Mixed Topics

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.

TOPLINE:

Black children with vitiligo are significantly more likely to be diagnosed with psychiatric disorders, including depression, suicidal ideation, and disruptive behavior disorders, than matched controls who did not have vitiligo, according to a case-control study.

METHODOLOGY:

• Researchers conducted a retrospective, single-center, case-control study at Texas Children’s Hospital in Houston on 327 Black children with vitiligo and 981 matched controls without vitiligo.
• The average age of participants was 11.7 years, and 62% were girls.
• The study outcome was the prevalence of psychiatric conditions and rates of treatment (pharmacotherapy and/or psychotherapy) initiation for those conditions.

TAKEAWAY:

• Black children with vitiligo were more likely to be diagnosed with depression (odds ratio [OR], 3.63; P < .001), suicidal ideation (OR, 2.88; P = .005), disruptive behavior disorders (OR, 7.68; P < .001), eating disorders (OR, 15.22; P = .013), generalized anxiety disorder (OR, 2.61; P < .001), and substance abuse (OR, 2.67; P = .011).
• The likelihood of having a psychiatric comorbidity was not significantly different between children with segmental vitiligo and those with generalized vitiligo or between girls and boys.
• Among the patients with vitiligo and psychiatric comorbidities, treatment initiation rates were higher for depression (76.5%), disruptive behavior disorders (82.1%), and eating disorders (100%).
• Treatment initiation rates were lower in patients with vitiligo diagnosed with generalized anxiety disorder (55.3%) and substance abuse (61.5%). Treatment was not initiated in 14% patients with suicidal ideation.

IN PRACTICE:

“Pediatric dermatologists have an important role in screening for psychiatric comorbidities, and implementation of appropriate screening tools while treating vitiligo is likely to have a bidirectional positive impact,” the authors wrote, adding: “By better understanding psychiatric comorbidities of African American children with vitiligo, dermatologists can be more aware of pediatric mental health needs and provide appropriate referrals.”

SOURCE:

This study was led by Emily Strouphauer, BSA, Baylor College of Medicine, Houston, and was published online in JAAD International.

LIMITATIONS:

The study limitations were the retrospective design, small sample size, and heterogeneity in the control group.

DISCLOSURES:

The study did not receive any funding. The authors declared no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Black children with vitiligo are significantly more likely to be diagnosed with psychiatric disorders, including depression, suicidal ideation, and disruptive behavior disorders, than matched controls who did not have vitiligo, according to a case-control study.

METHODOLOGY:

• Researchers conducted a retrospective, single-center, case-control study at Texas Children’s Hospital in Houston on 327 Black children with vitiligo and 981 matched controls without vitiligo.
• The average age of participants was 11.7 years, and 62% were girls.
• The study outcome was the prevalence of psychiatric conditions and rates of treatment (pharmacotherapy and/or psychotherapy) initiation for those conditions.

TAKEAWAY:

• Black children with vitiligo were more likely to be diagnosed with depression (odds ratio [OR], 3.63; P < .001), suicidal ideation (OR, 2.88; P = .005), disruptive behavior disorders (OR, 7.68; P < .001), eating disorders (OR, 15.22; P = .013), generalized anxiety disorder (OR, 2.61; P < .001), and substance abuse (OR, 2.67; P = .011).
• The likelihood of having a psychiatric comorbidity was not significantly different between children with segmental vitiligo and those with generalized vitiligo or between girls and boys.
• Among the patients with vitiligo and psychiatric comorbidities, treatment initiation rates were higher for depression (76.5%), disruptive behavior disorders (82.1%), and eating disorders (100%).
• Treatment initiation rates were lower in patients with vitiligo diagnosed with generalized anxiety disorder (55.3%) and substance abuse (61.5%). Treatment was not initiated in 14% patients with suicidal ideation.

IN PRACTICE:

“Pediatric dermatologists have an important role in screening for psychiatric comorbidities, and implementation of appropriate screening tools while treating vitiligo is likely to have a bidirectional positive impact,” the authors wrote, adding: “By better understanding psychiatric comorbidities of African American children with vitiligo, dermatologists can be more aware of pediatric mental health needs and provide appropriate referrals.”

SOURCE:

This study was led by Emily Strouphauer, BSA, Baylor College of Medicine, Houston, and was published online in JAAD International.

LIMITATIONS:

The study limitations were the retrospective design, small sample size, and heterogeneity in the control group.

DISCLOSURES:

The study did not receive any funding. The authors declared no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Black children with vitiligo are significantly more likely to be diagnosed with psychiatric disorders, including depression, suicidal ideation, and disruptive behavior disorders, than matched controls who did not have vitiligo, according to a case-control study.

METHODOLOGY:

• Researchers conducted a retrospective, single-center, case-control study at Texas Children’s Hospital in Houston on 327 Black children with vitiligo and 981 matched controls without vitiligo.
• The average age of participants was 11.7 years, and 62% were girls.
• The study outcome was the prevalence of psychiatric conditions and rates of treatment (pharmacotherapy and/or psychotherapy) initiation for those conditions.

TAKEAWAY:

• Black children with vitiligo were more likely to be diagnosed with depression (odds ratio [OR], 3.63; P < .001), suicidal ideation (OR, 2.88; P = .005), disruptive behavior disorders (OR, 7.68; P < .001), eating disorders (OR, 15.22; P = .013), generalized anxiety disorder (OR, 2.61; P < .001), and substance abuse (OR, 2.67; P = .011).
• The likelihood of having a psychiatric comorbidity was not significantly different between children with segmental vitiligo and those with generalized vitiligo or between girls and boys.
• Among the patients with vitiligo and psychiatric comorbidities, treatment initiation rates were higher for depression (76.5%), disruptive behavior disorders (82.1%), and eating disorders (100%).
• Treatment initiation rates were lower in patients with vitiligo diagnosed with generalized anxiety disorder (55.3%) and substance abuse (61.5%). Treatment was not initiated in 14% patients with suicidal ideation.

IN PRACTICE:

“Pediatric dermatologists have an important role in screening for psychiatric comorbidities, and implementation of appropriate screening tools while treating vitiligo is likely to have a bidirectional positive impact,” the authors wrote, adding: “By better understanding psychiatric comorbidities of African American children with vitiligo, dermatologists can be more aware of pediatric mental health needs and provide appropriate referrals.”

SOURCE:

This study was led by Emily Strouphauer, BSA, Baylor College of Medicine, Houston, and was published online in JAAD International.

LIMITATIONS:

The study limitations were the retrospective design, small sample size, and heterogeneity in the control group.

DISCLOSURES:

The study did not receive any funding. The authors declared no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Mobile images may be reliable for assessing cutaneous neurofibroma (cNF) features in patients with neurofibromatosis type 1 (NF1), according to a crowd-sourced registry study that also suggests correlations between cNF burden and quality of life (QoL), particularly the impact of facial severity on emotional well-being.

METHODOLOGY:

• To learn more about the association of cNFs with QoL, pain, and itch in patients with this rare disease, researchers enrolled 1016 individuals aged 40 years and older with NF1 who had at least one cNF, from May 2021 to December 2023, after reaching out to patient-led or NF1 advocacy organizations in 13 countries, including the United States.
• Participants provided demographic data, detailed photographs, and saliva samples for genetic sequencing, with 583 participants (mean age, 51.7 years; 65.9% women) submitting high-quality photographs from seven body regions at the time of the study analysis.
• A subset of 50 participants also underwent whole-body imaging.
• Four researchers independently rated the photographs for various cNF features, including general severity, number, size, facial severity, and subtypes.

TAKEAWAY:

• Based on evaluations by NF1 specialists, the agreement between mobile and whole-body images was “substantial” (74%-88% agreement) for the number of cNFs, general severity, and facial severity. Agreement between self-reported numbers of cNFs and investigator-rated numbers based on photographs was “minimal to fair.”
• Female sex, the number of cNFs, severity of cNFs on the face, and globular cNFs were associated with worse QoL (based on Skindex scores); severity of cNFs on the face had the strongest impact on overall QoL (P < .001).
• An increasing number of cNFs and worsening facial severity were strongly correlated with higher emotion subdomain scores.
• A higher number of cNFs, more severe cNFs on the face, and larger cNFs were all slightly associated with increased itch and pain (P < .01).

IN PRACTICE:

“To develop effective therapeutics, meaningful clinical outcomes that are tied with improvement in QoL for persons with NF1 must be clearly defined,” the authors wrote. The results of this study, they added, “suggested the benefit of this crowd-sourced resource by identifying the features of cNFs with the greatest association with QoL and symptoms of pain and itch in persons with NF1, highlighting new intervention strategies and features to target to most improve QoL in NF1.”

SOURCE:

The study was led by Michelle Jade Lin, BS, Stanford University School of Medicine, Redwood City, California, and was published online in JAMA Dermatology.

LIMITATIONS:

The study included only a small number of individuals from racial and ethnic minority groups and did not capture ethnicity information, which could have provided further insights into disease impact across different demographics.

DISCLOSURES:

This study was supported by Johns Hopkins University, Baltimore, and the Bloomberg Family Foundation. Ms. Lin reported support from the Stanford Medical Scholars Research Program. Three authors reported personal fees or grants outside this work. Other authors reported no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Mobile images may be reliable for assessing cutaneous neurofibroma (cNF) features in patients with neurofibromatosis type 1 (NF1), according to a crowd-sourced registry study that also suggests correlations between cNF burden and quality of life (QoL), particularly the impact of facial severity on emotional well-being.

METHODOLOGY:

• To learn more about the association of cNFs with QoL, pain, and itch in patients with this rare disease, researchers enrolled 1016 individuals aged 40 years and older with NF1 who had at least one cNF, from May 2021 to December 2023, after reaching out to patient-led or NF1 advocacy organizations in 13 countries, including the United States.
• Participants provided demographic data, detailed photographs, and saliva samples for genetic sequencing, with 583 participants (mean age, 51.7 years; 65.9% women) submitting high-quality photographs from seven body regions at the time of the study analysis.
• A subset of 50 participants also underwent whole-body imaging.
• Four researchers independently rated the photographs for various cNF features, including general severity, number, size, facial severity, and subtypes.

TAKEAWAY:

• Based on evaluations by NF1 specialists, the agreement between mobile and whole-body images was “substantial” (74%-88% agreement) for the number of cNFs, general severity, and facial severity. Agreement between self-reported numbers of cNFs and investigator-rated numbers based on photographs was “minimal to fair.”
• Female sex, the number of cNFs, severity of cNFs on the face, and globular cNFs were associated with worse QoL (based on Skindex scores); severity of cNFs on the face had the strongest impact on overall QoL (P < .001).
• An increasing number of cNFs and worsening facial severity were strongly correlated with higher emotion subdomain scores.
• A higher number of cNFs, more severe cNFs on the face, and larger cNFs were all slightly associated with increased itch and pain (P < .01).

IN PRACTICE:

“To develop effective therapeutics, meaningful clinical outcomes that are tied with improvement in QoL for persons with NF1 must be clearly defined,” the authors wrote. The results of this study, they added, “suggested the benefit of this crowd-sourced resource by identifying the features of cNFs with the greatest association with QoL and symptoms of pain and itch in persons with NF1, highlighting new intervention strategies and features to target to most improve QoL in NF1.”

SOURCE:

The study was led by Michelle Jade Lin, BS, Stanford University School of Medicine, Redwood City, California, and was published online in JAMA Dermatology.

LIMITATIONS:

The study included only a small number of individuals from racial and ethnic minority groups and did not capture ethnicity information, which could have provided further insights into disease impact across different demographics.

DISCLOSURES:

This study was supported by Johns Hopkins University, Baltimore, and the Bloomberg Family Foundation. Ms. Lin reported support from the Stanford Medical Scholars Research Program. Three authors reported personal fees or grants outside this work. Other authors reported no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Mobile images may be reliable for assessing cutaneous neurofibroma (cNF) features in patients with neurofibromatosis type 1 (NF1), according to a crowd-sourced registry study that also suggests correlations between cNF burden and quality of life (QoL), particularly the impact of facial severity on emotional well-being.

METHODOLOGY:

• To learn more about the association of cNFs with QoL, pain, and itch in patients with this rare disease, researchers enrolled 1016 individuals aged 40 years and older with NF1 who had at least one cNF, from May 2021 to December 2023, after reaching out to patient-led or NF1 advocacy organizations in 13 countries, including the United States.
• Participants provided demographic data, detailed photographs, and saliva samples for genetic sequencing, with 583 participants (mean age, 51.7 years; 65.9% women) submitting high-quality photographs from seven body regions at the time of the study analysis.
• A subset of 50 participants also underwent whole-body imaging.
• Four researchers independently rated the photographs for various cNF features, including general severity, number, size, facial severity, and subtypes.

TAKEAWAY:

• Based on evaluations by NF1 specialists, the agreement between mobile and whole-body images was “substantial” (74%-88% agreement) for the number of cNFs, general severity, and facial severity. Agreement between self-reported numbers of cNFs and investigator-rated numbers based on photographs was “minimal to fair.”
• Female sex, the number of cNFs, severity of cNFs on the face, and globular cNFs were associated with worse QoL (based on Skindex scores); severity of cNFs on the face had the strongest impact on overall QoL (P < .001).
• An increasing number of cNFs and worsening facial severity were strongly correlated with higher emotion subdomain scores.
• A higher number of cNFs, more severe cNFs on the face, and larger cNFs were all slightly associated with increased itch and pain (P < .01).

IN PRACTICE:

“To develop effective therapeutics, meaningful clinical outcomes that are tied with improvement in QoL for persons with NF1 must be clearly defined,” the authors wrote. The results of this study, they added, “suggested the benefit of this crowd-sourced resource by identifying the features of cNFs with the greatest association with QoL and symptoms of pain and itch in persons with NF1, highlighting new intervention strategies and features to target to most improve QoL in NF1.”

SOURCE:

The study was led by Michelle Jade Lin, BS, Stanford University School of Medicine, Redwood City, California, and was published online in JAMA Dermatology.

LIMITATIONS:

The study included only a small number of individuals from racial and ethnic minority groups and did not capture ethnicity information, which could have provided further insights into disease impact across different demographics.

DISCLOSURES:

This study was supported by Johns Hopkins University, Baltimore, and the Bloomberg Family Foundation. Ms. Lin reported support from the Stanford Medical Scholars Research Program. Three authors reported personal fees or grants outside this work. Other authors reported no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Obesity has now reached epidemic proportions, with global prevalence of the condition increasing more than threefold between 1975 and 2022. In the United States alone, roughly two in five adults have obesity. As healthcare providers are intimately aware, obesity is linked to many serious health conditions, including type 2 diabetes, cardiovascular disease, and metabolic-associated steatotic liver disease, as well as some forms of cancer. As such, it presents a major challenge to chronic disease prevention and overall health.

For many years, management of obesity was considered within the purview of primary care as part of chronic disease management. However, as obesity has become more common, our understanding of the underlying causes of obesity has improved, and optimal strategies to manage and treat obesity have evolved. A new field of obesity medicine has arisen, attracting specialists such as gastroenterologists, surgeons, endocrinologists, and others. From glucagon-like peptide 1 agonists to an expanding armamentarium of bariatric procedures, emerging therapeutics have revolutionized treatment of patients with obesity and related health conditions.

In this month’s Member Spotlight, we introduce you to gastroenterologist Dr. Janese Laster, who has built a successful career with a primary focus on obesity medicine. She shares her passionate perspective on why gastroenterologists should play a more prominent role in management of this complex, chronic disease. We also include a summary of obesity-related content presented as part of this spring’s AGA Post-Graduate Course, with helpful clinical pearls from experts Dr. Andres Acosta, Dr. Violeta Popov, Dr. Sonali Paul, and Dr. Pooja Singhal.

Also in our September issue, we highlight a recent, practice-changing randomized controlled trial from Clinical Gastroenterology and Hepatology supporting use of snare tip soft coagulation as the preferred thermal margin treatment to reduce recurrence rates following colorectal endoscopic mucosal resection. In our quarterly Perspectives column, Dr. Maggie Ham and Dr. Petr Protiva offer their insights into a pressing question on many of our minds — whether to take the 10-year “high-stakes” exam or opt for the Longitudinal Knowledge Assessment to maintain American Board of Internal Medicine certification. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.

Megan A. Adams, MD, JD, MSc

Editor in Chief

Obesity has now reached epidemic proportions, with global prevalence of the condition increasing more than threefold between 1975 and 2022. In the United States alone, roughly two in five adults have obesity. As healthcare providers are intimately aware, obesity is linked to many serious health conditions, including type 2 diabetes, cardiovascular disease, and metabolic-associated steatotic liver disease, as well as some forms of cancer. As such, it presents a major challenge to chronic disease prevention and overall health.

For many years, management of obesity was considered within the purview of primary care as part of chronic disease management. However, as obesity has become more common, our understanding of the underlying causes of obesity has improved, and optimal strategies to manage and treat obesity have evolved. A new field of obesity medicine has arisen, attracting specialists such as gastroenterologists, surgeons, endocrinologists, and others. From glucagon-like peptide 1 agonists to an expanding armamentarium of bariatric procedures, emerging therapeutics have revolutionized treatment of patients with obesity and related health conditions.

In this month’s Member Spotlight, we introduce you to gastroenterologist Dr. Janese Laster, who has built a successful career with a primary focus on obesity medicine. She shares her passionate perspective on why gastroenterologists should play a more prominent role in management of this complex, chronic disease. We also include a summary of obesity-related content presented as part of this spring’s AGA Post-Graduate Course, with helpful clinical pearls from experts Dr. Andres Acosta, Dr. Violeta Popov, Dr. Sonali Paul, and Dr. Pooja Singhal.

Also in our September issue, we highlight a recent, practice-changing randomized controlled trial from Clinical Gastroenterology and Hepatology supporting use of snare tip soft coagulation as the preferred thermal margin treatment to reduce recurrence rates following colorectal endoscopic mucosal resection. In our quarterly Perspectives column, Dr. Maggie Ham and Dr. Petr Protiva offer their insights into a pressing question on many of our minds — whether to take the 10-year “high-stakes” exam or opt for the Longitudinal Knowledge Assessment to maintain American Board of Internal Medicine certification. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.

Megan A. Adams, MD, JD, MSc

Editor in Chief

Obesity has now reached epidemic proportions, with global prevalence of the condition increasing more than threefold between 1975 and 2022. In the United States alone, roughly two in five adults have obesity. As healthcare providers are intimately aware, obesity is linked to many serious health conditions, including type 2 diabetes, cardiovascular disease, and metabolic-associated steatotic liver disease, as well as some forms of cancer. As such, it presents a major challenge to chronic disease prevention and overall health.

For many years, management of obesity was considered within the purview of primary care as part of chronic disease management. However, as obesity has become more common, our understanding of the underlying causes of obesity has improved, and optimal strategies to manage and treat obesity have evolved. A new field of obesity medicine has arisen, attracting specialists such as gastroenterologists, surgeons, endocrinologists, and others. From glucagon-like peptide 1 agonists to an expanding armamentarium of bariatric procedures, emerging therapeutics have revolutionized treatment of patients with obesity and related health conditions.

In this month’s Member Spotlight, we introduce you to gastroenterologist Dr. Janese Laster, who has built a successful career with a primary focus on obesity medicine. She shares her passionate perspective on why gastroenterologists should play a more prominent role in management of this complex, chronic disease. We also include a summary of obesity-related content presented as part of this spring’s AGA Post-Graduate Course, with helpful clinical pearls from experts Dr. Andres Acosta, Dr. Violeta Popov, Dr. Sonali Paul, and Dr. Pooja Singhal.

Also in our September issue, we highlight a recent, practice-changing randomized controlled trial from Clinical Gastroenterology and Hepatology supporting use of snare tip soft coagulation as the preferred thermal margin treatment to reduce recurrence rates following colorectal endoscopic mucosal resection. In our quarterly Perspectives column, Dr. Maggie Ham and Dr. Petr Protiva offer their insights into a pressing question on many of our minds — whether to take the 10-year “high-stakes” exam or opt for the Longitudinal Knowledge Assessment to maintain American Board of Internal Medicine certification. As always, thanks for reading and please don’t hesitate to reach out with suggestions for future coverage.

Megan A. Adams, MD, JD, MSc

Editor in Chief

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

Dermatology remains one of the most competitive specialties in the residency match, with successful applicants demonstrating a well-rounded application reflecting not only their academic excellence but also their dedication to research, community service, and hands-on clinical experience.¹ A growing emphasis on scholarly activities has made it crucial for applicants to stand out, with an increasing number opting to take gap years to engage in focused research endeavors.² In highly competitive specialties such as dermatology, successful applicants now report more than 20 research items on average.^3,4 This trend also is evident in primary care specialties, which have seen a 2- to 3-fold increase in reported research activities. The average unmatched applicant today lists more research items than the average matched applicant did a decade ago, underscoring the growing emphasis on scholarly activity.³

Ideally, graduate medical education should foster an environment of inquiry and scholarship, where residents develop new knowledge, evaluate research findings, and cultivate lifelong habits of inquiry. The Accreditation Council for Graduate Medical Education requires residents to engage in scholarship, such as case reports, research reviews, and original research.⁵ Research during residency has been linked to several benefits, including enhanced patient care through improved critical appraisal skills, clinical reasoning, and lifelong learning.^6,7 Additionally, students and residents who publish research are more likely to achieve higher rank during residency and pursue careers in academic medicine, potentially helping to address the decline in clinician investigators.^8,9 Publishing and presenting research also can enhance a residency program’s reputation, making it more attractive to competitive applicants, and may be beneficial for residents seeking jobs or fellowships.⁶

Dermatology residency programs vary in their structure and support for resident research. One survey revealed that many programs lack the necessary support, structure, and resources to effectively promote and maintain research training.¹ Additionally, residents have less exposure to researchers who could serve as mentors due to the growing demands placed on attending physicians in teaching hospitals.¹⁰

The Research Arms Race

The growing emphasis on scholarly activity for residency and fellowship applicants coupled with the use of research productivity to differentiate candidates has led some to declare a “research arms race” in residency selection.³ As one author stated, “We need less research, better research, and research done for the right reasons.”¹¹ Indeed, most articles authored by medical students are short reviews or case reports, with the majority (59% [207/350]) being cited zero times, according to one analysis.¹² Given the variable research infrastructure between programs and the decreasing availability of research mentors despite the growing emphasis on scholarly activity, applicants face an unfortunate dilemma. Until the system changes, those who protest this research arms race by not engaging in substantial scholarly activity are less likely to match into competitive specialties. Thus, the race continues.

The Value of Mentorship

Resident research success is impacted by having an effective faculty research mentor.¹³ Although all medical research at the student or resident levels should be conducted with a faculty mentor to oversee it, finding a mentor can be challenging. If a resident’s program boasts a strong research infrastructure or prolific faculty, building relationships with potential mentors is a logical first step for residents wishing to engage in research; however, if suitable mentors are lacking, efforts should be made by residents to establish these connections elsewhere, such as attending society meetings to network with potential mentors and applying to formal mentorship programs (eg, the American Society for Dermatologic Surgery’s Preceptor Program, the Women’s Dermatologic Society’s Mentorship Award). Unsolicited email inquiries asking, “Hi Dr. X, my name is Y, and I was wondering if you have any research projects I could help with?” often go unanswered. Instead, consider emailing or approaching potential mentors with a more developed proposition, such as the following example:

Hello Dr. X, my name is Y. I have enjoyed reading your publications on A, which inspired me to think about B. I reviewed the literature and noticed a potential to enhance our current understanding on the topic. My team and I conducted a systematic review of the available literature and drafted a manuscript summarizing our findings. Given your expertise in this field, would you be willing to collaborate on this paper? We would be grateful for your critical eye, suggestions for improvement, and overall thoughts.

This approach demonstrates initiative, provides a clear plan, and shows respect for the mentor’s expertise, increasing the likelihood of a positive response and fruitful collaboration. Assuming the resident’s working draft meets the potential mentor’s basic expectations, such a display of initiative is likely to impress them, and they may then offer opportunities to engage in meaningful research projects in the future. Everyone benefits! These efforts to establish connections with mentors can pave the way to further collaboration and meaningful research opportunities for dermatology residents.

The Systematic Review: An Attractive Option For Residents

There are several potential avenues for students or residents interested in pursuing research. Case reports and case series are relatively easy to compile, can be completed quickly, and often require minimal guidance from a faculty mentor; however, case reports rank low in the research hierarchy. Conversely, prospective blinded clinical trials provide some of the highest-quality evidence available but are challenging to conduct without a practicing faculty member to provide a patient cohort, often require extensive funding, and may involve complex statistical analyses beyond the expertise of most students or residents. Additionally, they may take years to complete, often extending beyond residency or fellowship application deadlines.

Most medical applicants likely hold at least some hesitation in churning out vast amounts of low-quality research merely to boost their publication count for the match process. Ideally, those who pursue scholarly activity should be driven by a genuine desire to contribute meaningfully to the medical literature. One particularly valuable avenue for trainees wishing to engage in research is the systematic review, which aims to identify, evaluate, and summarize the findings of all relevant individual studies regarding a research topic and answer a focused question. If performed thoughtfully, a systematic review can meaningfully contribute to the medical literature without requiring access to a prospectively followed cohort of patients or the constant supervision of a faculty mentor. Sure, systematic reviews may not be as robust as prospective cohort clinical trials, but they often provide comprehensive insights and are considered valuable contributions to evidence-based medicine. With the help of co-residents or medical students, a medical reference librarian, and a statistician—along with a working understanding of universally accepted quality measures—a resident physician and their team can produce a systematic review that ultimately may merit publication in a top-tier medical journal.

The remainder of this column will outline a streamlined approach to the systematic review writing process, specifically tailored for medical residents who may not have affiliations to a prolific research department or established relationships with faculty mentors in their field of interest. The aim is to offer a basic framework to help residents navigate the complexities of conducting and writing a high-quality, impactful systematic review. It is important to emphasize that resident research should always be conducted under the guidance of a faculty mentor, and this approach is not intended to encourage independent research and publication by residents. Instead, it provides steps that can be undertaken with a foundational understanding of accepted principles, allowing residents to compile a working draft of a manuscript in collaboration with a trusted faculty mentor.

The Systematic Review: A Simple Approach

Step 1: Choose a Topic—Once a resident has decided to embark on conducting a systematic review, the first step is to choose a topic, which requires consideration of several factors to ensure relevance, feasibility, and impact. Begin by identifying areas of clinical uncertainty or controversy in which a comprehensive synthesis of the literature could provide valuable insights. Often, such a topic can be gleaned from the conclusion section of other primary studies; statements such as “further study is needed to determine the efficacy of X” or “systematic reviews would be beneficial to ascertaining the impact of Y” may be a great place to start.

Next, ensure that sufficient primary studies exist to support a robust review or meta-analysis by conducting a preliminary literature search, which will confirm that the chosen topic is both researchable and relevant. A narrow, focused, well-defined topic likely will prove more feasible to review than a broad, ill-defined one. Once a topic is selected, it is advisable to discuss it with a faculty mentor before starting the literature search to ensure the topic’s feasibility and clinical relevance, helping to guide your research in a meaningful direction.

When deciding between a systematic review and a meta-analysis, the nature of the research question is an influential factor. A systematic review is particularly suitable for addressing broad questions or topics when the aim is to summarize and synthesize all relevant research studies; for example, a systematic review may investigate the various treatment options for atopic dermatitis and their efficacy, which allows for a comprehensive overview of the available treatments—both the interventions and the outcomes. In contrast, a meta-analysis is ideal for collecting and statistically combining quantitative data from multiple primary studies, provided there are enough relevant studies available in the literature.

Step 2: Build a Team—Recruiting a skilled librarian to assist with Medical Subject Headings (MeSH) terms and retrieving relevant papers is crucial for conducting a high-quality systematic review or meta-analysis. Medical librarians specializing in health sciences enhance the efficiency, comprehensiveness, and reliability of your literature search, substantially boosting your work’s credibility. These librarians are well versed in medical databases such as PubMed and Embase. Begin by contacting your institution’s library services, as there often are valuable resources and personnel available to assist you. Personally, I was surprised to find a librarian at my institution specifically dedicated to helping medical residents with such projects! These professionals are eager to help, and if provided with the scope and goal of your project, they can deliver literature search results in a digestible format. Similarly, seeking the expertise of a medical statistician is crucial to the accuracy and legitimacy of your study. In your final paper, it is important to recognize the contributions of the librarian and statistician, either as co-authors or in the acknowledgments section.

In addition, recruiting colleagues or medical students can be an effective strategy to make the project more feasible and offer collaborative benefits for all parties involved. Given the growing emphasis on research for residency and fellowship admissions, there usually is no shortage of motivated volunteers.

Next, identify the software tool you will use for your systematic review. Options range from simple spreadsheets such as Microsoft Excel to reference managers such as EndNote or Mendeley or dedicated systematic review tools. Academic institutions may subscribe to paid services such as Covidence (https://www.covidence.org), or you can utilize free alternatives such as Rayyan (https://www.rayyan.ai). Investing time in learning to navigate dedicated systematic review software can greatly enhance efficiency and reduce frustrations compared to more basic methods. Ultimately, staying organized, thorough, and committed is key.

Step 3: Conduct the Literature Review—At this point, your research topic has been decided, a medical reference librarian has provided the results of a comprehensive literature search, and a software tool has been chosen. The next task is to read hundreds or thousands of papers—easy, right? With your dedicated team assembled, the workload can be divided and conquered. The first step involves screening out duplicate and irrelevant studies based on titles and abstracts. Next, review the remaining papers in more detail. Those that pass this preliminary screen should be read in their entirety, and only the papers relevant to the research topic should be included in the final synthesis. If there are uncertainties about a study’s relevance, consulting a faculty mentor is advisable. To ensure the systematic review is as thorough as possible, pay special attention to the references section of each paper, as cited references can reveal relevant studies that may have been missed in the literature search.

Once all relevant papers are compiled and read, the relevant data points should be extracted and imputed into a data sheet. Collaborating with a medical statistician is crucial at this stage, as they can provide guidance on the most effective ways to structure and input data. After all studies are included, the relevant statistical analyses on the resultant dataset can be run.

Step 4: Write the Paper—In 2020, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was developed to ensure transparent and complete reporting of systematic reviews. A full discussion of PRISMA guidelines is beyond the scope of this paper; Page et al¹⁴ provided a summary, checklist, and flow diagram that is available online (https://www.prisma-statement.org). Following the PRISMA checklist and guidelines ensures a high-quality, transparent, and reliable systematic review. These guidelines not only help streamline and simplify the writing process but also enhance its efficiency and effectiveness. Discovering the PRISMA checklist can be transformative, providing a valuable roadmap that guides the author through each step of the reporting process, helping to avoid common pitfalls. This structured approach ultimately leads to a more comprehensive and trustworthy review.

Step 5: Make Finishing Touches—At this stage in the systematic review process, the studies have been compiled and thoroughly analyzed and the statistical analysis has been conducted. The results have been organized within a structured framework following the PRISMA checklist. With these steps completed, the next task is to finalize the manuscript and seek a final review from the senior author or faculty mentor. To streamline this process, it is beneficial to adhere to the formatting guidelines of the specific medical journal you intend to submit to. Check the author guidelines on the journal’s website and review recent systematic reviews published there as a reference. Even if you have not chosen a journal yet, formatting your manuscript according to a prestigious journal’s general style provides a strong foundation that can be easily adapted to fit another journal’s requirements if necessary.

Final Thoughts

Designing and conducting a systematic review is no easy task, but it can be a valuable skill for dermatology residents aiming to contribute meaningfully to the medical literature. The process of compiling a systematic review offers an opportunity for developing critical research skills, from formulating a research question to synthesizing evidence and presenting findings in a clear methodical way. Engaging in systematic review writing not only enhances the resident’s understanding of a particular topic but also demonstrates a commitment to scholarly activity—a key factor in an increasingly competitive residency and fellowship application environment.

The basic steps outlined in this article are just one way in which residents can begin to navigate the complexities of medical research, specifically the systematic review process. By assembling a supportive team, utilizing available resources, and adhering to established guidelines such as PRISMA, one can produce a high-quality, impactful review. Ultimately, the systematic review process is not just about publication—it is about fostering a habit of inquiry, improving patient care, and contributing to the ever-evolving field of medicine. With dedication and collaboration, even the most challenging aspects of research can be tackled, paving the way for future opportunities and professional growth. In this way, perhaps one day the spirit of the “research race” can shift from a frantic sprint to a graceful marathon, where each mile is run with heart and every step is filled with purpose.

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

To the Editor:

Chronic cutaneous lupus erythematosus (CCLE) is an inflammatory condition with myriad cutaneous manifestations. Most forms of CCLE have the potential to progress to systemic lupus erythematosus (SLE).¹

Blaschkolinear lupus erythematosus (BLE) is an exceedingly rare subtype of cutaneous lupus erythematosus that usually manifests during childhood as linear plaques along the lines of Blaschko.^2,3 Under normal conditions, Blaschko lines are not noticeable; they correspond to the direction of ectodermal cell migration during cutaneous embryogenesis.^4,5 The embryonic cells travel ventrolaterally, forming a V-shaped pattern on the back, an S-shaped pattern on the trunk, and an hourglass-shaped pattern on the face with several perpendicular intersections near the mouth and nose.⁶ During their migration, the cells are susceptible to somatic mutations and clonal expansion, resulting in a monoclonal population of genetically heterogenous cells. This phenomenon is known as somatic mosaicism and may lead to an increased susceptibility to an array of congenital and inflammatory dermatoses, such as cutaneous lupus erythematosus.⁴ Blaschkolinear entities tend to manifest in a unilateral distribution following exposure to a certain environmental trigger, such as trauma, viral illness, or UV radiation, although a trigger is not always present.⁷ We report a case of BLE manifesting on the head and neck in an adult patient.

A 46-year-old man presented with a pruritic rash of 3 months’ duration on the right cheek that extended inferiorly to the right upper chest. He had a medical history of well-controlled psoriasis, and he denied any antecedent trauma, fevers, chills, arthralgia, or night sweats. There had been no improvement with mometasone ointment 0.1% applied daily for 2 months as prescribed by his primary care provider. Physical examination revealed indurated, red-brown, atrophic plaques in a blaschkolinear distribution around the nose, right upper jaw, right side of the neck, and right upper chest (Figure, A).

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

A version of this article first appeared on Medscape.com.

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

A version of this article first appeared on Medscape.com.

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk.

Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. 

Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest “long-term processes and may aid in the identification of individuals at high risk,” the researchers wrote. 

In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of Mendelian randomization (MR) analysis, “indicating a possible causal relationship between leukocytes and depression,” they said. 

The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry. 
 

Inflammatory Phenotype

Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. 

To investigate further, the researchers employed a “triangulation” approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics.

In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). 

“The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank,” the authors reported. 

In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. 

The MR analysis suggested a possible causal relationship between leukocytes and depression. 

The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear.

“Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology,” the researchers wrote. 

A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. 

This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance.
 

Support for Precision Psychiatry

This study is “another strong indication that inflammation plays a role in depression,” Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn’t involved in the study, told this news organization. 

“The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory,” Dr. Miller said. 

“Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness,” Dr. Miller added. 

Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are “very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories.”

“There are better, more specific blood biomarkers for psychiatric disorders already available,” Dr. Niculescu told this news organization.

His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person’s future risk for these disorders, and inform more tailored medication choices. 

Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients’ conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said.

This study had no commercial funding. Yu Zeng and Dr. Miller had no relevant disclosures. Dr. Niculescu is a cofounder of MindX Sciences and is listed as inventor on a patent application filed by Indiana University.
 

A version of this article first appeared on Medscape.com.