Dr. Miguel D. Regueiro (Gastroenterology, University of Pittsburgh)
We can first ask some of our surgeons at the various sites what their thoughts would be regarding this case, but first, H. Iskandar, I have 2 questions for you. Your patient had been on infliximab and developed immunogenicity and then had been on adalimumab and developed antibodies. Did she respond to any of the anti-TNFs before she developed antibodies? Also, has she had genetic studies performed for any of the early-onset IBD syndromes?
Dr. Heba Iskandar (Gastroenterology, Emory)
She definitely responded to infliximab, although, as far as we know, that was before the diagnosis of her esophageal disease. She feels that she had less of a response to adalimumab. She was on adalimumab for about a year and a half and then those last 6 months of that period is when her esophageal disease developed and she had dysphasia, odynophagia, and weight loss. However, she had probably already developed antibodies at that point. And with dose escalation, there was no response. As far as genetic studies, we have not run any tests at this time.
Dr. Miguel D. Regueiro (Gastroenterology, University of Pittsburgh)
Thank you—that is important information. I would now like to ask our colleagues at Hershey, from a medical standpoint and from a surgical standpoint, what are your thoughts about this patient?
Dr. Andrew T. Tinsley (Gastroenterology, Penn State Hershey)
This is clearly a tough case that sits on the far end of the spectrum of disease that we encounter. It is not your typical Crohn's presentation, and in some ways, it is going to be trial and error as far as treatment options are concerned. We have had some experience with these foregut patients with Crohn's disease, and for us, anti-TNF agents have tended to produce the biggest response. I would also like to say that it is important to look closely at the biological drug and antibody levels to ensure they are interpreted correctly. Depending on the laboratory being used, antibodies can occasionally look like they are high when they are actually not. I make sure to verify the antibody units being used, and to see whether the drug levels make sense in this context. Finally, this particular patient also has concurrent hidradenitis. In my clinical experience, patients with severe bowel disease and hidradenitis frequently require very high anti-TNF dosing because of their overwhelming inflammatory burden. I have seen infliximab doses of 20 mg per kilogram every 4 to 6 weeks being necessary for a robust clinical response. Given that her primary problem seems to be the esophageal disease, adjunctive treatments that you might consider include topical therapy in the form of budesonide slurries, high-dose proton pump inhibitor or perhaps even a trial of enteral therapy. Given the particular territory that is involved in this patient, I am not sure that Dr. Koltun will be able to offer much, surgically.
Dr. Walter A. Koltun (Colon and Rectal Surgery, Penn State Hershey)
We do not operate on Crohn's disease. We operate on the complications of Crohn's disease. These complications include obstruction, fistula formation, abscess, bleeding, and perforation. She really does not have any of those complications. To get rid of her foci of disease, I would have to remove everything from her mouth to anus, and then some. I find it interesting that the patient has inflammation at the interface of her world and herself. In other words, her entire GI tract and her skin are affected. As Dr. Tinsley has said, I think this is some extreme end of the spectrum of IBD. She has an immune dysregulation that is dramatic and is something that probably deserves it's own title.
Dr. Miguel D. Regueiro (Gastroenterology, University of Pittsburgh)
To recap from Hershey, Dr. Tinsley has mentioned using a high dose of anti-TNF. And maybe I will put words in his mouth, but this might be a patient whom we would re-challenge with infliximab. He also suggests giving her a high-dose proton pump inhibitor and budesonide slurry. Dr. Koltun explained that surgery in this patient might not be the best option, given the exceptional distribution of her disease. To our colleagues at Dartmouth, what are your suggestions regarding medical and surgical care for this patient?
Dr. Corey A. Siegel (Gastroenterology, Dartmouth)
I will make a couple of comments and then pass the microphone along to some of my associates. I think that we have previously spoken about at least 1 patient with esophageal Crohn's disease at this conference. We do like the topical steroid approach, as Dr. Tinsley mentioned. The fact that she has already been on IV steroids makes me wonder how much bang for the buck you will get there. One drug that I do not believe has been mentioned during this conference yet is tacrolimus, which has some evidence of efficacy, albeit limited. I think that I have this drug in my bucket of Dr. “Bill Tremain tricks” (from the IBD Center at Mayo Clinic) that I pull out when I am really in trouble. I would have to recall what Bill has instructed us to aim for as goal and trough levels, but tacrolimus has been shown to be helpful and is something to consider. I believe that last time we discussed a similar case, and I provided an anecdote about one of my patients who still continues to do well on ustekinumab. I know that it is easy to just decide to try our newest drug, but my patient was a very similar young woman who is the same age and had the same phenotype of horrible esophageal disease and she now has no esophageal disease. It may be luck and it may be just her course of illness but, in her case, we did have great results with ustekinumab and there are some supporting data in the literature. From my standpoint, in addition to what Dr. Tinsley has mentioned, tacrolimus and ustekinumab are medications that I would consider. Campbell, do you have any additional thoughts?
Dr. L. Campbell Levy (Gastroenterology, Dartmouth)
The only thing that I will tack on to what Dr. Tinsley has said is that it does seem that she responded well to infliximab. It would be my guess that she never got adalimumab levels high enough to have a response because it sounds like she was fairly ill when it was tried. I think that she developed documented antibodies to infliximab. From what I heard, although she did not have severe esophageal disease at that time, infliximab did seem to be effective. Given that she has been responsive to anti-TNF in the past, in addition to topical steroids and what has already been mentioned, I would be tempted to think about using a high-dose anti-TNF. I would consider using certolizumab in combination with a thiopurine because I think that she was responsive to this type of drug regimen for several years.
Dr. Miguel D. Regueiro (Gastroenterology, University of Pittsburgh)
Some of the new ideas include tacrolimus and ustekinumab as well as going back to an anti-TNF and using a high dose of infliximab or certolizumab in combination with a thiopurine. From a surgical perspective, it seems like we are in agreement that surgery would not be a good option for this patient because she has panintestinal, mouth to anus involvement. She does have an obstruction at her ileum that could be fixed but she would still have horrific esophageal disease and doing an esophagectomy would be a major surgery with limited benefits given the extent of her disease. Hans, what are your thoughts?
Dr. Hans H. Herfarth (Gastroenterology, University of North Carolina)
Everybody has his or her own experience with these difficult cases. Dr. Isaacs and I share some of these patients, and as Dr. Siegel said, we can describe how we treated similar patients. I had a patient who was similar to the one described today, and my patient responded to a combination of thalidomide and infliximab. Aside from blocking TNF, thalidomide is known to inhibit angiogenesis and for this patient this highly unusual therapy worked. I had 2 other similar patients with esophageal Crohn's disease that responded very well to vedolizumab. Crohn's disease of the esophagus is probably a different entity than, for example, small bowel Crohn's disease. So I am wondering if you might continue the thalidomide, may be increasing the dose a little bit, and then start vedolizumab. Then you would have a combination approach that uses 2 mechanisms instead of 1. We have also had a good experience with subcutaneous methotrexate with an initial dose of IV steroids. Essentially, we can pool all of our experiences with challenging patients to provide treatment ideas but there is no standard, guideline-based, optimal therapeutic approach for these types of patients.
Dr. Kim L. Isaacs (Gastroenterology, University of North Carolina)
I would like to add 1 thing in regards to the axillary hidradenitis. Our dermatologists have greatly helped a few of my patients by removing the tracts and then doing laser hair removal in the axillary area, thereby taking away that nidus.
Dr. Miguel D. Regueiro (Gastroenterology, University of Pittsburgh)
H. Iskandar, you are probably going to end up with about 15 different opinions on how to treat this patient due to the complexity of this case. Hans has mentioned continuing the thalidomide and adding a biologic, encouraging you to maximize the dose of the biologic, whereas Kim has some suggestions for dealing with the axillary hidradenitis. Let us go to Boston.
Dr. Francis A. Farraye (Gastroenterology, Boston Medical Center)
This patient presented in her teens with very aggressive Crohn's disease. She has some additional, seemingly unrelated findings with cafe au lait spots and previous craniofacial surgeries. I would consult with the geneticists at Emory to determine whether they might know of 1 entity that would tie all of her problems together. Genetic studies are often quite valuable for children and young adults who present with such extreme disease. We would maximize her thalidomide dose. We are not as enthusiastic about the idea of giving a third anti-TNF because we know that the response to third anti-TNFs is not very good. We do like the idea of ustekinumab because, similar to our colleagues at Dartmouth, we have used ustekinumab off-label in patients with Crohn's disease with cutaneous manifestations and for hidradenitis. There are a number of published case reports that describe using ustekinumab for patients with hidradenitis. I am surprised that no one has recommended cyclosporine as a rescue therapy. In summary, I would confirm that she does not have a systemic genetic disorder, maximize her thalidomide, and consider starting ustekinumab.
Dr. Heba Iskandar (Gastroenterology, Emory)
I have read that doses of up to 200 mg of thalidomide can be beneficial. She has already been on thalidomide for about 6 months. I am getting electromyography because I am nervous about long-term use of this medication. I am wondering what the highest dose and the longest amount of time are that you would recommend for this patient if I were to choose to use thalidomide in combination with ustekinumab or vedolizumab? What is my end game? Thankfully, right now she is not sexually active so pregnancy is not a risk.
Dr. David G. Binion (Gastroenterology, University of Pittsburgh)
This is life-threatening Crohn's disease. Unfortunately we do not have a uniform terminology that helps us to differentiate these very severe cases. This is also a glaring example of why it is a disservice to lump patients with Crohn's disease into 1 category, when there is tremendous heterogeneity based on the severity of their illness. Severity can be defined as the anatomical extent of the illness, in this case with essentially the entire GI tract being involved, and the ability or inability to control inflammation with our current therapies. We have a hope that anti-TNFs will work effectively but when we look at our multi-year experiences, we see that about 50% of patients with Crohn's disease who have been maintained on an anti-TNF continue to have deterioration, suggesting that mechanisms other than TNF are driving their inflammation. In addition, I think it is important to remember that infliximab and adalimumab are not the same drug. Although both are classified as anti-TNF agents, they are different molecules with different spectrums of activity. The SWITCH trial by Geert Van Assche suggests that there is 30% drop off when infliximab responders are transitioned to adalimumab.1 We have seen this in a subgroup of our patients, where we may have reasonably good disease control with infliximab but loss of inflammation control with adalimumab. Although it is tempting to attribute this to drug levels, there are additional factors related to the intrinsic property of these different anti-cytokine antibodies and their in vivo spectrum of activity.
In addition, when we are challenged by a patient with severe and refractory inflammation, the use of combination immunosuppression is essential. There are additional immunomodulators that are routinely used in the management of rheumatologic disorders and in solid organ transplantation that could be considered in patients with IBD with this level of disease severity. When previously faced with patients with Crohn's disease suffering from severe esophageal disease, we have had some success with the use of mycophenolate mofetil. Mycophenolate mofetil is a selective inosine monophosphate dehydrogenase inhibitor that preferentially targets lymphocytes, which is why it has emerged as a superior agent in transplant immunosuppression. We can consider this agent a “second generation” version of the purine analog compounds routinely used in IBD management. Transplant level dosing of mycophenolate is associated with significant GI adverse events such as diarrhea, but lower dosages of these agents, particularly in combination with biological drugs, may be helpful for these severely ill individuals. The recent failure of the anti-TNF for the esophageal disease suggests a role for the agent ustekinumab in this setting.
The other issue worth highlighting from this case is the interpretation of laboratory results in the setting of active inflammation. This patient manifested active disease including weight loss, frank anemia with a hemoglobin of 10 but a ferritin level that demonstrated marked elevation. We need to remember that ferritin, along with other serum assays of nutritional status, will elevate artificially during the acute phase response, thus suggesting a falsely normal level. This will be true of the serum vitamin B12 monitoring which is an important consideration in the setting of thalidomide use. If a patient with Crohn's disease has low vitamin B12 and is attempting therapy with thalidomide, they may be at higher risk for developing neuropathy. Both thalidomide and vitamin B12 deficiency may contribute to peripheral neuropathy and an individual with both of these risk factors may be even more likely to develop neuropathy. It may be worthwhile to supplement with B12 if thalidomide is needed for ongoing therapy.
I have used thalidomide in about 10 refractory patients with Crohn's disease and a neuropathy has emerged in many of them. Unfortunately, this neuropathy can be permanent. So I would not necessarily want to use thalidomide as a long-term approach. One hundred mg daily is the thalidomide dose that we have most commonly used and we have not typically increased dosing for all of the reasons that we have discussed.
Dr. Miguel D. Regueiro (Gastroenterology, University of Pittsburgh)
I will just echo what D. G. Binion said before going to other sites. I would consider going up to 100 mg of thalidomide. Based on everything that was just mentioned, I would give her just a 6-month window on thalidomide. I would also try ustekinumab. You can get the genetic tests that Dr. Farraye alluded to, although we sometimes receive the test results and do not exactly know what we have or what the best treatment is. Nonetheless, I would start ustekinumab and increase thalidomide to 100 mg for 6 months. If that does not work, I would go back to infliximab and be very aggressive by starting with 10 mg/kg but with very regular checks of drug levels. Dr. Rosh, this is a young patient, so I would like to know your thoughts and then let us go to Children's Hospital of Pittsburgh.
Dr. Joel R. Rosh (Pediatric Gastroenterology, Atlantic Health)
I want to stress the urgency of this patient's situation. Dr. Binion described her condition as life threatening and I agree with that term. We had 1 similar patient. Your patient already has some evidence of stenosis at the IC valve and we are all mindful that the esophagus is developing stenosis. If you are looking for surgical options, another way to go is with an interventional endoscopist. For our patient, regular dilations of the esophagus have been really life saving and have allowed him to continue to eat. So that is 1 thing that you might want to consider. You might also want to think about obtaining a contrast study of the esophagus to give you some sense of the caliber of the esophagus and where a stenosis may be developing.
Your patient was diagnosed at age 15. It is a common practice for pediatric gastroenterologists to do an upper endoscopy and colonoscopy at the time of diagnosis. I do not know if this patient was diagnosed by a pediatric gastroenterologist or not but it might be helpful to know if the esophageal disease was present at the start. My guess is that it was and this speaks loudly to what many of our colleagues have already said, in that she did have a good response to anti-TNFs and that, perhaps, her esophageal disease was controlled. It was only when she started to show low drug levels and antibodies that they seemed to lose their effectiveness. The comments earlier about how to interpret antibodies are spot on. Her adalimumab antibody level was not impressive but her lack of good drug level was quite impressive. The advice of really optimizing anti-TNF and using combination therapy is valuable. The patient is female. There are some case reports of esophageal mucosal reaction to methotrexate. So this is someone who I would think of titrating with infliximab, and if that does not work, switching to ustekinumab because I think that you do have a good signal here that she responded to anti-TNF therapy in the past. And be really aggressive with keeping the esophagus open with regular dilations as necessary.
Dr. David J. Keljo (Pediatric Gastroenterology, Children's Hospital of Pittsburgh)
I have 2 quick comments. I would definitely send off the Emory Early IBD gene chip. I think it is possible that she has an nicotinamide adenine dinucleotide phosphate oxidase defect. If the ustekinumab fails, I would consider an autologous stem cell transplant. It amounts to an immunological reset and patients who have become allergic to infliximab typically tolerate it after the transplant.
Genetic testing was discussed with the patient and her parents. They mentioned that she had undergone some testing during her childhood after her craniofacial surgeries, and they preferred to hold off on further testing at the current time. We decided to start the patient on ustekinumab because it is FDA approved to treat Crohn's disease that has not responded to standard treatments and it also may be effective for her hidradenitis. The patient responded well to ustekinumab. After a total of 10 months on thalidomide, therapy was discontinued after she developed paresthesias on the lateral side of her feet, and electromyography showed signs of neuropathy. She was started on weight-based 6-MP and was able to taper off of systemic prednisone. Thereafter, she was started on a budesonide slurry 1 mg twice a day. At her latest clinic visit, she was eating well without symptoms and her weight was 172 pounds. A repeat upper endoscopy was scheduled for this month. If her esophagus were to show improvement at endoscopy, budesonide would be discontinued and 6-MP metabolites would be measured.
Approximately 20% to 25% of IBD cases are diagnosed before the age of 20 years.2,3 Familial evidence suggests that genetic susceptibility may play a greater role in childhood-onset IBD than in IBD that presents in adults.3 Crohn's disease in children may have clinical features that differ from those seen in adults. Childhood Crohn's disease has been shown to be anatomically progressive in over one-third of patients.4 Rapid early progression, often with ileal involvement, is particularly common among children older than 8 years.4 And, although esophageal Crohn's disease is an uncommon entity among adults, it is more frequently observed in children. Among 9900 patients with Crohn's disease who were evaluated at Mayo Clinic Rochester between 1976 and 1998, only 20 patients (0.2%) were identified as having esophageal involvement.5 All of these patients were diagnosed with extraesophageal Crohn's disease either before or at the same time that their esophageal Crohn's disease was initially identified. Esophageal ulcers, erosions, and erythema were common among these patients and 4 of them (20%) had esophageal strictures. The mean age at diagnosis in this cohort was 31 years.
Overall, the incidence of esophageal Crohn's disease in adults is estimated to range from 0.2% to 11.2%, but in children it may be as high as 43%.6,7 The incidence may actually be underestimated in the adult population because there are no guidelines for performing an upper endoscopy in asymptomatic adult Crohn's disease patients. Because of its greater incidence in younger patients, upper endoscopy is a standard diagnostic procedure for Crohn's disease in children. Common presenting symptoms of esophageal Crohn's disease include odynophagia, dysphagia, heartburn, chest pain, and aphthous ulcers. It is less usual for patients to present with strictures or with fistulizing disease that involves the bronchus, mediastinum, or stomach.8 The clinical diagnosis of esophageal Crohn's disease can be difficult and is made through a combination of historical, endoscopic, and pathologic findings. Multiple esophageal biopsies taken at endoscopy are required both to establish the diagnosis and to rule out other entities, such as gastroesophageal reflux, viral esophagitis, and malignancy.
Extraintestinal manifestations are common among patients with Crohn's disease that involves the esophagus.9 An early study of London reported that 7 of 9 patients with esophageal Crohn's disease had at least 1 extraintestinal manifestation, with arthritis, episcleritis, and erythema nodosum being the most frequently observed.10 Skin manifestations that one typically associates with IBD in children include pyoderma gangrenosum, orofacial disease, erythema nodosum, and idiopathic lymphedema.11 The patient whom we described in this conference had tenacious, multifocal hidradenitis suppurativa.
Hidradenitis suppurativa typically occurs in adolescents and adults, rarely manifesting before puberty. Hidradenitis is 2- to 5-times more common among females than males, with some studies finding a relationship with body mass index, menstruation, and inflammatory or autoimmune disorders.12 When onset is years after puberty, comorbidities such as diabetes and metabolic syndrome are often present.12–15 In addition to episodic inflammation, features of hidradenitis suppurativa include comedo-like follicular occlusions, mucopurulent discharge, and progressive scarring. Lesions may present insidiously, with erythema progressing to painful blocked pores, sinus tracts, cysts, and abscesses that can restrict one's movement.14 An immunological association between hidradenitis and Crohn's disease has been investigated, with the similar presence of numerous CD4+ CD161+ lymphocytes in a Crohn's disease fistula and hidradenitis suppurativa lesion curettages being noteworthy.16 Numerous case reports have described hidradenitis in patients with Crohn's disease whose skin lesions improved when the patient was treated with infliximab.17–21
In addition to the presence of extraintestinal manifestations, patients with esophageal Crohn's disease frequently demonstrate a more severe form of illness than those with Crohn's disease of the lower GI tract and are often refractory to treatment. There are no standard guidelines for the treatment of esophageal Crohn's disease. Topical therapy is often used in conjunction with systemic medication. For example, building on its effectiveness in treating eosinophilic esophagitis, topical treatment with oral viscous budesonide (budesonide slurry) has been shown to be a beneficial adjuvant treatment for esophageal Crohn's disease.8,22,23 Systemic treatments that may be effective for esophageal Crohn's disease include proton pump inhibitors, corticosteroids, antimetabolites, antirejection medications, and anti-TNF agents.9,24,25 Anti-TNF agents are more appropriate for patients with moderate-to-severe disease. However, anti-TNFs are known to carry the risk of consequential side effects, including the risk of serious infections and certain types of cancer.26,27 In addition, serial treatment with different anti-TNFs may have limited benefit. Patients who have experienced treatment failures with 1 or more anti-TNF agents are less likely to respond to subsequent anti-TNF therapy.28–30
Ustekinumab is a human monoclonal antibody against interleukin-12 and interleukin-23 that was approved for the treatment of moderately to severely active Crohn's disease in patients aged 18 years or older in 2016. A retrospective study of 122 patients with Crohn's disease that had failed immunomodulators and at least 1 anti-TNF noted clinical benefit from ustekinumab in 93% and 68% of patients at 6 and 12 months, respectively.31 In a randomized controlled trial of 526 adult patients with moderate-to-severe Crohn's disease who failed previous anti-TNF treatment, 145 patients initially responded to ustekinumab and demonstrated significantly higher rates of response (69.4% versus 42.5%, P < 0.001) and clinical remission (41.7% versus 27.4%, P = 0.03) at 22 weeks than those on placebo.32 Of greater relevance to our patient, a recent report describes a 23-year-old man with oral and esophageal Crohn's disease refractory to combination treatment with high-dose prednisone, swallowed fluticasone, aggressive acid suppression, and certolizumab pegol, who was treated successfully and entered remission with ustekinumab.33 In addition, ustekinumab may be effective in treating hidradenitis, which made it an attractive choice for the patient who was presented.34,35
However, there is a subset of patients with esophageal Crohn's disease who do not respond to traditional or more innovative therapies.36 Thalidomide has recently been shown to be successful in treating selected, refractory cases of Crohn's disease, although its use is greatly limited by serious side effects, including dose-dependent neuropathy.37–40 Thalidomide was first found to be teratogenic in 1957 after it was prescribed to pregnant women to alleviate morning sickness.41 The offspring of these women had a rare birth defect that involved short, malformed limbs known as phocomelia.42 For this reason, women of childbearing age who take thalidomide are advised to abstain from sexual intercourse or use 2 forms of contraception if they are sexually active; they also must have a negative pregnancy test within 24 hours of starting thalidomide and must take a pregnancy test every week for the first 4 weeks after starting thalidomide and then every 2 to 4 weeks thereafter while taking thalidomide. Short-term use of thalidomide may play a role in the management of extremely difficult cases, including patients with esophageal Crohn's disease.43 Patients with life-threatening Crohn's disease who do not respond to any therapy and who are not surgical candidates may benefit from an autologous stem cell transplant, although this treatment is experimental at this time.44,45
Management dilemmas are not uncommon for practitioners that care for patients with refractory Crohn's disease. The young woman described in this conference had severe and aggressive disease in her esophagus as well as her ileum, colon, and perianal region. Her management was complicated by the presence of hidradenitis suppurativa, significant weight loss, anemia, and C. difficile infection. Because of the rarity of esophageal Crohn's disease in adults, appropriate and effective treatment algorithms have not been established. In addition to the standard armamentarium of IBD medications, proton pump inhibitors, oral viscous budesonide, the immunomodulator thalidomide, antirejection medications, and newer biologics may play a role in achieving symptom management and mucosal healing when traditional treatments fail (Table 2).8,24,39,46,47 The risks and benefits of many of these medications must be evaluated carefully to avoid causing lasting side effects. Because of frequent relapses, patients with esophageal Crohn's disease should undergo regular EGD, dilation of strictures, and assessment of disease activity, even when they are not experiencing characteristic symptoms.
H. Iskandar has consulted for UCB and AbbVie. J. B. Greer holds a grant from AbbVie. A. T. Tinsley has previously consulted for Janssen Pharmaceutica and is involved in ongoing consulting and lecturing for AbbVie. C. A. Siegel serves as a consultant to AbbVie, Amgen, Lilly, Janssen, Sandoz, Pfizer, Prometheus, Takeda, UCB, has delivered CME activities to American Regent, AbbVie, Janssen, Pfizer, Takeda, and has received grant support from AbbVie, Janssen, Pfizer, and Takeda. H. H. Herfarth receives consulting fees from Pfizer, Celltrion, Samsung, Merck, and UCB. F. A. Farraye serves on the Advisory Boards of AbbVie, Braintree Labs, Janssen, Merck, Pfizer, Salix, and Takeda; is a member of the DSMB for Mesoblast and Protagonist; receives book royalties from Jones and Bartlett and Slack; and is a shareholder of Cellceutix. D. G. Binion has grant support from Janssen, Merck, and UCB and has received honoraria from Janssen, AbbVie, and Synthetic Biologics. J. R. Rosh serves as a consultant to and has received grant support from AbbVie and Janssen. K. L. Isaacs consults on the Data Safety Monitoring Board for Medimmune and Janssen. M. D. Regueiro serves on the Advisory Boards and consults for AbbVie, Janssen, Pfizer, Takeda, and UCB. The remaining authors have no conflict of interest to disclose.
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