 --> 00:08:13,600 to exclude. Do we wanna just quickly go 225 00:08:13,600 --> 00:08:14,100 through, 226 00:08:14,535 --> 00:08:16,295 their table one and kinda who was actually 227 00:08:16,295 --> 00:08:17,975 in the trial? And then we can maybe 228 00:08:17,975 --> 00:08:19,995 get through their methods and intervention. 229 00:08:21,415 --> 00:08:23,495 So, Robert, who did the Yeah. Manage to 230 00:08:23,495 --> 00:08:24,314 actually enroll? 231 00:08:25,495 --> 00:08:28,375 So based on these inclusion criteria where you 232 00:08:28,375 --> 00:08:30,790 had to have some changes in your pulmonary 233 00:08:30,790 --> 00:08:31,290 function, 234 00:08:31,590 --> 00:08:34,950 the mean FEV one was 70% predicted. The 235 00:08:34,950 --> 00:08:37,429 mean FVC was 77% 236 00:08:37,429 --> 00:08:40,230 predicted. Mean ratio was point seven two. Mean 237 00:08:40,230 --> 00:08:43,370 DLCO was 70% predicted. So these are kind 238 00:08:43,590 --> 00:08:44,169 of moderate 239 00:08:45,065 --> 00:08:45,884 to to mild, 240 00:08:46,424 --> 00:08:48,205 abnormalities in pulmonary function. 241 00:08:48,585 --> 00:08:50,184 Also, all the patients, again, because this is 242 00:08:50,184 --> 00:08:53,485 an included criterion, had pulmonary abnormalities and lymphadenopathy. 243 00:08:54,504 --> 00:08:57,209 For the demographics, importantly, the trial is conducted 244 00:08:57,209 --> 00:08:59,769 in The Netherlands, so they only had seven 245 00:08:59,769 --> 00:09:01,549 percent black patients, which is unfortunate. 246 00:09:02,089 --> 00:09:04,490 It was also not a particularly overweight group. 247 00:09:04,490 --> 00:09:06,889 Their mean BMI was twenty six point four, 248 00:09:06,889 --> 00:09:09,449 and that may may or may not translate 249 00:09:09,449 --> 00:09:11,445 to The United States. Yeah. I like it. 250 00:09:11,445 --> 00:09:12,004 I think, 251 00:09:12,485 --> 00:09:14,164 the only other things I'd call out because 252 00:09:14,164 --> 00:09:16,024 it, is the 253 00:09:16,565 --> 00:09:18,664 when you talk about their pulmonary or parenchymal 254 00:09:18,725 --> 00:09:21,764 abnormalities, there were interestingly lower overall rates of 255 00:09:21,764 --> 00:09:23,365 fibrosis in the group. I think it was 256 00:09:23,365 --> 00:09:25,679 around, like, ten to fourteen percent in the 257 00:09:25,679 --> 00:09:26,960 two arms. So it was a lot of, 258 00:09:26,960 --> 00:09:27,620 like, the, 259 00:09:28,399 --> 00:09:31,059 parenchymal involvement. I'm assuming a lot of nodular 260 00:09:31,200 --> 00:09:33,379 issues, but not a lot of frank fibrosis 261 00:09:33,440 --> 00:09:34,100 and scarring. 262 00:09:34,720 --> 00:09:37,215 And so, hopefully, theoretically, at least, like, a 263 00:09:37,215 --> 00:09:39,295 a place where an intervention may still have 264 00:09:39,295 --> 00:09:41,615 some time to be really effective in undoing 265 00:09:41,615 --> 00:09:42,595 some of that damage. 266 00:09:43,055 --> 00:09:44,735 The only other two things I'd mentioned too 267 00:09:44,735 --> 00:09:46,595 is that the epidemiology 268 00:09:46,975 --> 00:09:48,894 here was not quite what I would have 269 00:09:48,894 --> 00:09:49,394 expected, 270 00:09:49,855 --> 00:09:51,455 at least for a US cohort. I know 271 00:09:51,455 --> 00:09:52,915 this was not done in The US. 272 00:09:53,269 --> 00:09:55,769 So it was mostly men. There were around 273 00:09:56,070 --> 00:09:59,210 seventy percent plus male patients in the trial 274 00:09:59,669 --> 00:10:00,970 and were overwhelmingly 275 00:10:01,509 --> 00:10:02,410 white or Caucasian. 276 00:10:03,350 --> 00:10:05,350 And that's kind of the opposite, actually, I 277 00:10:05,350 --> 00:10:07,029 feel like, of what we see with sarcoid 278 00:10:07,029 --> 00:10:09,004 in The US where it's more common in 279 00:10:09,004 --> 00:10:11,024 black and in female patients. And so, 280 00:10:11,644 --> 00:10:14,045 I think helpful, Robert, that you called out 281 00:10:14,045 --> 00:10:15,805 some of these things that may or may 282 00:10:15,805 --> 00:10:17,644 not align with the patients that the three 283 00:10:17,644 --> 00:10:19,725 of us at least are more likely to 284 00:10:19,725 --> 00:10:21,024 see here in The US. 285 00:10:21,659 --> 00:10:23,659 So, Robert, can you tell us about what 286 00:10:23,659 --> 00:10:25,740 they ended up doing for these patients? What 287 00:10:25,740 --> 00:10:27,659 was the protocol for the two drugs? And 288 00:10:27,659 --> 00:10:29,259 then what kind of endpoints were they looking 289 00:10:29,259 --> 00:10:29,759 for? 290 00:10:31,019 --> 00:10:32,799 Yeah. The protocol was, 291 00:10:33,995 --> 00:10:34,654 a prespecified 292 00:10:35,595 --> 00:10:38,495 titration for, for both medications and 293 00:10:38,955 --> 00:10:41,754 globally, this was a decrease in prednisone over 294 00:10:41,754 --> 00:10:43,434 the study period, which was a twenty four 295 00:10:43,434 --> 00:10:46,735 week period. And they, they measured lung function, 296 00:10:47,850 --> 00:10:50,329 throughout the study period as well as quality 297 00:10:50,329 --> 00:10:51,230 of life measures, 298 00:10:52,649 --> 00:10:54,829 and an increase in methotrexate 299 00:10:55,289 --> 00:10:56,990 in the other arm. So 300 00:10:57,529 --> 00:10:59,370 they we went over the study period from 301 00:10:59,370 --> 00:11:01,610 forty milligrams a day of prednisone down to 302 00:11:01,610 --> 00:11:04,315 ten milligrams a day, and they went up 303 00:11:04,315 --> 00:11:06,495 from fifteen milligrams a week 304 00:11:06,795 --> 00:11:07,455 of methotrexate 305 00:11:08,075 --> 00:11:10,815 up to twenty five, milligrams a week. 306 00:11:11,355 --> 00:11:14,154 Forty milligrams is a relatively high starting dose 307 00:11:14,154 --> 00:11:14,894 of prednisone 308 00:11:15,690 --> 00:11:18,169 in reference to the SARCOI trial, which you 309 00:11:18,169 --> 00:11:19,070 previously covered, 310 00:11:19,690 --> 00:11:23,049 Lou. We put twenty milligrams of prednisolone seems 311 00:11:23,049 --> 00:11:25,610 non inferior to forty milligrams in that trial, 312 00:11:25,610 --> 00:11:27,309 and there's no difference in any outcome. 313 00:11:27,850 --> 00:11:29,370 But regardless, they try to get down to 314 00:11:29,370 --> 00:11:30,590 a lower dose of prednisone. 315 00:11:31,504 --> 00:11:33,904 And also anecdotally, I'd be curious to hear 316 00:11:33,904 --> 00:11:35,445 what would you think about this. 317 00:11:35,825 --> 00:11:37,105 The trying to get up to twenty five 318 00:11:37,105 --> 00:11:39,345 milligrams a week of methotrexate is a lot. 319 00:11:39,345 --> 00:11:40,865 As we'll talk about, not not a whole 320 00:11:40,865 --> 00:11:42,384 lot of the patients were actually able to 321 00:11:42,384 --> 00:11:44,084 achieve that dose in this trial. 322 00:11:45,210 --> 00:11:47,049 Yeah. I think it's a a great point. 323 00:11:47,049 --> 00:11:49,529 I have definitely seen it here, but I 324 00:11:49,529 --> 00:11:50,590 don't know that I, 325 00:11:51,289 --> 00:11:53,389 see it in the kind of standard protocolized 326 00:11:53,610 --> 00:11:54,970 way that they were doing it in the 327 00:11:54,970 --> 00:11:56,830 trial. Like, I feel like when I've seen 328 00:11:57,044 --> 00:11:57,544 Methotrexate 329 00:11:57,924 --> 00:12:00,424 pushed beyond fifteen, because that's typically also, 330 00:12:01,284 --> 00:12:02,904 around where we're starting, is, 331 00:12:03,845 --> 00:12:06,884 someone who really tolerates it really well and 332 00:12:06,884 --> 00:12:08,184 has partial improvement. 333 00:12:09,204 --> 00:12:11,899 But it's not a kinda across the board 334 00:12:12,039 --> 00:12:13,720 dose increase that we're doing in a, like, 335 00:12:13,720 --> 00:12:15,100 a rigid way here. 336 00:12:16,200 --> 00:12:17,960 Yeah. I I I think the risk of 337 00:12:17,960 --> 00:12:19,960 going blindly towards a high dose like that 338 00:12:19,960 --> 00:12:21,559 is that someone has side effects, they don't 339 00:12:21,559 --> 00:12:23,080 tolerate it, and then they wanna stop the 340 00:12:23,080 --> 00:12:24,139 medication altogether, 341 00:12:24,725 --> 00:12:25,925 which is you run a little bit of 342 00:12:25,925 --> 00:12:27,445 a less risk in a trial where you're 343 00:12:27,445 --> 00:12:29,045 sort of in a well communication and well 344 00:12:29,045 --> 00:12:31,365 monitored status, but probably is why in in 345 00:12:31,365 --> 00:12:32,264 clinical practice, 346 00:12:32,644 --> 00:12:34,404 we really usually get to a lower dose 347 00:12:34,404 --> 00:12:36,085 and then sort of assess where we are 348 00:12:36,085 --> 00:12:37,870 a bit. Although, as you guys already talked 349 00:12:37,870 --> 00:12:39,710 about, that can be tough with methotrexate, which 350 00:12:39,710 --> 00:12:41,309 takes a little while to act. Right? Because 351 00:12:41,309 --> 00:12:43,070 you might have to be patient and and 352 00:12:43,070 --> 00:12:44,990 wait for that to kick in. Right. And 353 00:12:44,990 --> 00:12:46,529 and I did like that they had 354 00:12:47,950 --> 00:12:48,929 established protocol 355 00:12:49,465 --> 00:12:50,985 for dealing with some of the side effects, 356 00:12:50,985 --> 00:12:52,284 so switching to subcutaneous 357 00:12:52,585 --> 00:12:55,784 methotrexate, which is better tolerated, reducing the dosage 358 00:12:55,784 --> 00:12:57,485 before actually crossing over. 359 00:12:57,865 --> 00:12:59,804 So what outcomes were they looking for? 360 00:13:00,825 --> 00:13:03,404 The primary endpoint was change in FVC 361 00:13:04,179 --> 00:13:06,660 over the study period. We talked about the 362 00:13:06,660 --> 00:13:08,040 limitations of this metric 363 00:13:08,660 --> 00:13:10,259 in when we talked about the, 364 00:13:11,220 --> 00:13:12,920 impulsive trials for IPF. 365 00:13:13,940 --> 00:13:16,259 FVC is known to correlate with mortality in 366 00:13:16,259 --> 00:13:18,440 the setting of interstitial lung disease. 367 00:13:19,495 --> 00:13:21,815 I wasn't able to find anything about, in 368 00:13:21,815 --> 00:13:25,095 sarcoidosis specifically, how it matches up, although we 369 00:13:25,095 --> 00:13:27,674 have some indication that in the general population, 370 00:13:28,134 --> 00:13:30,134 lung function is important over the course of 371 00:13:30,134 --> 00:13:30,714 a lifetime. 372 00:13:31,179 --> 00:13:33,259 And, you know, I think the FEC as, 373 00:13:33,259 --> 00:13:36,379 or as an outcome is an interesting one 374 00:13:36,379 --> 00:13:39,420 and reasonable in this standard for, a couple 375 00:13:39,420 --> 00:13:41,340 of reasons. The first is that, you know, 376 00:13:41,340 --> 00:13:45,095 obviously we think physiologically, it makes sense that 377 00:13:45,154 --> 00:13:46,674 a metric like this that we're measuring will 378 00:13:46,674 --> 00:13:49,315 be correlated with disease severity. But also if 379 00:13:49,315 --> 00:13:51,095 you were trying to look in this population 380 00:13:51,154 --> 00:13:53,875 at a more clinically meaningful outcome, you would 381 00:13:53,875 --> 00:13:56,034 need huge numbers because, like, this is a 382 00:13:56,034 --> 00:13:58,110 pretty healthy population. So you're not gonna have 383 00:13:58,110 --> 00:14:00,509 mortality. Right? You're probably not even gonna have 384 00:14:00,509 --> 00:14:01,009 hospitalization. 385 00:14:01,389 --> 00:14:02,290 Right? And so, 386 00:14:02,750 --> 00:14:04,690 if you were trying to look for something, 387 00:14:04,830 --> 00:14:07,309 you know, clinically impactful like we often do, 388 00:14:07,309 --> 00:14:09,470 you would just need enormous numbers given the 389 00:14:09,470 --> 00:14:10,990 rate of event would be so low. So 390 00:14:10,990 --> 00:14:13,375 I think choosing a physiologic metric, while it 391 00:14:13,375 --> 00:14:15,134 might have its own limitations, makes a lot 392 00:14:15,134 --> 00:14:15,714 of sense. 393 00:14:16,495 --> 00:14:19,375 Absolutely. Especially with a disease like sarcoid that's, 394 00:14:19,375 --> 00:14:21,375 like, not all that common in and of 395 00:14:21,375 --> 00:14:23,875 itself. You know? I feel like there's always 396 00:14:23,934 --> 00:14:24,434 this 397 00:14:24,975 --> 00:14:27,534 tug of war between what's practically doable and 398 00:14:27,534 --> 00:14:28,595 what's, like, the optimal 399 00:14:29,190 --> 00:14:31,350 outcome or steady design, and I I kinda 400 00:14:31,350 --> 00:14:32,009 feel like, 401 00:14:32,470 --> 00:14:35,210 maybe that's what was done here just given 402 00:14:35,269 --> 00:14:37,429 the overall rates of sarcoid in a population. 403 00:14:37,429 --> 00:14:38,009 You know? 404 00:14:38,549 --> 00:14:41,029 Hundred percent. And another important point is that 405 00:14:41,029 --> 00:14:42,389 they did get at some of these more 406 00:14:42,389 --> 00:14:45,065 patient centered outcomes with the health related quality 407 00:14:45,065 --> 00:14:46,985 of life. So it it's not as if 408 00:14:46,985 --> 00:14:48,605 we're only looking at FVC. 409 00:14:49,225 --> 00:14:50,044 Yeah. Absolutely. 410 00:14:50,424 --> 00:14:52,264 Well, in regards to FVC, this is a 411 00:14:52,264 --> 00:14:54,345 non inferiority trial. So, Robert, can you maybe 412 00:14:54,345 --> 00:14:56,024 just walk us through that a little bit, 413 00:14:56,024 --> 00:14:57,644 what they chose and what that means? 414 00:14:58,860 --> 00:14:59,360 Sure. 415 00:14:59,980 --> 00:15:02,000 So most trials are superiority trials. 416 00:15:02,460 --> 00:15:04,620 That means that the whole confidence interval has 417 00:15:04,620 --> 00:15:05,120 to 418 00:15:05,500 --> 00:15:07,440 go on one side of of the null, 419 00:15:08,779 --> 00:15:11,605 and implies that one drug is better than 420 00:15:11,605 --> 00:15:14,485 the other. A non inferiority trial is instead 421 00:15:14,485 --> 00:15:16,644 asking the question, is this drug not that 422 00:15:16,644 --> 00:15:18,965 much worse than another drug trial? And you 423 00:15:18,965 --> 00:15:20,644 pick a non inferiority margin, 424 00:15:21,285 --> 00:15:22,425 which is the 425 00:15:22,965 --> 00:15:26,200 boundary beyond which one drug is unacceptably worse 426 00:15:26,200 --> 00:15:26,519 than. 427 00:15:28,039 --> 00:15:29,659 The trick is that you have to pick 428 00:15:29,720 --> 00:15:31,500 this number. And so, 429 00:15:32,759 --> 00:15:33,419 it wasn't 430 00:15:34,440 --> 00:15:37,000 entirely clear to me why they picked 5% 431 00:15:37,000 --> 00:15:37,899 in this trial. 432 00:15:38,504 --> 00:15:40,745 They they said in their supplement because FEC 433 00:15:40,745 --> 00:15:43,384 measurements show biologic variation, and variation less than 434 00:15:43,384 --> 00:15:45,485 5% is not considered clinically relevant. 435 00:15:46,024 --> 00:15:48,985 Five to me, 5% seems pretty small, actually, 436 00:15:48,985 --> 00:15:50,745 so that it's a pretty stringent margin. I'd 437 00:15:50,745 --> 00:15:52,445 be curious to see what you all think. 438 00:15:54,450 --> 00:15:56,309 But, that's how they set up the trial. 439 00:15:57,649 --> 00:15:59,570 Yeah. I think that's that's reasonable enough. I 440 00:15:59,570 --> 00:16:01,330 think somewhere in that, like, five to 10% 441 00:16:01,330 --> 00:16:04,289 range decline in in FEC is often what 442 00:16:04,289 --> 00:16:06,850 it'd take to be a significant change. And 443 00:16:06,850 --> 00:16:07,350 so, 444 00:16:08,304 --> 00:16:09,664 somewhere on the lower bound of that, but 445 00:16:09,664 --> 00:16:11,825 I still think, you know, overall, a relatively 446 00:16:11,825 --> 00:16:14,705 reasonable cut reasonable cut point here. So, Robert, 447 00:16:14,705 --> 00:16:16,065 we talked a little bit about what they 448 00:16:16,065 --> 00:16:17,745 did and who was in the trial. What 449 00:16:17,745 --> 00:16:18,565 did they find? 450 00:16:19,105 --> 00:16:20,784 The top line result of this trial was 451 00:16:20,784 --> 00:16:21,629 that methotrexate 452 00:16:22,009 --> 00:16:22,909 was noninferior 453 00:16:23,370 --> 00:16:24,110 to prednisone 454 00:16:24,569 --> 00:16:25,549 for FVC 455 00:16:26,329 --> 00:16:27,789 at twenty four weeks. 456 00:16:28,329 --> 00:16:30,409 The between group difference in least squares mean 457 00:16:30,409 --> 00:16:33,389 change was minus 1.17 percentage points favoring prednisone. 458 00:16:34,514 --> 00:16:36,835 They also break down the differences between groups 459 00:16:36,835 --> 00:16:38,195 by week as there were a lot of 460 00:16:38,195 --> 00:16:40,355 questions as to the time to effect of 461 00:16:40,355 --> 00:16:42,215 methotrexate as compared with prednisone. 462 00:16:42,915 --> 00:16:45,634 And it seems at the beginning of the 463 00:16:45,634 --> 00:16:48,670 trial that prednisone does better in terms of 464 00:16:48,670 --> 00:16:50,990 changes in FVC as well as quality of 465 00:16:50,990 --> 00:16:51,490 life. 466 00:16:52,029 --> 00:16:53,970 And then throughout the trial, those 467 00:16:54,590 --> 00:16:56,769 changes kind of, even out. 468 00:16:57,149 --> 00:16:58,450 In terms of other outcomes, 469 00:16:58,910 --> 00:17:00,290 adherence was a 470 00:17:01,274 --> 00:17:03,434 challenge in this trial. We knew that people 471 00:17:03,434 --> 00:17:05,835 were going to have difficulty tolerating both of 472 00:17:05,835 --> 00:17:08,234 these drugs, and there was a significant number 473 00:17:08,234 --> 00:17:10,575 who crossed over in both groups. 474 00:17:11,755 --> 00:17:12,255 So 475 00:17:12,569 --> 00:17:14,490 nine out of seventy patients in the prednisone 476 00:17:14,490 --> 00:17:17,549 group had methotrexate added to their regimen and 477 00:17:17,690 --> 00:17:19,950 eight out of sixty eight switched to prednisone 478 00:17:20,169 --> 00:17:21,470 due to an adverse effect. 479 00:17:21,849 --> 00:17:24,169 So this presents a challenge for interpretation of 480 00:17:24,169 --> 00:17:25,470 the results, right, because 481 00:17:26,095 --> 00:17:28,434 the crossover between groups in a non inferiority 482 00:17:28,575 --> 00:17:30,815 trial make the groups look more similar. It'll 483 00:17:30,815 --> 00:17:31,955 make the treatment 484 00:17:32,335 --> 00:17:33,394 look non inferior. 485 00:17:34,095 --> 00:17:35,615 Yeah. I think it's a good point. I 486 00:17:35,615 --> 00:17:37,855 think it's interesting too as this maybe we 487 00:17:37,855 --> 00:17:39,535 can segue a little bit into thinking about 488 00:17:39,535 --> 00:17:41,109 safety because, you know, so many of our 489 00:17:41,109 --> 00:17:42,809 drugs have these tough side effects. 490 00:17:43,269 --> 00:17:44,789 But, yeah, to your point, if there's a 491 00:17:44,789 --> 00:17:46,549 lot of crossover, which I think this is 492 00:17:46,549 --> 00:17:49,109 definitely a a fair amount of, I think 493 00:17:49,109 --> 00:17:50,630 it's not so high that it makes it, 494 00:17:50,630 --> 00:17:51,369 like, uninterpretable 495 00:17:51,829 --> 00:17:53,795 for me. But I do think it's it 496 00:17:53,795 --> 00:17:55,795 is something to keep in mind that when 497 00:17:55,795 --> 00:17:57,654 you have that much crossover, you're effectively 498 00:17:58,195 --> 00:18:00,755 not really treating the two groups all that 499 00:18:00,755 --> 00:18:02,355 differently. And so to your point, it can 500 00:18:02,355 --> 00:18:03,255 push you towards 501 00:18:03,714 --> 00:18:05,974 not being able to show a meaningful difference. 502 00:18:07,299 --> 00:18:08,740 I want to dive into some of the 503 00:18:08,740 --> 00:18:10,759 differences we see in the results on timing, 504 00:18:10,900 --> 00:18:13,220 right? So you talked about the overall results, 505 00:18:13,220 --> 00:18:14,759 Robert, that the top line, 506 00:18:15,140 --> 00:18:16,980 but there were some things that looked like 507 00:18:16,980 --> 00:18:18,339 they might be a little bit different in 508 00:18:18,339 --> 00:18:19,859 timing of the impact of these. Can you 509 00:18:19,859 --> 00:18:20,920 comment on that? 510 00:18:23,365 --> 00:18:25,144 Yeah. So in general, 511 00:18:25,684 --> 00:18:27,765 the thought that people had before the study 512 00:18:27,765 --> 00:18:30,484 that prednisone works faster, I think was born 513 00:18:30,484 --> 00:18:32,904 out by these data. They have four different, 514 00:18:33,605 --> 00:18:36,025 versions of quality of life metrics 515 00:18:36,809 --> 00:18:39,690 and all four of them favor prednisone at 516 00:18:39,690 --> 00:18:41,230 the four week time point. 517 00:18:41,690 --> 00:18:43,450 But then as the trial goes on, you 518 00:18:43,450 --> 00:18:44,909 see less and less of that. 519 00:18:45,849 --> 00:18:47,309 Could that be due to crossover? 520 00:18:47,929 --> 00:18:50,954 Maybe. But in general, the confidence interval start 521 00:18:50,954 --> 00:18:51,615 to inter 522 00:18:51,914 --> 00:18:54,795 to overlap between prednisone and methotrexate later on 523 00:18:54,795 --> 00:18:55,535 in the trial. 524 00:18:55,914 --> 00:18:58,954 That that's also true for the FEC, the 525 00:18:58,954 --> 00:18:59,855 primary endpoint. 526 00:19:00,875 --> 00:19:01,375 Corey. 527 00:19:02,569 --> 00:19:04,410 Yeah. I think one thing that's kinda hard 528 00:19:04,410 --> 00:19:06,569 for me about some of the secondary outcomes 529 00:19:06,569 --> 00:19:08,490 that you're talking about is that they ran 530 00:19:08,490 --> 00:19:10,809 a lot of tests in this trial. Like, 531 00:19:10,809 --> 00:19:13,450 they ran more than 14 of them, and 532 00:19:13,450 --> 00:19:15,950 they did not control for multiplicity. And so 533 00:19:16,170 --> 00:19:17,470 I think it can be helpful, 534 00:19:18,794 --> 00:19:20,315 in a saying here where it seems like 535 00:19:20,315 --> 00:19:21,755 things are all kind of pointing in the 536 00:19:21,755 --> 00:19:22,494 same direction 537 00:19:22,875 --> 00:19:24,474 that maybe I'm a little less concerned. But 538 00:19:24,474 --> 00:19:25,835 I always have kind of nagging in the 539 00:19:25,835 --> 00:19:27,434 back of my mind that, like, you know, 540 00:19:27,434 --> 00:19:29,134 if you run enough tests, eventually, 541 00:19:29,674 --> 00:19:32,075 you'll find some things that are statistically different. 542 00:19:32,075 --> 00:19:33,534 And it makes me wonder whether 543 00:19:33,970 --> 00:19:35,430 some of the outcomes 544 00:19:36,210 --> 00:19:38,210 some of the differences in the outcomes early 545 00:19:38,210 --> 00:19:39,269 may have just been 546 00:19:39,650 --> 00:19:41,509 some statistical noise. 547 00:19:41,890 --> 00:19:43,330 Yeah. It's a great point. You always have 548 00:19:43,330 --> 00:19:44,690 to sort of think about how much we're 549 00:19:44,690 --> 00:19:46,769 looking at. I think the night the interesting 550 00:19:46,769 --> 00:19:47,414 thing here 551 00:19:47,815 --> 00:19:49,275 too, going into it, is that mechanistically, 552 00:19:49,654 --> 00:19:51,815 some of this might make sense. Right? With 553 00:19:51,815 --> 00:19:54,615 mprednisone having, as you guys mentioned, that right 554 00:19:54,615 --> 00:19:56,634 up front, people feel a lot better. 555 00:19:57,494 --> 00:20:00,450 You know, anecdotally, that especially the, like, just 556 00:20:00,529 --> 00:20:02,369 feeling of it maybe wears off for a 557 00:20:02,369 --> 00:20:04,130 little bit but then also methotrexate takes some 558 00:20:04,130 --> 00:20:05,970 time to kick in and so maybe these 559 00:20:05,970 --> 00:20:07,730 two groups get closer together by the end 560 00:20:07,730 --> 00:20:10,210 of the end of the treatment period. Yeah. 561 00:20:10,210 --> 00:20:12,450 I think it's worth talking about too, if 562 00:20:12,450 --> 00:20:14,945 we're thinking about, you know, if if our 563 00:20:14,945 --> 00:20:17,105 takeaway seems to be that there's ultimately in 564 00:20:17,105 --> 00:20:18,705 the long run, maybe not a huge difference 565 00:20:18,705 --> 00:20:20,705 between the two medications, but there's some changes 566 00:20:20,705 --> 00:20:22,465 in timing. I think it's worth talking about 567 00:20:22,465 --> 00:20:24,225 the side effect profiles of the two drugs 568 00:20:24,225 --> 00:20:26,465 because they were pretty different and that could, 569 00:20:26,465 --> 00:20:28,644 you know, weigh pretty heavily into your counseling 570 00:20:28,705 --> 00:20:29,365 of patients. 571 00:20:30,059 --> 00:20:31,839 So, Robert, I'm wondering if you could kinda 572 00:20:31,899 --> 00:20:33,579 help us think through the side effects that 573 00:20:33,579 --> 00:20:34,559 folks were experiencing. 574 00:20:35,500 --> 00:20:37,980 Sure. Side effects were very common in both 575 00:20:37,980 --> 00:20:40,539 groups. Ninety six percent of the prednisone patients 576 00:20:40,539 --> 00:20:42,859 and ninety four percent of the methotrexate patients 577 00:20:42,859 --> 00:20:45,664 had some adverse effect. Most of them were 578 00:20:45,664 --> 00:20:47,845 mild, so lots of insomnia in the prednisone 579 00:20:47,904 --> 00:20:50,785 group. The methotrexate patients had more headache, cough, 580 00:20:50,785 --> 00:20:51,285 rash. 581 00:20:52,144 --> 00:20:54,884 The known side effect profile of methotrexate 582 00:20:55,184 --> 00:20:57,684 is established in other diseases. It causes GI 583 00:20:57,970 --> 00:21:00,870 symptoms, LFT abnormalities, moles, nausea, fatigue. 584 00:21:02,130 --> 00:21:02,950 What actually, 585 00:21:03,890 --> 00:21:05,650 happened in the trial, though, is that about 586 00:21:05,650 --> 00:21:07,410 twenty five percent of the patients treated with 587 00:21:07,410 --> 00:21:09,910 mastrexate had liver enzyme elevation, 588 00:21:10,515 --> 00:21:13,255 and two patients stopped the drug because of 589 00:21:13,714 --> 00:21:14,214 them. 590 00:21:14,595 --> 00:21:16,295 The authors highlight three, 591 00:21:17,234 --> 00:21:20,934 serious adverse events related to treatment, two respiratory 592 00:21:21,154 --> 00:21:23,714 infections, and one episode of gastroenteritis in the 593 00:21:23,714 --> 00:21:26,960 methotrexate group, and just one episode of treatment, 594 00:21:26,960 --> 00:21:29,460 immersion of diabetes in the prednisone group. 595 00:21:29,839 --> 00:21:32,480 And so the serious adverse events were low 596 00:21:32,480 --> 00:21:32,980 overall. 597 00:21:33,279 --> 00:21:35,119 In the methotrexate group, eight out of the 598 00:21:35,119 --> 00:21:37,220 sixty day patients had to switch to prednisone 599 00:21:37,519 --> 00:21:40,075 due to an adverse effect that included six 600 00:21:40,075 --> 00:21:42,414 GI side effects, two with LFT abnormalities. 601 00:21:44,315 --> 00:21:46,394 And then, five of the sixty eight had 602 00:21:46,394 --> 00:21:48,634 progressive disease or cough and had prednisone added 603 00:21:48,634 --> 00:21:49,134 on. 604 00:21:49,994 --> 00:21:51,515 Nine out of the seventy patients in the 605 00:21:51,515 --> 00:21:53,054 prednisone group had methotrexate 606 00:21:53,434 --> 00:21:53,934 added. 607 00:21:54,990 --> 00:21:56,210 Overall, I thought there was 608 00:21:56,670 --> 00:21:59,309 a reasonable side effect profile and that, 609 00:22:00,509 --> 00:22:02,029 that most of the side effects were able 610 00:22:02,029 --> 00:22:03,710 to be managed, but some patients didn't have 611 00:22:03,710 --> 00:22:04,690 to cross over. 612 00:22:05,230 --> 00:22:07,575 Yeah. And I think, this really just underscores 613 00:22:07,575 --> 00:22:09,255 how important it was that they spelled out 614 00:22:09,255 --> 00:22:11,095 how they were going to deal with side 615 00:22:11,095 --> 00:22:13,414 effects up in their protocol. Just when you 616 00:22:13,414 --> 00:22:15,654 see that, you know, ninety five percent of 617 00:22:15,654 --> 00:22:17,035 patients give or take, 618 00:22:17,414 --> 00:22:19,255 in the trial had some kind of side 619 00:22:19,255 --> 00:22:19,755 effect. 620 00:22:20,149 --> 00:22:21,909 I think one thing that was interesting to 621 00:22:21,909 --> 00:22:22,490 me too, 622 00:22:23,029 --> 00:22:25,210 here is that the side effects from methotrexate 623 00:22:25,429 --> 00:22:27,509 seemed more transient. Like they seemed to go 624 00:22:27,509 --> 00:22:29,750 away by week twenty four at a slightly 625 00:22:29,750 --> 00:22:32,069 higher rate. About two thirds of them had 626 00:22:32,069 --> 00:22:34,630 resolved at week twenty four with methotrexate, whereas 627 00:22:34,630 --> 00:22:37,424 a little under fifty percent had resolved at 628 00:22:37,424 --> 00:22:38,805 week twenty four with prednisone. 629 00:22:39,585 --> 00:22:41,045 And I don't know that I 630 00:22:41,585 --> 00:22:42,085 have 631 00:22:43,105 --> 00:22:46,085 a great explanation for that other than whether, 632 00:22:46,224 --> 00:22:48,384 like, weight gain just takes a long time 633 00:22:48,384 --> 00:22:50,230 to go away. And maybe that's what part 634 00:22:50,230 --> 00:22:52,569 of what we're seeing. The, like, prednisone group, 635 00:22:53,589 --> 00:22:56,169 on average gained, like, five kilos in weight. 636 00:22:56,789 --> 00:22:58,149 And it could just be that it you 637 00:22:58,149 --> 00:22:59,909 know, that's a thing that's gonna linger with 638 00:22:59,909 --> 00:23:01,529 people, as I am unfortunately 639 00:23:01,829 --> 00:23:04,069 quite familiar with, that weight loss can take 640 00:23:04,069 --> 00:23:04,649 some time. 641 00:23:05,125 --> 00:23:08,184 I generally think of prednisone as dose related 642 00:23:08,404 --> 00:23:10,804 side effect drug. Some of it is about 643 00:23:10,804 --> 00:23:13,924 cumulative lifetime prednisone dosing, but also the longer 644 00:23:13,924 --> 00:23:15,444 you're on it, the more some of those 645 00:23:15,444 --> 00:23:17,125 issues start to rear their head too. Now 646 00:23:17,125 --> 00:23:18,724 we all have had people who get it 647 00:23:18,724 --> 00:23:20,769 right away and can't sleep at all. But 648 00:23:20,769 --> 00:23:22,450 sometimes if the it's gonna be more of 649 00:23:22,450 --> 00:23:24,130 the insidious side effects, like some of the 650 00:23:24,130 --> 00:23:25,829 weight gain, skin striations, 651 00:23:26,289 --> 00:23:27,990 like change to, adiposity 652 00:23:28,289 --> 00:23:30,609 deposits, like, that is like no one notices 653 00:23:30,609 --> 00:23:32,210 in the first week or two weeks or 654 00:23:32,210 --> 00:23:34,210 three weeks, but then they start to, keep 655 00:23:34,210 --> 00:23:35,804 an eye on it later. I also think 656 00:23:35,804 --> 00:23:36,304 methotrexate 657 00:23:36,605 --> 00:23:38,605 is one drug that you get at first, 658 00:23:38,605 --> 00:23:40,444 and then you kinda maybe feel not great. 659 00:23:40,444 --> 00:23:41,964 And then as you sort of settle into 660 00:23:41,964 --> 00:23:43,724 it, it's a pretty well tolerated drug. So 661 00:23:43,724 --> 00:23:45,345 that could help explain it as well. 662 00:23:47,164 --> 00:23:48,284 So I'll kick it to both of you 663 00:23:48,284 --> 00:23:49,799 guys. We've talked about a lot of great 664 00:23:49,799 --> 00:23:50,940 stuff. We talked about 665 00:23:51,559 --> 00:23:53,400 the outcomes. We talked about the adverse effects. 666 00:23:53,400 --> 00:23:55,320 We talked about, some of the some of 667 00:23:55,320 --> 00:23:57,960 the crossover between this. Other major discussion points 668 00:23:57,960 --> 00:23:59,320 that you think people should keep in mind 669 00:23:59,320 --> 00:24:01,480 when they're interpreting this trial or things that 670 00:24:01,559 --> 00:24:03,480 either limitations or just kind of points of 671 00:24:03,480 --> 00:24:05,964 interest that you guys noted. Yeah. A couple 672 00:24:05,964 --> 00:24:07,804 of things that came up for me. I'll 673 00:24:07,804 --> 00:24:10,605 just highlight the the fact that our US 674 00:24:10,605 --> 00:24:12,865 population is a little bit different. Right? Specifically, 675 00:24:13,005 --> 00:24:15,325 the incidence of metabolic syndrome is higher. The 676 00:24:15,325 --> 00:24:17,740 average BMI is higher. So that that may 677 00:24:17,740 --> 00:24:20,720 affect the adverse effect profile of prednisone specifically. 678 00:24:21,500 --> 00:24:22,859 The other thing about this trial is that 679 00:24:22,859 --> 00:24:25,599 it was twenty four weeks long, and we 680 00:24:25,660 --> 00:24:27,339 really wanna know what are the changes in 681 00:24:27,339 --> 00:24:29,599 the long term in somebody's lung function? What 682 00:24:29,704 --> 00:24:32,204 what are the the rates of exacerbations 683 00:24:32,505 --> 00:24:33,005 and 684 00:24:33,305 --> 00:24:33,805 hospitalization 685 00:24:34,265 --> 00:24:36,505 and ultimately more mortality with, 686 00:24:37,065 --> 00:24:38,924 sticking to one strategy or another. 687 00:24:40,984 --> 00:24:42,960 The the other, I think, elephant in the 688 00:24:42,960 --> 00:24:44,720 room is that a lot of experts are 689 00:24:44,720 --> 00:24:47,220 using upfront combined abatrazate 690 00:24:47,599 --> 00:24:48,579 and prednisone. 691 00:24:49,680 --> 00:24:51,700 This trial didn't address that directly. 692 00:24:52,400 --> 00:24:54,319 So I'm curious what what your all thoughts 693 00:24:54,319 --> 00:24:56,180 are about where do we go from here. 694 00:24:56,365 --> 00:24:58,125 Yeah. I agree. I think, ultimately, one of 695 00:24:58,125 --> 00:25:00,204 my takeaways here is that both these drugs 696 00:25:00,204 --> 00:25:02,444 seem to work, but prednisone maybe works faster 697 00:25:02,444 --> 00:25:04,605 with at the cost of maybe some more 698 00:25:04,605 --> 00:25:05,345 side effects. 699 00:25:05,724 --> 00:25:07,804 It makes me wonder whether a shorter birth 700 00:25:07,964 --> 00:25:08,865 burst of prednisone, 701 00:25:09,409 --> 00:25:11,089 maybe at a lower dose, like, you know, 702 00:25:11,089 --> 00:25:13,669 where the this trial was designed before, 703 00:25:14,369 --> 00:25:14,869 SarQuart 704 00:25:15,250 --> 00:25:17,009 was released, which we talked about earlier on 705 00:25:17,009 --> 00:25:18,929 the podcast, but that showed no difference in 706 00:25:18,929 --> 00:25:19,429 efficacy. 707 00:25:20,130 --> 00:25:22,289 Though admittedly side effects either between forty and 708 00:25:22,289 --> 00:25:23,750 twenty milligrams of prednisone. 709 00:25:24,335 --> 00:25:26,255 So I wonder whether maybe a lower dose 710 00:25:26,255 --> 00:25:28,815 with a shorter burst of prednisone upfront could 711 00:25:28,815 --> 00:25:31,375 capture some of that early improvement benefit and 712 00:25:31,375 --> 00:25:34,275 then kind of transitioning quickly into the therapeutic 713 00:25:34,335 --> 00:25:36,575 effect of methotrexate. And maybe that captures the 714 00:25:36,575 --> 00:25:38,821 best of both worlds, but I don't know 715 00:25:38,821 --> 00:25:41,144 that I have enough data to make an 716 00:25:41,144 --> 00:25:43,468 informed statement about it. So that is something 717 00:25:43,468 --> 00:25:45,792 I would love to see in the future 718 00:25:45,792 --> 00:25:48,115 here. Yeah. You're hitting the nail ahead. Often 719 00:25:48,115 --> 00:25:50,439 on Rapid Fire Journal Club, we are using 720 00:25:50,439 --> 00:25:52,763 practice defining trials. Right? Like, this is, like, 721 00:25:52,763 --> 00:25:54,565 what we do now. I think this is 722 00:25:54,565 --> 00:25:56,565 different. I think this is an exciting time 723 00:25:56,565 --> 00:25:58,644 for Sarcoid in that we are doing there 724 00:25:58,644 --> 00:26:00,485 are two sets of trials out there. There 725 00:26:00,485 --> 00:26:02,325 are novel therapeutics that are coming out that 726 00:26:02,325 --> 00:26:04,325 are working their way through phases one, two, 727 00:26:04,325 --> 00:26:06,485 and coming up to three. And then there 728 00:26:06,485 --> 00:26:09,045 are now these, like, breed trials, Sarcoort, this 729 00:26:09,045 --> 00:26:11,490 one, where we're actually looking at the upfront 730 00:26:11,630 --> 00:26:13,869 routine management. These are not new drugs. We've 731 00:26:13,869 --> 00:26:15,549 been doing this for a long time, but 732 00:26:15,549 --> 00:26:17,070 trying to hone in on what might be 733 00:26:17,070 --> 00:26:17,890 the best protocols. 734 00:26:18,509 --> 00:26:20,430 So I think we can say from this 735 00:26:20,430 --> 00:26:22,509 trial that it seems in a pretty well 736 00:26:22,509 --> 00:26:24,849 conducted trial that in terms of efficacy reduction, 737 00:26:25,234 --> 00:26:28,115 that there's non inferiority between these two drugs 738 00:26:28,115 --> 00:26:29,955 and that maybe there's a little bit difference 739 00:26:29,955 --> 00:26:30,695 in the timing. 740 00:26:31,234 --> 00:26:33,154 But Robert, your question is very valid. It's 741 00:26:33,154 --> 00:26:34,914 like, does that change what I'm gonna do? 742 00:26:34,914 --> 00:26:36,994 Or am I gonna do a different third 743 00:26:36,994 --> 00:26:38,595 option, which is a combination of these two 744 00:26:38,595 --> 00:26:40,679 drugs that I think works really well? We 745 00:26:40,679 --> 00:26:42,599 are planning on some episodes here on Paul 746 00:26:42,599 --> 00:26:43,740 and Pepys on this, 747 00:26:44,119 --> 00:26:44,619 on 748 00:26:45,000 --> 00:26:47,500 sarcoid treatment. And I would divide it into 749 00:26:47,799 --> 00:26:50,460 mild or early pranquebel lung disease and sarcoid, 750 00:26:50,519 --> 00:26:52,779 and then sort of advanced progressive fibrosis 751 00:26:53,079 --> 00:26:55,240 disease associated with sarcoid. So please stay tuned 752 00:26:55,240 --> 00:26:57,204 to those. And Robert and Luke, you'll both 753 00:26:57,204 --> 00:26:59,284 be invited to join for that to continue 754 00:26:59,284 --> 00:27:01,444 this discussion. But I think that your question 755 00:27:01,444 --> 00:27:03,605 hones in on this is, this trial you 756 00:27:03,605 --> 00:27:05,224 should know as a Poem Fellow. 757 00:27:05,525 --> 00:27:07,924 Does it, is it practice defining? Does it 758 00:27:07,924 --> 00:27:09,910 change or do things? Probably not yet. It's 759 00:27:09,910 --> 00:27:12,230 just gonna be in informational into some of 760 00:27:12,230 --> 00:27:14,809 these expert discussions going forward, I would think. 761 00:27:15,190 --> 00:27:17,450 It also serves as a scaffold for 762 00:27:17,990 --> 00:27:20,390 future trials. As we talked about, there there's 763 00:27:20,390 --> 00:27:22,809 no established protocols out there, 764 00:27:23,815 --> 00:27:26,394 for define one, for defining who gets treatment 765 00:27:26,455 --> 00:27:28,855 is challenging and then for, 766 00:27:29,414 --> 00:27:30,555 having established 767 00:27:31,015 --> 00:27:32,235 TAPRs. So now 768 00:27:32,855 --> 00:27:34,934 future clinical trials can refine on what they 769 00:27:34,934 --> 00:27:37,160 did here. Yeah. Absolutely. I love it. I 770 00:27:37,160 --> 00:27:38,680 think one of my big takeaways here is 771 00:27:38,680 --> 00:27:39,820 that we need more research. 772 00:27:41,000 --> 00:27:42,200 Oh, well. That's it. 773 00:27:42,680 --> 00:27:44,519 Do you guys so we usually end with 774 00:27:44,519 --> 00:27:45,820 a bottom line, or I kinda 775 00:27:46,519 --> 00:27:48,119 swooped in and gave my bottom line. Or 776 00:27:48,119 --> 00:27:50,025 anything else to add to that for the 777 00:27:50,345 --> 00:27:52,424 last takeaway sentence for this from either of 778 00:27:52,424 --> 00:27:53,005 you guys? 779 00:27:53,305 --> 00:27:54,904 Yeah. I think the way that I think 780 00:27:54,904 --> 00:27:56,825 about this is that, at least with respect 781 00:27:56,825 --> 00:27:59,724 to lung function changes, both methotrexate and prednisone 782 00:27:59,785 --> 00:28:02,605 are reasonable upfront initial therapy options, 783 00:28:03,230 --> 00:28:06,529 for patients with pulmonary sarcoidosis and parenchymal involvement. 784 00:28:07,390 --> 00:28:09,390 But their side effect profiles and their onset 785 00:28:09,390 --> 00:28:11,950 of action probably differ. And so you can 786 00:28:11,950 --> 00:28:14,590 inform some shared decision making around your treatment 787 00:28:14,590 --> 00:28:16,590 plan, whether it's, you know, one of these 788 00:28:16,590 --> 00:28:18,049 two or that third thing. 789 00:28:18,404 --> 00:28:20,664 I think this is really helpful data to 790 00:28:20,805 --> 00:28:22,585 kind of guide your discussion with patients. 791 00:28:23,605 --> 00:28:25,605 All right. All right. Well, this is a 792 00:28:25,605 --> 00:28:27,845 to be continued rapid fire journal club. Thank 793 00:28:27,845 --> 00:28:29,125 you, Robert. Thank you, Luke. I think this 794 00:28:29,125 --> 00:28:30,725 is a great discussion. Let us know what 795 00:28:30,725 --> 00:28:32,085 your guys' thoughts are, or if you have 796 00:28:32,085 --> 00:28:33,910 any other questions that you have for us, 797 00:28:33,910 --> 00:28:35,269 and and we'll address them in some future 798 00:28:35,269 --> 00:28:35,769 episodes.