An unfortunate fact for many physicians practicing in the United States is that they will contend with medical malpractice suits at some point in their careers. While data specific to gastroenterology malpractice claims is difficult to find,¹ the Physician Insurers Association of America has reported that out of the 28 specialty fields of medicine analyzed from 1985 to 2004, gastroenterology ranked 21st in the number of claims reported², representing about 2% of the total overall number of claims.

JAMA

Professional liability

Patients can allege or establish malpractice liability against a doctor based on a number of things; we will discuss a few of the most common types of liability, offer suggestions as to how you might minimize your risk of being sued, and how best to cope when you are sued.

Negligence: One of the most common theories you may be sued under is negligence. To state a negligence claim against a physician, a plaintiff must show that the doctor owed the patient a duty recognized by law, that the physician breached that duty, that the alleged breach resulted in injury to the patient, and that the patient sustained legally recognized damages as a result. In a lawsuit brought on the basis of claimed medical negligence, a patient claims that a physician, in the course of rendering treatment, failed to meet the applicable standard of care.

Contractual liability of doctor to patient: Physicians and patients can enter into express written contracts regarding the care provided. These contracts can include various treatment plans, the likelihood of success, and even the physician’s promise to cure. Traditionally, courts have respected a physician’s freedom to contract as he or she chooses. However, once a contract is formed, a plaintiff may have a cause of action for breach of contract if the outcome of the treatment is not what was promised.
 

Minimizing risk

Another opportunity to decrease your chances of being sued is to keep informed about recent developments in your field. Make a point to read pertinent literature, attend seminars, and do whatever is necessary to stay aware of, and to incorporate into your practice, current methods of treatment and diagnosis.

Physicians should also be cognizant of contractual liability. When discussing treatment, never guarantee results. Additionally, once a physician-patient relationship is established, you cannot withdraw from the relationship without providing adequate notice to the patient in time to obtain alternative care. Terminating the relationship without such is called abandonment, and can result in professional discipline and civil liability.

Conclusion

Before a lawsuit, and as a regular part of your practice, it is important that you thoroughly and legibly document all aspects of care provided, stay current with medical advances, and take the time to create a relationship with your patients involving quality communication. It is impossible for us to provide you with enough information to adequately prepare you for the day on which you may be sued. We nevertheless hope that following the aforementioned suggestions will be of some help.

References

1. Medical Malpractice Claims and Risk Management in Gastroenterology and Gastrointestinal Endoscopy. American Society for Gastrointestinal Endoscopy, 2017. <www.asge.org>.

2. Physician Insurers Association of America. PIAA Claim Trend Analysis: Gastroenterology, iv. Lawrenceville, N.J.: PIAA, 2004. <http://www.piaa.us>.

3. Kane C., Policy Research Perspective: Medical Liability Claim Frequency: 2007-2008 Snapshot of Physicians, American Medical Association, 2010.

4. Schaffer A.C., et al. JAMA Internal Med. 2017;177(5):710-8.

5. Dodge A.M. Wilsonville, Ore. Book Partners, Inc. 2001.

An unfortunate fact for many physicians practicing in the United States is that they will contend with medical malpractice suits at some point in their careers. While data specific to gastroenterology malpractice claims is difficult to find,¹ the Physician Insurers Association of America has reported that out of the 28 specialty fields of medicine analyzed from 1985 to 2004, gastroenterology ranked 21st in the number of claims reported², representing about 2% of the total overall number of claims.

JAMA

Professional liability

Patients can allege or establish malpractice liability against a doctor based on a number of things; we will discuss a few of the most common types of liability, offer suggestions as to how you might minimize your risk of being sued, and how best to cope when you are sued.

Negligence: One of the most common theories you may be sued under is negligence. To state a negligence claim against a physician, a plaintiff must show that the doctor owed the patient a duty recognized by law, that the physician breached that duty, that the alleged breach resulted in injury to the patient, and that the patient sustained legally recognized damages as a result. In a lawsuit brought on the basis of claimed medical negligence, a patient claims that a physician, in the course of rendering treatment, failed to meet the applicable standard of care.

Contractual liability of doctor to patient: Physicians and patients can enter into express written contracts regarding the care provided. These contracts can include various treatment plans, the likelihood of success, and even the physician’s promise to cure. Traditionally, courts have respected a physician’s freedom to contract as he or she chooses. However, once a contract is formed, a plaintiff may have a cause of action for breach of contract if the outcome of the treatment is not what was promised.
 

Minimizing risk

Another opportunity to decrease your chances of being sued is to keep informed about recent developments in your field. Make a point to read pertinent literature, attend seminars, and do whatever is necessary to stay aware of, and to incorporate into your practice, current methods of treatment and diagnosis.

Physicians should also be cognizant of contractual liability. When discussing treatment, never guarantee results. Additionally, once a physician-patient relationship is established, you cannot withdraw from the relationship without providing adequate notice to the patient in time to obtain alternative care. Terminating the relationship without such is called abandonment, and can result in professional discipline and civil liability.

Conclusion

Before a lawsuit, and as a regular part of your practice, it is important that you thoroughly and legibly document all aspects of care provided, stay current with medical advances, and take the time to create a relationship with your patients involving quality communication. It is impossible for us to provide you with enough information to adequately prepare you for the day on which you may be sued. We nevertheless hope that following the aforementioned suggestions will be of some help.

References

1. Medical Malpractice Claims and Risk Management in Gastroenterology and Gastrointestinal Endoscopy. American Society for Gastrointestinal Endoscopy, 2017. <www.asge.org>.

2. Physician Insurers Association of America. PIAA Claim Trend Analysis: Gastroenterology, iv. Lawrenceville, N.J.: PIAA, 2004. <http://www.piaa.us>.

3. Kane C., Policy Research Perspective: Medical Liability Claim Frequency: 2007-2008 Snapshot of Physicians, American Medical Association, 2010.

4. Schaffer A.C., et al. JAMA Internal Med. 2017;177(5):710-8.

5. Dodge A.M. Wilsonville, Ore. Book Partners, Inc. 2001.

An unfortunate fact for many physicians practicing in the United States is that they will contend with medical malpractice suits at some point in their careers. While data specific to gastroenterology malpractice claims is difficult to find,¹ the Physician Insurers Association of America has reported that out of the 28 specialty fields of medicine analyzed from 1985 to 2004, gastroenterology ranked 21st in the number of claims reported², representing about 2% of the total overall number of claims.

JAMA

Professional liability

Patients can allege or establish malpractice liability against a doctor based on a number of things; we will discuss a few of the most common types of liability, offer suggestions as to how you might minimize your risk of being sued, and how best to cope when you are sued.

Negligence: One of the most common theories you may be sued under is negligence. To state a negligence claim against a physician, a plaintiff must show that the doctor owed the patient a duty recognized by law, that the physician breached that duty, that the alleged breach resulted in injury to the patient, and that the patient sustained legally recognized damages as a result. In a lawsuit brought on the basis of claimed medical negligence, a patient claims that a physician, in the course of rendering treatment, failed to meet the applicable standard of care.

Contractual liability of doctor to patient: Physicians and patients can enter into express written contracts regarding the care provided. These contracts can include various treatment plans, the likelihood of success, and even the physician’s promise to cure. Traditionally, courts have respected a physician’s freedom to contract as he or she chooses. However, once a contract is formed, a plaintiff may have a cause of action for breach of contract if the outcome of the treatment is not what was promised.
 

Minimizing risk

Another opportunity to decrease your chances of being sued is to keep informed about recent developments in your field. Make a point to read pertinent literature, attend seminars, and do whatever is necessary to stay aware of, and to incorporate into your practice, current methods of treatment and diagnosis.

Physicians should also be cognizant of contractual liability. When discussing treatment, never guarantee results. Additionally, once a physician-patient relationship is established, you cannot withdraw from the relationship without providing adequate notice to the patient in time to obtain alternative care. Terminating the relationship without such is called abandonment, and can result in professional discipline and civil liability.

Conclusion

Before a lawsuit, and as a regular part of your practice, it is important that you thoroughly and legibly document all aspects of care provided, stay current with medical advances, and take the time to create a relationship with your patients involving quality communication. It is impossible for us to provide you with enough information to adequately prepare you for the day on which you may be sued. We nevertheless hope that following the aforementioned suggestions will be of some help.

References

1. Medical Malpractice Claims and Risk Management in Gastroenterology and Gastrointestinal Endoscopy. American Society for Gastrointestinal Endoscopy, 2017. <www.asge.org>.

2. Physician Insurers Association of America. PIAA Claim Trend Analysis: Gastroenterology, iv. Lawrenceville, N.J.: PIAA, 2004. <http://www.piaa.us>.

3. Kane C., Policy Research Perspective: Medical Liability Claim Frequency: 2007-2008 Snapshot of Physicians, American Medical Association, 2010.

4. Schaffer A.C., et al. JAMA Internal Med. 2017;177(5):710-8.

5. Dodge A.M. Wilsonville, Ore. Book Partners, Inc. 2001.

The 2017 AGA Women’s Leadership Conference brought together 38 women from across the United States and Mexico for an inspiring and productive meeting. The group included 21 early-career and 17 experienced track women in GI. Among the attendees were 3 PhDs, 9 private practitioners, 1 pediatric gastroenterologist, and 25 academic gastroenterologists. We were particularly fortunate to benefit from the strong representation of AGA leadership, including Marcia Cruz-Correa, MD, PhD, AGAF (At-Large Councillor) and Deborah Proctor, MD, AGAF (Education and Training Councillor), as well as Ellen Zimmermann, MD, AGAF (Chair of the Women’s Committee) and Sheila Crowe, MD, AGAF (President, AGA Institute Governing Board).

The AGA leaders in attendance shared inspiring stories of their own paths to leadership. These paths were not linear and it was reassuring to discover common themes of finding and developing personal strengths, identifying passions, and building areas of expertise. We learned, how once identified, strengths and passions can be connected to areas of need within a home institution or an organization such as the AGA. Dr. Zimmermann offered moving commentary about her own journey as a clinician, scientist, and mother. She encouraged those in attendance with small children to take the time to be present at home, knowing that there will be opportunities to assume leadership roles in the future. Of course, for others, the time to assume leadership roles may be now, and the Women’s Leadership Conference offered the chance to network and forge new connections within the AGA.

Dr. Garman is an assistant professor of medicine in the division of gastroenterology at Duke University, Durham, N.C. Dr. Alaparthi is managing partner of Gastroenterology Center of Connecticut and assistant clinical professor of medicine at Yale School of Medicine, Conn., and Frank Netter School of Medicine, Conn.

The 2017 AGA Women’s Leadership Conference brought together 38 women from across the United States and Mexico for an inspiring and productive meeting. The group included 21 early-career and 17 experienced track women in GI. Among the attendees were 3 PhDs, 9 private practitioners, 1 pediatric gastroenterologist, and 25 academic gastroenterologists. We were particularly fortunate to benefit from the strong representation of AGA leadership, including Marcia Cruz-Correa, MD, PhD, AGAF (At-Large Councillor) and Deborah Proctor, MD, AGAF (Education and Training Councillor), as well as Ellen Zimmermann, MD, AGAF (Chair of the Women’s Committee) and Sheila Crowe, MD, AGAF (President, AGA Institute Governing Board).

The AGA leaders in attendance shared inspiring stories of their own paths to leadership. These paths were not linear and it was reassuring to discover common themes of finding and developing personal strengths, identifying passions, and building areas of expertise. We learned, how once identified, strengths and passions can be connected to areas of need within a home institution or an organization such as the AGA. Dr. Zimmermann offered moving commentary about her own journey as a clinician, scientist, and mother. She encouraged those in attendance with small children to take the time to be present at home, knowing that there will be opportunities to assume leadership roles in the future. Of course, for others, the time to assume leadership roles may be now, and the Women’s Leadership Conference offered the chance to network and forge new connections within the AGA.

Dr. Garman is an assistant professor of medicine in the division of gastroenterology at Duke University, Durham, N.C. Dr. Alaparthi is managing partner of Gastroenterology Center of Connecticut and assistant clinical professor of medicine at Yale School of Medicine, Conn., and Frank Netter School of Medicine, Conn.

The 2017 AGA Women’s Leadership Conference brought together 38 women from across the United States and Mexico for an inspiring and productive meeting. The group included 21 early-career and 17 experienced track women in GI. Among the attendees were 3 PhDs, 9 private practitioners, 1 pediatric gastroenterologist, and 25 academic gastroenterologists. We were particularly fortunate to benefit from the strong representation of AGA leadership, including Marcia Cruz-Correa, MD, PhD, AGAF (At-Large Councillor) and Deborah Proctor, MD, AGAF (Education and Training Councillor), as well as Ellen Zimmermann, MD, AGAF (Chair of the Women’s Committee) and Sheila Crowe, MD, AGAF (President, AGA Institute Governing Board).

The AGA leaders in attendance shared inspiring stories of their own paths to leadership. These paths were not linear and it was reassuring to discover common themes of finding and developing personal strengths, identifying passions, and building areas of expertise. We learned, how once identified, strengths and passions can be connected to areas of need within a home institution or an organization such as the AGA. Dr. Zimmermann offered moving commentary about her own journey as a clinician, scientist, and mother. She encouraged those in attendance with small children to take the time to be present at home, knowing that there will be opportunities to assume leadership roles in the future. Of course, for others, the time to assume leadership roles may be now, and the Women’s Leadership Conference offered the chance to network and forge new connections within the AGA.

Dr. Garman is an assistant professor of medicine in the division of gastroenterology at Duke University, Durham, N.C. Dr. Alaparthi is managing partner of Gastroenterology Center of Connecticut and assistant clinical professor of medicine at Yale School of Medicine, Conn., and Frank Netter School of Medicine, Conn.

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

Copyright Elsevier/AGA

Testing on or off PPI?

For symptoms attributable to GERD that persist despite properly administered PPI therapy, the 2013 American College of Gastroenterology guidelines suggest upper endoscopy with esophageal biopsies for typical symptoms and appropriate referrals for atypical symptoms.²⁴ However, if these evaluations are unremarkable, reflux monitoring is recommended, with PPI status for testing guided by the pre-test probability of GERD: with a low pre-test probability of GERD, reflux testing is best performed off PPI with either pH or combined pH-impedance testing. In contrast, with a high pre-test probability of GERD, testing is best performed on PPI with combined pH-impedance testing. A similar concept is proposed in the Rome IV approach (Figure 2)²³ and on GERD consensus guidelines:⁷ when heartburn or chest pain persists despite PPI therapy and endoscopy and esophageal biopsies are normal, evidence for GERD (past esophagitis, Barrett’s esophagus, peptic stricture, or prior positive reflux testing) prompts pH-impedance monitoring on PPI therapy (i.e., proven GERD). Those without this evidence for proven GERD (i.e., unproven GERD) are best tested off PPI, and the test utilized can be either pH alone or combined pH-impedance.

GERD phenotypes and management

The presence or absence of the two core metrics on ambulatory reflux monitoring – abnormal AET and positive SRA – can stratify symptomatic GERD patients into phenotypes that predict symptomatic improvement with antireflux therapy and guide management of symptoms (Figure 3).^25,26 The presence of both abnormal AET and positive SRA suggests “strong” evidence for GERD, for which symptom improvement is likely with maximization of antireflux therapy, which can include BID PPI, baclofen (to decrease transient LES relaxations), alginates (such as Gaviscon), and consideration of endosopic or surgical antireflux procedures such as fundoplication or magnetic sphincter augmentation. Abnormal AET but negative SRA is regarded as “good” evidence for GERD, for which similar antireflux therapies can be advocated. Normal AET but positive SRA is designated as “reflux hypersensitivity,”²³ with increasing proportions of patients meeting this phenotype when tested with combined pH-impedance and off PPI therapy.²⁷ Both normal AET and negative SRA suggest equivocal evidence for GERD and the likely presence of a functional esophageal disorder, such as functional heartburn.²³ For reflux hypersensitivity and especially functional esophageal disorders, antireflux therapy is unlikely to be as effective and management can include pharmacologic neuromodulation (such as tricyclic antidepressants administered at bedtime) as well as adjunctive nonpharmacologic approaches (such as stress reduction, relaxation, hypnosis, or cognitive-behavioral therapy).

The future of reflux diagnostics

Conclusions

For esophageal symptoms potentially attributable to GERD that persist despite optimized PPI therapy, esophageal testing should be undertaken, starting with endoscopy and biopsies and proceeding to ambulatory reflux monitoring with HRM. The decisions between pH testing alone versus combined pH-impedance monitoring, and between testing on or off PPI therapy, can be guided either by the pre-test probability of GERD or whether GERD has been proven or unproven in prior evaluations (Figure 2). Elevated AET and positive SRA with impedance-detected reflux events can predict the likelihood of successful management outcomes from antireflux therapy. These two core metrics can be utilized to phenotype GERD and guide management approaches for persisting symptoms (Figure 3). Novel impedance metrics (baseline mucosal impedance, postreflux swallow-induced peristaltic wave index) and markers for esophageal mucosal damage continue to be studied as potential markers for evidence of longitudinal reflux exposure.

Dr. Patel is assistant professor of medicine, division of gastroenterology, Duke University School of Medicine and the Durham Veterans Affairs Medical Center, Durham, N.C. Dr. Gyawali is professor of medicine, division of gastroenterology, Washington University School of Medicine, St. Louis, Mo.

References

1. Shaheen N.J., et al. Am J Gastroenterol. 2006;101:2128-38.

2. Patel A., Gyawali C.P.. Switzerland: Springer International, 2016.

3. Vakil N., et al. Am J Gastroenterol. 2006;101:1900-20; quiz 1943.

4. Fass R., et al. Arch Intern Med. 1999;159:2161-8.

5. Numans M.E., et al. Ann Intern Med. 2004;140:518-27.

6. Shaheen N.J., et al. Aliment Pharmacol Ther. 2011;33:225-34.

7. Roman S., et al. Neurogastroenterol Motil Mar 31. doi: 10.1111/nmo.13067. [Epub ahead of print] 2017.

8. Dellon E.S., et al. Am J Gastroenterol. 2013;108:679-92; quiz 693.

9. Pandolfino JE, Vela MF. Gastrointest Endosc. 2009;69:917-30, 930 e1.

10. Shay S., et al. Am J Gastroenterol. 2004;99:1037-43.

11. Zerbib F., et al. Clin Gastroenterol Hepatol. 2013;11:366-72.

12. Wiener G.J., et al. Am J Gastroenterol 1988;83:358-61.

13. Weusten B.L., et al. Gastroenterology. 1994;107:1741-5.

14. Ghillebert G., et al. Gut 1990;31:738-44.

15. Kushnir V.M., et al. Aliment Pharmacol Ther. 2012;35(9):1080-7.

16. Bredenoord A.J., et al. Am J Gastroenterol. 2006;101:453-9.

17. Patel A., et al. Clin Gastroenterol Hepatol. 2015;13:884-91.

18. Slaughter J.C., et al. Clin Gastroenterol Hepatol. 2011;9:868-74.

19. Kavitt R.T., et al. Am J Gastroenterol. 2012;107:1826-32.

20. Kahrilas P.J., et al. Gastroenterology 2008;135:1383-91, 1391 e1-5.

21. Kessing B.F., et al. Clin Gastroenterol Hepatol. 2011;9:1020-4.

22. Kahrilas P.J., et al. Neurogastroenterol Motil. 2015;27:160-74.

23. Aziz A, et al. Esophageal disorders. Gastroenterology 2016;150:1368-79.

24. Katz P.O., et al. Am J Gastroenterol. 2013;108:308-28; quiz 329.

25. Boeckxstaens G., et al. Gut 2014;63:1185-93.

26. Patel A., et al. Neurogastroenterol Motil. 2016;28:513-21.

27. Patel A., et al. Neurogastroenterol Motil. 2016;28:1382-90.

28. Martinucci I., et al. Neurogastroenterol Motil. 2014;26:546-55.

29. Ates F., et al. Gastroenterology 2015;148:334-43.

30. Kessing B.F., et al. Am J Gastroenterol. 2011;106:2093-7.

31. Patel A., et al. Aliment Pharmacol Ther. 2016;44:890-8.

32. Frazzoni M., et al. Neurogastroenterol Motil. 2016.

33. Frazzoni M., et al. Neurogastroenterol Motil. 2013;25:399-406, e295.

34. Vela M.F., et al. Am J Gastroenterol. 2011;106:844-50.
 

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

Copyright Elsevier/AGA

Testing on or off PPI?

For symptoms attributable to GERD that persist despite properly administered PPI therapy, the 2013 American College of Gastroenterology guidelines suggest upper endoscopy with esophageal biopsies for typical symptoms and appropriate referrals for atypical symptoms.²⁴ However, if these evaluations are unremarkable, reflux monitoring is recommended, with PPI status for testing guided by the pre-test probability of GERD: with a low pre-test probability of GERD, reflux testing is best performed off PPI with either pH or combined pH-impedance testing. In contrast, with a high pre-test probability of GERD, testing is best performed on PPI with combined pH-impedance testing. A similar concept is proposed in the Rome IV approach (Figure 2)²³ and on GERD consensus guidelines:⁷ when heartburn or chest pain persists despite PPI therapy and endoscopy and esophageal biopsies are normal, evidence for GERD (past esophagitis, Barrett’s esophagus, peptic stricture, or prior positive reflux testing) prompts pH-impedance monitoring on PPI therapy (i.e., proven GERD). Those without this evidence for proven GERD (i.e., unproven GERD) are best tested off PPI, and the test utilized can be either pH alone or combined pH-impedance.

GERD phenotypes and management

The presence or absence of the two core metrics on ambulatory reflux monitoring – abnormal AET and positive SRA – can stratify symptomatic GERD patients into phenotypes that predict symptomatic improvement with antireflux therapy and guide management of symptoms (Figure 3).^25,26 The presence of both abnormal AET and positive SRA suggests “strong” evidence for GERD, for which symptom improvement is likely with maximization of antireflux therapy, which can include BID PPI, baclofen (to decrease transient LES relaxations), alginates (such as Gaviscon), and consideration of endosopic or surgical antireflux procedures such as fundoplication or magnetic sphincter augmentation. Abnormal AET but negative SRA is regarded as “good” evidence for GERD, for which similar antireflux therapies can be advocated. Normal AET but positive SRA is designated as “reflux hypersensitivity,”²³ with increasing proportions of patients meeting this phenotype when tested with combined pH-impedance and off PPI therapy.²⁷ Both normal AET and negative SRA suggest equivocal evidence for GERD and the likely presence of a functional esophageal disorder, such as functional heartburn.²³ For reflux hypersensitivity and especially functional esophageal disorders, antireflux therapy is unlikely to be as effective and management can include pharmacologic neuromodulation (such as tricyclic antidepressants administered at bedtime) as well as adjunctive nonpharmacologic approaches (such as stress reduction, relaxation, hypnosis, or cognitive-behavioral therapy).

The future of reflux diagnostics

Conclusions

For esophageal symptoms potentially attributable to GERD that persist despite optimized PPI therapy, esophageal testing should be undertaken, starting with endoscopy and biopsies and proceeding to ambulatory reflux monitoring with HRM. The decisions between pH testing alone versus combined pH-impedance monitoring, and between testing on or off PPI therapy, can be guided either by the pre-test probability of GERD or whether GERD has been proven or unproven in prior evaluations (Figure 2). Elevated AET and positive SRA with impedance-detected reflux events can predict the likelihood of successful management outcomes from antireflux therapy. These two core metrics can be utilized to phenotype GERD and guide management approaches for persisting symptoms (Figure 3). Novel impedance metrics (baseline mucosal impedance, postreflux swallow-induced peristaltic wave index) and markers for esophageal mucosal damage continue to be studied as potential markers for evidence of longitudinal reflux exposure.

Dr. Patel is assistant professor of medicine, division of gastroenterology, Duke University School of Medicine and the Durham Veterans Affairs Medical Center, Durham, N.C. Dr. Gyawali is professor of medicine, division of gastroenterology, Washington University School of Medicine, St. Louis, Mo.

References

1. Shaheen N.J., et al. Am J Gastroenterol. 2006;101:2128-38.

2. Patel A., Gyawali C.P.. Switzerland: Springer International, 2016.

3. Vakil N., et al. Am J Gastroenterol. 2006;101:1900-20; quiz 1943.

4. Fass R., et al. Arch Intern Med. 1999;159:2161-8.

5. Numans M.E., et al. Ann Intern Med. 2004;140:518-27.

6. Shaheen N.J., et al. Aliment Pharmacol Ther. 2011;33:225-34.

7. Roman S., et al. Neurogastroenterol Motil Mar 31. doi: 10.1111/nmo.13067. [Epub ahead of print] 2017.

8. Dellon E.S., et al. Am J Gastroenterol. 2013;108:679-92; quiz 693.

9. Pandolfino JE, Vela MF. Gastrointest Endosc. 2009;69:917-30, 930 e1.

10. Shay S., et al. Am J Gastroenterol. 2004;99:1037-43.

11. Zerbib F., et al. Clin Gastroenterol Hepatol. 2013;11:366-72.

12. Wiener G.J., et al. Am J Gastroenterol 1988;83:358-61.

13. Weusten B.L., et al. Gastroenterology. 1994;107:1741-5.

14. Ghillebert G., et al. Gut 1990;31:738-44.

15. Kushnir V.M., et al. Aliment Pharmacol Ther. 2012;35(9):1080-7.

16. Bredenoord A.J., et al. Am J Gastroenterol. 2006;101:453-9.

17. Patel A., et al. Clin Gastroenterol Hepatol. 2015;13:884-91.

18. Slaughter J.C., et al. Clin Gastroenterol Hepatol. 2011;9:868-74.

19. Kavitt R.T., et al. Am J Gastroenterol. 2012;107:1826-32.

20. Kahrilas P.J., et al. Gastroenterology 2008;135:1383-91, 1391 e1-5.

21. Kessing B.F., et al. Clin Gastroenterol Hepatol. 2011;9:1020-4.

22. Kahrilas P.J., et al. Neurogastroenterol Motil. 2015;27:160-74.

23. Aziz A, et al. Esophageal disorders. Gastroenterology 2016;150:1368-79.

24. Katz P.O., et al. Am J Gastroenterol. 2013;108:308-28; quiz 329.

25. Boeckxstaens G., et al. Gut 2014;63:1185-93.

26. Patel A., et al. Neurogastroenterol Motil. 2016;28:513-21.

27. Patel A., et al. Neurogastroenterol Motil. 2016;28:1382-90.

28. Martinucci I., et al. Neurogastroenterol Motil. 2014;26:546-55.

29. Ates F., et al. Gastroenterology 2015;148:334-43.

30. Kessing B.F., et al. Am J Gastroenterol. 2011;106:2093-7.

31. Patel A., et al. Aliment Pharmacol Ther. 2016;44:890-8.

32. Frazzoni M., et al. Neurogastroenterol Motil. 2016.

33. Frazzoni M., et al. Neurogastroenterol Motil. 2013;25:399-406, e295.

34. Vela M.F., et al. Am J Gastroenterol. 2011;106:844-50.
 

Introduction

Chronic esophageal symptoms attributed to gastroesophageal reflux disease (GERD) are common presenting symptoms in gastroenterology, leading to high healthcare costs and adverse quality of life globally.^1,2 The clinical diagnosis of GERD hinges on the presence of “troublesome” compatible typical symptoms (heartburn, acid regurgitation) or evidence of mucosal injury on endoscopy (esophagitis, Barrett’s esophagus, peptic stricture).³ With the growing availability of proton pump inhibitors (PPIs), patients and clinicians often utilize an empiric therapeutic trial of PPI as an initial test, with symptom improvement in the absence of alarm symptoms indicating a high likelihood of GERD.⁴ A meta-analysis of studies that used objective measures of GERD (in this case, 24-hour pH monitoring) showed that the “PPI test” has a sensitivity of 78%, but a specificity of only 54%, as a diagnostic approach to GERD symptoms.⁵ Apart from noncardiac chest pain, the diagnostic yield is even lower for atypical and extra-esophageal symptoms such as cough or laryngeal symptoms.⁶

The “nuts and bolts” of reflux testing

Ambulatory reflux testing assesses esophageal reflux burden and symptom-reflux association (SRA). Individual reflux events are identified as either a drop in esophageal pH to less than 4 (acid reflux events), or a sharp decrease in esophageal impedance measurements in a retrograde fashion (impedance-detected reflux events), with subsequent recovery to the baseline in each instance. Ambulatory reflux testing affords insight into three areas: 1) measurement of esophageal acid exposure time (AET); the cumulative time duration when distal esophageal pH is less than 4 at the recording site, reported as a percentage of the recording period; 2) measurement of the number of reflux events both acidic (from pH monitoring) and weakly acidic/alkaline (from impedance monitoring); and 3) quantitative evaluation of the association between reported symptom episodes and reflux events.

Copyright Elsevier/AGA

Testing on or off PPI?

For symptoms attributable to GERD that persist despite properly administered PPI therapy, the 2013 American College of Gastroenterology guidelines suggest upper endoscopy with esophageal biopsies for typical symptoms and appropriate referrals for atypical symptoms.²⁴ However, if these evaluations are unremarkable, reflux monitoring is recommended, with PPI status for testing guided by the pre-test probability of GERD: with a low pre-test probability of GERD, reflux testing is best performed off PPI with either pH or combined pH-impedance testing. In contrast, with a high pre-test probability of GERD, testing is best performed on PPI with combined pH-impedance testing. A similar concept is proposed in the Rome IV approach (Figure 2)²³ and on GERD consensus guidelines:⁷ when heartburn or chest pain persists despite PPI therapy and endoscopy and esophageal biopsies are normal, evidence for GERD (past esophagitis, Barrett’s esophagus, peptic stricture, or prior positive reflux testing) prompts pH-impedance monitoring on PPI therapy (i.e., proven GERD). Those without this evidence for proven GERD (i.e., unproven GERD) are best tested off PPI, and the test utilized can be either pH alone or combined pH-impedance.

GERD phenotypes and management

The presence or absence of the two core metrics on ambulatory reflux monitoring – abnormal AET and positive SRA – can stratify symptomatic GERD patients into phenotypes that predict symptomatic improvement with antireflux therapy and guide management of symptoms (Figure 3).^25,26 The presence of both abnormal AET and positive SRA suggests “strong” evidence for GERD, for which symptom improvement is likely with maximization of antireflux therapy, which can include BID PPI, baclofen (to decrease transient LES relaxations), alginates (such as Gaviscon), and consideration of endosopic or surgical antireflux procedures such as fundoplication or magnetic sphincter augmentation. Abnormal AET but negative SRA is regarded as “good” evidence for GERD, for which similar antireflux therapies can be advocated. Normal AET but positive SRA is designated as “reflux hypersensitivity,”²³ with increasing proportions of patients meeting this phenotype when tested with combined pH-impedance and off PPI therapy.²⁷ Both normal AET and negative SRA suggest equivocal evidence for GERD and the likely presence of a functional esophageal disorder, such as functional heartburn.²³ For reflux hypersensitivity and especially functional esophageal disorders, antireflux therapy is unlikely to be as effective and management can include pharmacologic neuromodulation (such as tricyclic antidepressants administered at bedtime) as well as adjunctive nonpharmacologic approaches (such as stress reduction, relaxation, hypnosis, or cognitive-behavioral therapy).

The future of reflux diagnostics

Conclusions

For esophageal symptoms potentially attributable to GERD that persist despite optimized PPI therapy, esophageal testing should be undertaken, starting with endoscopy and biopsies and proceeding to ambulatory reflux monitoring with HRM. The decisions between pH testing alone versus combined pH-impedance monitoring, and between testing on or off PPI therapy, can be guided either by the pre-test probability of GERD or whether GERD has been proven or unproven in prior evaluations (Figure 2). Elevated AET and positive SRA with impedance-detected reflux events can predict the likelihood of successful management outcomes from antireflux therapy. These two core metrics can be utilized to phenotype GERD and guide management approaches for persisting symptoms (Figure 3). Novel impedance metrics (baseline mucosal impedance, postreflux swallow-induced peristaltic wave index) and markers for esophageal mucosal damage continue to be studied as potential markers for evidence of longitudinal reflux exposure.

Dr. Patel is assistant professor of medicine, division of gastroenterology, Duke University School of Medicine and the Durham Veterans Affairs Medical Center, Durham, N.C. Dr. Gyawali is professor of medicine, division of gastroenterology, Washington University School of Medicine, St. Louis, Mo.

References

1. Shaheen N.J., et al. Am J Gastroenterol. 2006;101:2128-38.

2. Patel A., Gyawali C.P.. Switzerland: Springer International, 2016.

3. Vakil N., et al. Am J Gastroenterol. 2006;101:1900-20; quiz 1943.

4. Fass R., et al. Arch Intern Med. 1999;159:2161-8.

5. Numans M.E., et al. Ann Intern Med. 2004;140:518-27.

6. Shaheen N.J., et al. Aliment Pharmacol Ther. 2011;33:225-34.

7. Roman S., et al. Neurogastroenterol Motil Mar 31. doi: 10.1111/nmo.13067. [Epub ahead of print] 2017.

8. Dellon E.S., et al. Am J Gastroenterol. 2013;108:679-92; quiz 693.

9. Pandolfino JE, Vela MF. Gastrointest Endosc. 2009;69:917-30, 930 e1.

10. Shay S., et al. Am J Gastroenterol. 2004;99:1037-43.

11. Zerbib F., et al. Clin Gastroenterol Hepatol. 2013;11:366-72.

12. Wiener G.J., et al. Am J Gastroenterol 1988;83:358-61.

13. Weusten B.L., et al. Gastroenterology. 1994;107:1741-5.

14. Ghillebert G., et al. Gut 1990;31:738-44.

15. Kushnir V.M., et al. Aliment Pharmacol Ther. 2012;35(9):1080-7.

16. Bredenoord A.J., et al. Am J Gastroenterol. 2006;101:453-9.

17. Patel A., et al. Clin Gastroenterol Hepatol. 2015;13:884-91.

18. Slaughter J.C., et al. Clin Gastroenterol Hepatol. 2011;9:868-74.

19. Kavitt R.T., et al. Am J Gastroenterol. 2012;107:1826-32.

20. Kahrilas P.J., et al. Gastroenterology 2008;135:1383-91, 1391 e1-5.

21. Kessing B.F., et al. Clin Gastroenterol Hepatol. 2011;9:1020-4.

22. Kahrilas P.J., et al. Neurogastroenterol Motil. 2015;27:160-74.

23. Aziz A, et al. Esophageal disorders. Gastroenterology 2016;150:1368-79.

24. Katz P.O., et al. Am J Gastroenterol. 2013;108:308-28; quiz 329.

25. Boeckxstaens G., et al. Gut 2014;63:1185-93.

26. Patel A., et al. Neurogastroenterol Motil. 2016;28:513-21.

27. Patel A., et al. Neurogastroenterol Motil. 2016;28:1382-90.

28. Martinucci I., et al. Neurogastroenterol Motil. 2014;26:546-55.

29. Ates F., et al. Gastroenterology 2015;148:334-43.

30. Kessing B.F., et al. Am J Gastroenterol. 2011;106:2093-7.

31. Patel A., et al. Aliment Pharmacol Ther. 2016;44:890-8.

32. Frazzoni M., et al. Neurogastroenterol Motil. 2016.

33. Frazzoni M., et al. Neurogastroenterol Motil. 2013;25:399-406, e295.

34. Vela M.F., et al. Am J Gastroenterol. 2011;106:844-50.
 

Dear Trainees and Early-Career GIs,

As I begin my time as President of AGA, I am reflecting on other new beginnings in my career. Though time has passed, I vividly recall the excitement and uncertainty of beginning training and, subsequently, my career. It’s a career that I’ve enjoyed immensely and I hope that you will as well.

AGA Institute

Dear Trainees and Early-Career GIs,

As I begin my time as President of AGA, I am reflecting on other new beginnings in my career. Though time has passed, I vividly recall the excitement and uncertainty of beginning training and, subsequently, my career. It’s a career that I’ve enjoyed immensely and I hope that you will as well.

AGA Institute

Dear Trainees and Early-Career GIs,

As I begin my time as President of AGA, I am reflecting on other new beginnings in my career. Though time has passed, I vividly recall the excitement and uncertainty of beginning training and, subsequently, my career. It’s a career that I’ve enjoyed immensely and I hope that you will as well.

AGA Institute

Dear Colleagues,

Congratulations to the new gastroenterology fellows who have just begun their fellowships and also to those who have just finished and are starting their careers. It is certainly an exciting time of year for so many! A letter from AGA President Sheila Crowe, included in this issue, details the benefits and opportunities our organization offers GIs entering practice and academia.

Sincerely,

Bryson W. Katona, MD, PhD

Editor in Chief

Dr. Bryson W. Katona is an instructor of medicine in the division of gastroenterology at the University of Pennsylvania.

Dear Colleagues,

Congratulations to the new gastroenterology fellows who have just begun their fellowships and also to those who have just finished and are starting their careers. It is certainly an exciting time of year for so many! A letter from AGA President Sheila Crowe, included in this issue, details the benefits and opportunities our organization offers GIs entering practice and academia.

Sincerely,

Bryson W. Katona, MD, PhD

Editor in Chief

Dr. Bryson W. Katona is an instructor of medicine in the division of gastroenterology at the University of Pennsylvania.

Dear Colleagues,

Congratulations to the new gastroenterology fellows who have just begun their fellowships and also to those who have just finished and are starting their careers. It is certainly an exciting time of year for so many! A letter from AGA President Sheila Crowe, included in this issue, details the benefits and opportunities our organization offers GIs entering practice and academia.

Sincerely,

Bryson W. Katona, MD, PhD

Editor in Chief

Dr. Bryson W. Katona is an instructor of medicine in the division of gastroenterology at the University of Pennsylvania.

Minocycline, an antibiotic that has immune-modulating properties and crosses the blood-brain barrier, appears to delay conversion to multiple sclerosis in patients who have an initial focal demyelinating event, according to a report published online June 1 in the New England Journal of Medicine.

Two small clinical trials involving patients with relapsing-remitting multiple sclerosis (MS) recently showed that minocycline reduces the number of lesions detected on MRI with gadolinium enhancement. So researchers led by Luanne M. Metz, MD, of the Cumming School of Medicine and the Hotchkiss Brain Institute, Calgary, Alta., conducted a randomized, double-blind, placebo-controlled trial at 12 Canadian MS clinics to determine whether the drug might delay conversion to MS after a first, clinically isolated demyelinating event, such as optic neuritis or a brainstem, cerebral, cerebellar, or myelopathy syndrome.

copyright Zerbor/Thinkstock

Minocycline, an antibiotic that has immune-modulating properties and crosses the blood-brain barrier, appears to delay conversion to multiple sclerosis in patients who have an initial focal demyelinating event, according to a report published online June 1 in the New England Journal of Medicine.

Two small clinical trials involving patients with relapsing-remitting multiple sclerosis (MS) recently showed that minocycline reduces the number of lesions detected on MRI with gadolinium enhancement. So researchers led by Luanne M. Metz, MD, of the Cumming School of Medicine and the Hotchkiss Brain Institute, Calgary, Alta., conducted a randomized, double-blind, placebo-controlled trial at 12 Canadian MS clinics to determine whether the drug might delay conversion to MS after a first, clinically isolated demyelinating event, such as optic neuritis or a brainstem, cerebral, cerebellar, or myelopathy syndrome.

copyright Zerbor/Thinkstock

Minocycline, an antibiotic that has immune-modulating properties and crosses the blood-brain barrier, appears to delay conversion to multiple sclerosis in patients who have an initial focal demyelinating event, according to a report published online June 1 in the New England Journal of Medicine.

Two small clinical trials involving patients with relapsing-remitting multiple sclerosis (MS) recently showed that minocycline reduces the number of lesions detected on MRI with gadolinium enhancement. So researchers led by Luanne M. Metz, MD, of the Cumming School of Medicine and the Hotchkiss Brain Institute, Calgary, Alta., conducted a randomized, double-blind, placebo-controlled trial at 12 Canadian MS clinics to determine whether the drug might delay conversion to MS after a first, clinically isolated demyelinating event, such as optic neuritis or a brainstem, cerebral, cerebellar, or myelopathy syndrome.

copyright Zerbor/Thinkstock

This newsletter, Practical Considerations for Moderate to Severe Asthma, Part 1: Management, Biomarkers, and When to Refer, provides detailed guidance for nurse practitioners and physician assistants on how to identify, evaluate, and treat patients with poorly controlled, moderate to severe asthma.

Click here to read the supplement

Clinical Research Coordinator
Boys Town National Research Hospital
Boys Town, Nebraska

Kevin R. Murphy, MD

Director of Allergy, Asthma, and Pulmonary Research
Boys Town National Research Hospital
Boys Town, Nebraska
Department of Pediatrics
University of Nebraska Medical Center
Creighton University School of Medicine
Omaha, Nebraska

This newsletter, Practical Considerations for Moderate to Severe Asthma, Part 1: Management, Biomarkers, and When to Refer, provides detailed guidance for nurse practitioners and physician assistants on how to identify, evaluate, and treat patients with poorly controlled, moderate to severe asthma.

Click here to read the supplement

Clinical Research Coordinator
Boys Town National Research Hospital
Boys Town, Nebraska

Kevin R. Murphy, MD

Director of Allergy, Asthma, and Pulmonary Research
Boys Town National Research Hospital
Boys Town, Nebraska
Department of Pediatrics
University of Nebraska Medical Center
Creighton University School of Medicine
Omaha, Nebraska

This newsletter, Practical Considerations for Moderate to Severe Asthma, Part 1: Management, Biomarkers, and When to Refer, provides detailed guidance for nurse practitioners and physician assistants on how to identify, evaluate, and treat patients with poorly controlled, moderate to severe asthma.

Click here to read the supplement

Clinical Research Coordinator
Boys Town National Research Hospital
Boys Town, Nebraska

Kevin R. Murphy, MD

Director of Allergy, Asthma, and Pulmonary Research
Boys Town National Research Hospital
Boys Town, Nebraska
Department of Pediatrics
University of Nebraska Medical Center
Creighton University School of Medicine
Omaha, Nebraska

PART 1

Robert E. Gutman, MD
FPMRS Program Director
MedStar Washington Hospital Center
Associate Professor
Departments of Urology and Obstetrics/Gynecology
Georgetown University
Washington, DC

Elizabeth R. Mueller, MD, MSME
Professor, Departments of Urology and Obstetrics/Gynecology
Loyola University Chicago Stritch School of Medicine
Loyola University Medical Center
Maywood, Illinois

Janet Bickel, MA
Leadership and Career Development Coach
Falls Church, Virginia

Kristin M. Jacobs, MD
Steering Committee Chair, AUGS-SGS Group of FPRN®
FPMRS Fellow, Division of Urogynecology and Reconstructive Pelvic Surgery
Brown University
Providence, Rhode Island

Lior Lowenstein, MD, MS, MHA
Clinical Associate Professor, Department of Obstetrics and Gynecology
Rambam Health Center Campus, Ruth and Bruce Rappaport Faculty of Medicine
Technion Israel Institute of Technology
Haifa, Israel

Drs. Gutman, Jacobs, and Lowenstein and Ms. Bickel report no financial relationships relevant to their articles. Dr. Mueller reports that she is an investigator for and is on the advisory board of Astellas Medical and Scientific Affairs.

Photo: 3D4Medical / Science Source

PART 2

Geoffrey W. Cundiff, MD
Dr. Victor Gomel Professor and Head
Department of Obstetrics and Gynaecology
University of Bristish Columbia
Vancouver, British Columbia

Kimberly Kenton, MD,  MS
Professor, Obstetrics and Gynaecology and Urology
Divison Chief and Fellowship Program Director
Female Pelvis Medicine and Reconstructive Surgery
Medicial Director, Women's Integrated Pelvic Health Program
Northwestern Medicine/Northwestern University Feinberg School of Medicince
Chicago, Illinois

Denise M. Elser, MD
Urogynecologist
Women's Health Institute of Illinois
Oak Lawn, Illinois

Drs. Cundiff and Elser report no financial relationships relevant to their articles. Dr. Kenton reports that she receives grant or research support from Boston Scientific and the National Institutes of Health, and that she serves as an expert witness for the Butler Snow Law Firm/Ethicon.

Illustration: Science Picture Co/ Science Source

PART 1

Robert E. Gutman, MD
FPMRS Program Director
MedStar Washington Hospital Center
Associate Professor
Departments of Urology and Obstetrics/Gynecology
Georgetown University
Washington, DC

Elizabeth R. Mueller, MD, MSME
Professor, Departments of Urology and Obstetrics/Gynecology
Loyola University Chicago Stritch School of Medicine
Loyola University Medical Center
Maywood, Illinois

Janet Bickel, MA
Leadership and Career Development Coach
Falls Church, Virginia

Kristin M. Jacobs, MD
Steering Committee Chair, AUGS-SGS Group of FPRN®
FPMRS Fellow, Division of Urogynecology and Reconstructive Pelvic Surgery
Brown University
Providence, Rhode Island

Lior Lowenstein, MD, MS, MHA
Clinical Associate Professor, Department of Obstetrics and Gynecology
Rambam Health Center Campus, Ruth and Bruce Rappaport Faculty of Medicine
Technion Israel Institute of Technology
Haifa, Israel

Drs. Gutman, Jacobs, and Lowenstein and Ms. Bickel report no financial relationships relevant to their articles. Dr. Mueller reports that she is an investigator for and is on the advisory board of Astellas Medical and Scientific Affairs.

Photo: 3D4Medical / Science Source

PART 2

Geoffrey W. Cundiff, MD
Dr. Victor Gomel Professor and Head
Department of Obstetrics and Gynaecology
University of Bristish Columbia
Vancouver, British Columbia

Kimberly Kenton, MD,  MS
Professor, Obstetrics and Gynaecology and Urology
Divison Chief and Fellowship Program Director
Female Pelvis Medicine and Reconstructive Surgery
Medicial Director, Women's Integrated Pelvic Health Program
Northwestern Medicine/Northwestern University Feinberg School of Medicince
Chicago, Illinois

Denise M. Elser, MD
Urogynecologist
Women's Health Institute of Illinois
Oak Lawn, Illinois

Drs. Cundiff and Elser report no financial relationships relevant to their articles. Dr. Kenton reports that she receives grant or research support from Boston Scientific and the National Institutes of Health, and that she serves as an expert witness for the Butler Snow Law Firm/Ethicon.

Illustration: Science Picture Co/ Science Source

PART 1

Robert E. Gutman, MD
FPMRS Program Director
MedStar Washington Hospital Center
Associate Professor
Departments of Urology and Obstetrics/Gynecology
Georgetown University
Washington, DC

Elizabeth R. Mueller, MD, MSME
Professor, Departments of Urology and Obstetrics/Gynecology
Loyola University Chicago Stritch School of Medicine
Loyola University Medical Center
Maywood, Illinois

Janet Bickel, MA
Leadership and Career Development Coach
Falls Church, Virginia

Kristin M. Jacobs, MD
Steering Committee Chair, AUGS-SGS Group of FPRN®
FPMRS Fellow, Division of Urogynecology and Reconstructive Pelvic Surgery
Brown University
Providence, Rhode Island

Lior Lowenstein, MD, MS, MHA
Clinical Associate Professor, Department of Obstetrics and Gynecology
Rambam Health Center Campus, Ruth and Bruce Rappaport Faculty of Medicine
Technion Israel Institute of Technology
Haifa, Israel

Drs. Gutman, Jacobs, and Lowenstein and Ms. Bickel report no financial relationships relevant to their articles. Dr. Mueller reports that she is an investigator for and is on the advisory board of Astellas Medical and Scientific Affairs.

Photo: 3D4Medical / Science Source

PART 2

Geoffrey W. Cundiff, MD
Dr. Victor Gomel Professor and Head
Department of Obstetrics and Gynaecology
University of Bristish Columbia
Vancouver, British Columbia

Kimberly Kenton, MD,  MS
Professor, Obstetrics and Gynaecology and Urology
Divison Chief and Fellowship Program Director
Female Pelvis Medicine and Reconstructive Surgery
Medicial Director, Women's Integrated Pelvic Health Program
Northwestern Medicine/Northwestern University Feinberg School of Medicince
Chicago, Illinois

Denise M. Elser, MD
Urogynecologist
Women's Health Institute of Illinois
Oak Lawn, Illinois

Drs. Cundiff and Elser report no financial relationships relevant to their articles. Dr. Kenton reports that she receives grant or research support from Boston Scientific and the National Institutes of Health, and that she serves as an expert witness for the Butler Snow Law Firm/Ethicon.

Illustration: Science Picture Co/ Science Source

BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.

SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.

The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.

Study Design

Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.

Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.

Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).

The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.

ENDEAR Final Results

At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.

Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.

Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.

The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.

Good News, Bad News

Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”

—Glenn S. Williams

Suggested Reading

Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.

BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.

SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.

The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.

Study Design

Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.

Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.

Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).

The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.

ENDEAR Final Results

At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.

Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.

Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.

The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.

Good News, Bad News

Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”

—Glenn S. Williams

Suggested Reading

Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.

BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.

SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.

The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.

Study Design

Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.

Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.

Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).

The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.

ENDEAR Final Results

At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.

Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.

Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.

The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.

Good News, Bad News

Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”

—Glenn S. Williams

Suggested Reading

Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.

Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.^1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.^1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.^1,2

Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.^1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.¹ The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.^1,2,5

Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.

Case Report

A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.

At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.

Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.

The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.

Comment

Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.^1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.⁴ Indolent systemic mastocytosis is the most common variant.^2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.^1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.^1,2

The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.^1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).⁷ Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.^1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.² Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.^2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.^2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.^7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.^5,7

Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,^6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.^2,7 Alternative therapies such as NB-UVB² or psoralen plus UVA phototherapy¹¹ also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria^12,13 to atopic dermatitis¹⁴ to psoriasis.¹⁵ This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.^2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.^2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.² Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.¹² Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.¹⁶

Although ISM is currently considered an incurable chronic condition,⁶ this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.

Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.^1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.^1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.^1,2

Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.^1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.¹ The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.^1,2,5

Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.

Case Report

A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.

At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.

Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.

The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.

Comment

Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.^1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.⁴ Indolent systemic mastocytosis is the most common variant.^2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.^1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.^1,2

The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.^1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).⁷ Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.^1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.² Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.^2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.^2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.^7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.^5,7

Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,^6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.^2,7 Alternative therapies such as NB-UVB² or psoralen plus UVA phototherapy¹¹ also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria^12,13 to atopic dermatitis¹⁴ to psoriasis.¹⁵ This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.^2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.^2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.² Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.¹² Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.¹⁶

Although ISM is currently considered an incurable chronic condition,⁶ this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.

Systemic mastocytosis is a heterogeneous disorder of stem cell origin defined by abnormal hyperplasia and accumulation of mast cells (MCs) in one or more tissues.^1,2 The most commonly affected tissues are the bone marrow, gastrointestinal tract, and skin. Based on a number of major and minor criteria defined by the World Health Organization (WHO), the mastocytoses are subdivided into 7 variants that range from isolated cutaneous involvement to widespread systemic disease.^1-4 The most frequently diagnosed subtype is indolent systemic mastocytosis (ISM), a chronic disorder characterized by diffuse cutaneous macules and papules as well as bone marrow involvement in the form of multifocal dense infiltrates of MCs that frequently are phenotypically positive for c-KIT and tryptase. Serum tryptase levels are nearly invariably elevated in patients with this condition.^1,2

Symptoms of ISM are determined by the intermittent release of histamine and leukotrienes from hyperproliferating MCs as well as IL-6 and eosinophil chemotactic factors. As the burden of MC secretory products increases, patients experience worsening pruritus, flushing, palpitations, vomiting, and anaphylaxis in severe instances.^1,2,5 The mainstay of treatment of this condition involves symptom control through the inhibition of MC mediators.¹ The majority of patients respond well to antihistamines, antileukotriene agents, and oral corticosteroids during severe episodes of MC degranulation.^1,2,5

Unfortunately, some patients are unable to achieve adequate symptom control through the use of mediator-targeting treatments alone. In these cases, physicians often are faced with the following treatment dilemma: Either attempt to use therapies such as interferon alfa, which is cytoreductive to MCs, or 2-chlorodeoxyadenosine to reduce the overall MC burden, or turn to newer nonimmunosuppressive second-line options. We present the case of a patient with chronic ISM with progressive cutaneous lesions and poorly controlled pruritus that was previously managed with topical corticosteroids and antihistamines who responded favorably to treatment with narrowband UVB (NB-UVB) phototherapy.

Case Report

A 57-year-old woman presented with a 10-year history of widespread red-brown macules and papules on the trunk and upper and lower extremities. The lesions were intermittently pruritic, a symptom that was exacerbated on sun and heat exposure. A skin biopsy performed by an outside dermatologist 9 years prior confirmed the presence of mastocytosis. The patient was originally treated with triamcinolone cream and oral antihistamines, which controlled her symptoms successfully for nearly a decade.

At the current presentation, the patient reported increasingly severe pruritus and lesional spread to the neck and face of 15 months’ duration. She denied any symptoms of flushing, diarrhea, syncopal episodes, or lightheadedness. Physical examination revealed a well-appearing middle-aged woman with multiple 3- to 8-mm, red-brown, blanchable macules and papules with areas coalescing into plaques that primarily involved the legs (Figure 1A); arms; back; and to a lesser extent the abdomen, neck, and face. There was no palpable lymphadenopathy.

Laboratory results revealed a complete blood cell count and basic metabolic profile within reference range; however, the serum tryptase level was elevated at 65 ng/mL (reference range, <11.4 ng/mL). A positron emission tomography–computed tomography scan was negative, as well as a c-KIT mutation analysis. A review of the skin biopsy from 9 years prior demonstrated slight acanthosis with dermal proliferation of mononuclear cells (Figure 2A), some of which had abundant cytoplasm and oval-shaped nuclei. There were few eosinophils and marked dermal telangiectasias. Giemsa stain revealed increased numbers of MCs in the upper dermis (Figure 2B). A bone marrow biopsy performed 9 years later showed multifocal lesions composed of MCs with associated lymphoid aggregates without notable myelodyspoiesis (or myeloproliferative neoplasm). These features were all consistent with WHO criteria for ISM. Based on the most current clinical, laboratory, and histopathologic findings, the patient was diagnosed with category IB ISM.

The patient’s symptoms had remained stable for 9 years with a regimen of triamcinolone cream 0.1% twice daily, doxepin cream 5% daily as needed, and oral fexofenadine 180 mg once daily. The patient continues to use topical steroids and oral antihistamines. Due to inadequate symptom control, breakthrough pruritus, and the development of new skin lesions on the head and neck, she was started on NB-UVB treatment 2 months after presentation. The patient’s symptoms and the extent of cutaneous maculopapular lesions improved after 20 light treatments (Figure 1B), with even more dramatic results after 40 cycles of therapy (Figure 1C). Overall, the lower legs have proved most recalcitrant to this treatment modality. She is currently continuing to receive NB-UVB treatment twice weekly.

Comment

Systemic mastocytosis is a heterogeneous disorder characterized by the proliferation and accumulation of atypical MCs in tissues, principally in the bone marrow and skin, though involvement of the gastrointestinal tract, liver, spleen, and lymphatic system also have been reported.^1,2,6 The WHO classification of mastocytosis divides this condition into 7 subtypes.⁴ Indolent systemic mastocytosis is the most common variant.^2,6 The etiology of ISM is not fully understood, but there is evidence suggesting that an activating mutation of KIT proto-oncogene receptor tyrosine kinase, KIT (usually D816V), present in the MCs of nearly 80% of patients with ISM may be involved.^1,3-5,7 Patients occasionally present with predominantly cutaneous findings but typically seek medical attention due to the recurrent systemic symptoms of the disease (eg, pruritus, flushing, syncope, palpitations, headache, dyspepsia, vomiting, diarrhea), which are related to the release of MC mediators.^1,2

The management of ISM is complex and based primarily on symptom reduction without alteration of disease course.^1,2,5,7 Patients should avoid symptom triggers such as heat, humidity, emotional and physical stress, alcohol, and certain medications (ie, aspirin, opioids, radiocontrast agents).⁷ Patients are initially treated with histamine H1- and H2-receptor antagonists to alleviate MC mediator release symptoms.^1,2,8 Although H1 blockers are most effective in mitigating cutaneous symptoms and limiting pruritus, H2 blockers are used to control gastric hypersecretion and dyspepsia.² Proton pump inhibitors are useful in patients with peptic ulcer disease who are unresponsive to H2-receptor antagonist therapy.^2,7 Cromolyn sodium and ketotifen fumarate are MC stabilizers that help prevent degranulation, which is helpful in relieving most major ISM symptoms. Leukotriene antagonists, such as zafirlukast, montelukast sodium, or zileuton, also may be employed to target the proinflammatory and pruritogenic leukotrienes, also products of the MC protein.^2,7 Imatinib mesylate and masitinib mesylate, both tyrosine kinase inhibitors, have been shown to improve symptoms and reduce MC mediator levels in ISM; however, most patients harbor the resistant KIT D816V mutation, which limits the utility of this medication.Patients with sensitive KIT mutations or those who have the wild-type KIT D816 mutation may be more appropriate candidates for imatinib or masitinib therapy, which can ameliorate symptoms of flushing, pruritus, and depression.^7-10 Treatment with omalizumab, a humanized murine anti-IgE monoclonal antibody, can be effective in treating recurrent, treatment-refractory anaphylaxis in ISM patients.^5,7

Symptoms unresponsive to these therapies can be effectively treated with a short course of oral corticosteroids,^6,7 while MC cytoreductive therapies such as interferon alfa or 2-chlorodeoxyadenosine (cladribine/2-CdA) are reserved for refractory cases.^2,7 Alternative therapies such as NB-UVB² or psoralen plus UVA phototherapy¹¹ also have demonstrated success in treating ISM symptoms. In the past, NB-UVB has shown efficacy in controlling pruriginous conditions ranging from chronic urticaria^12,13 to atopic dermatitis¹⁴ to psoriasis.¹⁵ This evidence has spurred studies to evaluate if NB-UVB has a role in the management of uncontrolled cases of cutaneous and ISM.^2,13,16,17 To date, the evidence has been promising. The majority of patients treated with this regimen report subjective reduction in pruritus in addition to clinical cutaneous disease burden.^2,11 Also, laboratory analysis demonstrates decreased levels of tryptase in patients utilizing NB-UVB phototherapy.² Thus far, the use of NB-UVB phototherapy in the treatment of pruriginous disorders such as ISM has not been associated with any severe side effects such as increased rates of anaphylaxis, though some research has suggested that this therapy may lower the threshold for patients to develop symptomatic dermographism.¹² Overall, patients treated with NB-UVB phototherapy report improved quality of life related to more effective symptom control.¹⁶

Although ISM is currently considered an incurable chronic condition,⁶ this case illustrates that symptomatic management is possible, even in cases of long-standing, severe disease. Patients should still be encouraged to avoid triggering factors and be vigilant in preventing potential anaphylaxis. However, NB-UVB phototherapy provides a supplemental or alternative treatment choice when other therapies have failed. We hope that the success of NB-UVB demonstrated in this case provides further evidence that this light-based therapy is a valuable treatment option in mastocytosis patients with unremitting or poorly controlled symptoms.