Methotrexate Safety Tips (7.31.2026) Save

It's the 31st of July. This is the RheumNow podcast and I'm Dr. Jack Cush. On this podcast, we're going to cover yet more gout because this is the last day of our campaign on gout. It's more than a flare. I think we've made that point throughout the month. We have a lot of other interesting topics to discuss.

Let's start with an EMA announcement. The EMA actually announced two things regarding upadacitinib in the last week. They approved upadacitinib for use in alopecia areata. But I posted what I thought was more interesting, and that was the approval for the treatment of adults and adolescents with non-segmental vitiligo, NSV. It's the most popular and common form of vitiligo. It is the only systemic therapy approved for vitiligo in the EU. It's up for consideration in the United States and hopefully that'll happen sometime too. Again, JAK inhibitors seem to look great in all things skin. It may be the only drug that a dermatologist needs to prescribe.

Speaking of dermatologists, hidradenitis suppurativa — we share those patients; I do with my dermatologist. I don't know if you see them. I think they should be primarily managed by the dermatologist. They have a lot of skin complications that we're not aware of. We're good at managing the systemic and biologic therapies. There are three therapies that are actually FDA approved for hidradenitis: secukinumab, adalimumab, and bimekizumab. I posted this week a new report. It's two phase three trials — STOP-HS1 and STOP-HS2 — with a new JAK1-selective drug, povorcitinib. Again, they published their phase three results; both trials had about 600-plus patients. Their primary outcome is the HiSCR50 — maybe it's like an ACR50 — roughly 42% in both trials on the JAK inhibitor povorcitinib versus 29%. That is significant. No new signals. Given it's a dermatology study, they see more of that JAK-associated acne with JAK inhibitors; fungitis was another common side effect. Nothing big — they didn't report much in the way of the things you worry about, you know: death, myocardial infarction, cancer, shingles.

A report this week about psoriasis patients and the risk of myocardial dysfunction. This is a cohort of over a thousand patients with psoriasis who were compared to controls who had no skin disease, no inflammatory disease. All patients were assessed clinically and by echo, and when they looked at the psoriasis cohort they had significantly more echo evidence of myocardial dysfunction — 17% versus 6%. And myocardial dysfunction was unrelated to systemic activity or skin activity. Higher BMI and diabetes were other independent associations with myocardial dysfunction. So you don't have to be obese or have diabetes with psoriasis to get the myocardial complications. That's the takeaway from the study.

Another study — this one was STOP-HZ. The other one was STOP-HS hidradenitis. This is STOP-HZ for herpes zoster. It looked at a small cohort of 30 patients who were going on to povorcitinib and were given the recombinant zoster vaccine, aka Shingrix, on day one and then two months later at week eight. They also either started povorcitinib on day one or week eight, and the question was: would it impair the humoral responses to the vaccine? The tofacitinib patients had fewer rises in varicella zoster vaccine titers at week 8 — 45% versus 80%. That was at week 8. But when you got out beyond that, there wasn't much difference. So the question is: do you wait to give the JAK inhibitor — like do you wait one or two weeks like you do with methotrexate? I think you should if you can. The good thing about JAKs is that they work fast, and that should maybe be one of the reasons why you're starting it in some patients. In others you can wait a week or two, but if you have to go ahead, just make sure they get their second vaccine and they'll be caught up. Because they're still going to be at risk — they're on a JAK inhibitor and you're inhibiting alpha interferon and other interferons, and lord knows what, but mainly it's interferon I believe that drives that risk for zoster.

Eric Topol put up an interesting tweet this week that I also retweeted, and it's where we're going in the future. This is an AI model trained to look at 3.7 million electronic health records, and it was shown in this AI model to be very effective at predicting cancer one year before clinical diagnosis. Again, this is one of the wonders of AI, especially when we apply it to large data sets in your hospital system or your clinic. You might worry about that — some people do have privacy issues — but what's the tradeoff? I think there needs to be careful oversight. There needs to be protocols and rules. But boy, the benefits seem to be outstanding.

Let's get into RA. A retrospective study looked at over 2,000 patients with RA. As you know, inflammation drives risk of venous thromboembolic events, VTE. RA
patients are at higher risk of VTEs. And that's presumably because they have more activity. It could be because they're on drugs that cause more VTEs like JAK inhibitors. But is it the people go on JAK inhibitors that have — they go on JAK inhibitors because they have a lot of activity? Again, disentangling that can be a little bit complicated.

Well, it gets a little bit more complicated because in this study, they actually clarify something. What happens in 2,187 RA patients who are initiating menopausal hormonal therapy? They compared that cohort one to four to unexposed controls. And yes, the VTE incidence was higher in the hormonal therapy group. It was roughly about double the risk, 6.5 versus 3.3 events per 1,000 years. So again, that's a significant increase. The use of hormonal therapy was associated with a doubling basically of risk. And most of that risk was driven by deep vein thrombosis — the hazard ratio 1.92, hazard ratio for DVT was 2.3.

So my colleagues at UT Southwestern did an interesting study where they looked at all the labs done in conjunction with methotrexate use. They had a cohort of almost 2,500 patients — 13% RA, 11% psoriatic arthritis, 15% inflammatory arthritis — and they looked at whether labs are done Q3 or Q6 and did it correlate with anything, correlate clinically, correlate with other lab changes that you would worry about. So there was no difference between Q3, Q6 and correlations with ALT, AST, white blood cell count, hematocrit, MCV, platelets, and FIB-4 scores.

Again, I think that this is one of many lines of evidence that say patients on chronic methotrexate don't really need monthly labs and they probably don't even need every three-month labs. I do think when you're starting out, you got to adhere to protocol. It's every month for a few months and then every three months until they're stable — stable on their dose, stable and responding to methotrexate. And then you can go to every six months. I know the guidelines say something. So it has to do with whether you are worried about guidelines and you're very medico-legal in what you do, or you're going to do the right thing for you, your clinic, and the patients. Me, I'll do it every six months.

Speaking of the FIB-4 — it's also known as the Fibrosis-4 score. It's a predictive measure based on labs and it predicts liver fibrosis. It's calculated based on age and platelet count. So here's a study of 174 RA, PsA, and PSO patients on methotrexate. 11% developed fibrosis. And fibrosis was confirmed by elastography. No mention of biopsies here, but elastography was the main method and that's fairly sensitive. But the association of the FIB-4 score and diagnosed fibrosis had an AUC of 68. That's not great. And there have been other studies — I think we've reported here — that say that, you know, it's probably not worth doing in your RA patients. But if you're worried about liver fibrosis — I am not in RA, I might be in PsA and PSO — then maybe you can do that. And again, look it up on your phone. You can plug in the numbers and get your FIB-4 score. They use a certain cutoff that had the best predictive AUC, and a cutoff I think was 1.62, but again you should look at the literature on that and make your own cutoff.

Two RCTs of almost 400 gout patients starting allopurinol. The question is do difficult gout patients have a harder time getting to target or a harder time controlling disease if they have, for instance, tophi or worse disease. So that's what the study looked at. 31% of their cohort — that's like 31% of 383 — at 12 months were equally able to achieve a target of less than 6 mg/dL or less than 0.36 mmol/L. It didn't matter whether you had tophi or not. Equal success in doing that — 70% versus 73% — and equally the same number of gout flares in month 11. It's a 12-month study. They're starting allopurinol. In month 11, 71% and 79% are still having flares. This is the hazard of using urate-lowering therapy without concomitant prophylaxis. And again, it's a study, so they're going to pick up things with greater sensitivity than you will in your clinic. But I thought that was a really important study.

Another important study about colchicine comes from a UK primary care database looking at a 20-year use of new initiators of colchicine, and that number was 31,000, compared to people not going on colchicine — equal number in that cohort. They were followed for almost five years. Colchicine initiators had a 12% lower risk of joint arthroplasty, hazard ratio 0.88. It was even lower in gout patients who also had a known history of hip and knee OA on top of their gout — now it was a 23% drop. Colchicine as a preventative for joint replacement. How is that happening? Well, it is anti-inflammatory. There is an
inflammation component that drives osteoarthritis intermittently, but it's — I think it's interesting data. I like the report that I put up. Of course, I put it up. I'm sure I must have liked it on wider implications of dactylitis. The sausage digit that we see is often associated mainly with psoriatic arthritis, according to them. I don't know that it's mainly in psoriatic arthritis, to me. But I like that they talked about that — sausage digit dactylitis is not a diagnosis. It's a clinical finding for which you have to identify the disease association, and there are many. I wrote them down on a napkin that I can't find, but oh, here it is under here. But there's a lot of them, you know — MCTD, systemic sclerosis, JIA, reactive arthritis, sarcoidosis, sickle cell disease, TB, non-tuberculous mycobacterial infections, leprosy, Lyme disease, and syphilis, to name a few. CPPD is on the list, but that's pretty rare, is it not? Gout — it's also really quite rare. But again, dactylitis does occur in a number of different disorders.

Lastly, we have a few more things. One — July is not just gout month on RheumNow. July and all of rheumatology is Juvenile Arthritis Month. 300,000 kids in the United States have juvenile arthritis, and they don't all have access. And part of that problem is there's a serious shortage of pediatric rheumatologists. You, me, and everyone we know have got to drive people to go into pediatric rheumatology. I almost — actually, Still's disease is why I got into rheumatology. And I wanted to go to the pediatric rheumatology clinic, even when I was an adult. At some point they said you can't do that anymore. But I did it for many years. So again, it's a real big thing. CARRA and the Arthritis Foundation are on it. I think they need your help and you need to be on it as well.

Two more reports. Janet Pope published an interesting article on tips for safe allopurinol use in gout. Start low, go slow — reduces hypersensitivity reactions. But recognize that if you start low at 100 and you go up to 200, then 300, the slower you go, the slower you're going to get to your target. But also, every time you increase, you may increase gout flares. Again, you need to choose — your initial dose should be 100, but lower if the GFR is less than 30 cc's per minute. Second, if they're in an attack, you can start allopurinol. You don't have to wait until the attack ends. But when starting allopurinol, you need to prophylax. Do you do it without prophylaxis? I think the data is overwhelming that everybody should be on prophylaxis when starting urate-lowering therapy. You really want to know about how serious that is — start someone on a uricase drug. Oh my god, they're going to flare a whole bunch. Look at the original febuxostat studies done by Michael Becker — a ton of flares when they were starting febux.

Point number three: in Southeast Asians, Han Chinese, Thai, Koreans, everyone should be tested for HLA-B*58:01. Yes, you should do it, or could do it, in African-Americans, but the cost experience and the cost-efficacy analyses aren't great — but it's not a bad idea to do if you have access to it. I don't have access to it.

Fourth point: SGLT2 inhibitors are really good at managing gout and lowering uric acid levels and being uricosuric, but initially they may cause instability of gout and more attacks.

And lastly, beware of lupus patients with gout, because they may be on azathioprine. They may have CKD, and if you put them on allopurinol — uh oh — azathioprine plus allopurinol: bad combination. Really bad. Don't do it. It's going to end up in Stevens-Johnson or TEN or something ugly. Use febuxostat or another drug, or stop the azathioprine.

Lastly, Nicola Dalbeth, who has been helping the RheumNow team in guiding this month on gout and the content we put up, has a really nice short read on gout remission. OMERACT — an organization she was involved with — defines gout remission as the absence of gout flares in the last 12 months, with second, the absence of subcutaneous tophi, with third, a serum urate at target or below 6 milligrams per deciliter or 0.36 millimoles per liter. Again, this captures both the inflammatory disease control and control of the urate crystal burden, which again is a systemic problem.

So they showed in studies that it is a possibility that you can achieve remission in the majority of patients in gout. She points out a study where patients receiving urate-lowering therapy in a treat-to-target fashion — 58% of them achieved remission, the remission definition from OMERACT, compared to those who had symptom-driven care, where remission was only seen in 31%, and that was highly significant. Remission is the goal — not just in gout, but in most things we have.

I'm going to make a pitch for education. You know what I've learned mostly during this month on gout is — god, we know so much, and yeah, we are great at managing, but the educational gap is gigantic. Only 1.3% of all gout patients will see a
rheumatologist and there's 12.1 million in the United States. You need to be lecturing on this. You need to be handing out brochures. We have downloads on the website. There are four infographics that are really great that you could have and hand out. You could do them, put two on one side, two on the other side. It's a one pager. Give it to patients, give it to residents, give it to your primary care doctors. It covers the diagnosis and treatment.

And then I have my gout card which I wrote. This is a card that you can, as you print it out, you can take it to the printer and have them print it up on 3.5 by 2.5 cards that you can hand out to every patient. I've been doing this for years. And you know, gout patients would rather look at a card in their pocket than go see you. But if they see a card in their pocket that reminds them they should go see you and what they shouldn't do in the meantime, the patient's going to be better off.

Again, education is our biggest chasm in gout. Maybe in all rheumatology, but let's start with gout. That's it for this week. Take care of yourself.