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Cerclage plus progesterone for preventing preterm births
DALLAS – Placing a cerclage conferred additional benefit over vaginal progesterone alone for women with extreme short cervixes and singleton pregnancies, in a recent study. Those who received rescue cerclage in addition to vaginal progesterone had a 92% overall reduction in spontaneous preterm birth rates, and infants had fewer neonatal ICU admissions and neonatal complications.
The single-center retrospective cohort study of 75 women with cervical length less than 10 cm who were receiving vaginal progesterone was presented by Christopher Enakpene, MD, at the meeting sponsored by the Society for Maternal-Fetal Medicine.
Women who received rescue cerclage in addition to progesterone delivered at a mean 34.3 weeks gestational age, compared with 27.5 weeks for those receiving progesterone alone (P less than .001).
There were 13 neonatal ICU admissions for infants born to the 36 patients in the cerclage group, compared with 23 for the 39 women receiving progesterone alone (P = .009). And there were seven perinatal or neonatal deaths among the group who did not receive cerclage; no deaths occurred in the cerclage group.
“Premature cervical ripening plays a significant role in spontaneous preterm birth,” said Dr. Enakpene. “And studies have shown that, the shorter the cervix, the higher the risk of spontaneous preterm birth.”
Preterm birth, said Dr. Enakpene, is the top cause of neonatal morbidity and mortality both in the United States and worldwide; it is associated with 70% of neonatal deaths and half of all neurodevelopmental delay, he said.
At the University of Illinois at Chicago, where Dr. Enakpene is a maternal-fetal medicine fellow in the department of obstetrics and gynecology, all pregnant women are screened for cervical length by transvaginal ultrasound during their second trimester.
If screening reveals cervical length of less than 20 mm, the patient receives vaginal progesterone, “the current standard of care in singleton pregnancy with incidental short cervix,” said Dr. Enakpene. Vaginal progesterone can reduce the risk of spontaneous preterm birth by about half, he said.
At his facility, women with a short cervix then receive serial cervical length assessments every week or 2 until 24 weeks’ gestation, to identify women whose cervixes continue to shorten. For these women, it’s usually physician preference that determines whether cerclage is placed to reinforce the progressively shortening cervix, said Dr. Enakpene.
There had been previous retrospective work showing that cerclage was more effective at preventing spontaneous preterm birth than was doing nothing when a woman with a singleton pregnancy had a short cervix. However, Dr. Enakpene said that vaginal progesterone alone had not been compared with continuing progesterone and adding a cerclage.
During the study period, 310 women with cervical length of less than 20 mm were placed on progesterone. These women were included in the study cohort if, over the course of at least two cervical length measurements, their cervix shortened to less than 10 mm while they were on vaginal progesterone. They could not have indications that delivery was imminent when the 10 mm threshold was met, said Dr. Enakpene.
Women with known intrauterine fetal death, an undesired pregnancy, or any sign of intra-amniotic infection or fetal anomalies were excluded from the study.
A total of 75 women met final inclusion criteria, and received cerclage (n = 36), or not (n = 39) according to physician judgment. Demographic and pregnancy-specific characteristics were generally similar between the two groups.
In their statistical analysis, Dr. Enakpene and his colleagues used Kaplan-Meier survival analysis to look at pregnancy latency over time for women who did – or didn’t – receive a cerclage. There were significantly fewer spontaneous preterm births before 24, 28, and 34 weeks gestational age in the cerclage group (P less than .001 for all).
Dr. Enakpene acknowledged the study’s limitations, including its retrospective nature, the small sample size, and the fact that cerclage placement was done by the preference of the attending physician. However, this study was the first to examine rescue cerclage as add-on to vaginal progesterone, he said, adding, “Following this study, we are designing a prospective randomized interventional study to address this important topic.”
Dr. Enakpene reported that he had no conflicts of interest, and reported no outside sources of funding.
SOURCE: Enakpene C et al. Am J Obstet Gynecol. 2018 Jan;218:S72-S73.
DALLAS – Placing a cerclage conferred additional benefit over vaginal progesterone alone for women with extreme short cervixes and singleton pregnancies, in a recent study. Those who received rescue cerclage in addition to vaginal progesterone had a 92% overall reduction in spontaneous preterm birth rates, and infants had fewer neonatal ICU admissions and neonatal complications.
The single-center retrospective cohort study of 75 women with cervical length less than 10 cm who were receiving vaginal progesterone was presented by Christopher Enakpene, MD, at the meeting sponsored by the Society for Maternal-Fetal Medicine.
Women who received rescue cerclage in addition to progesterone delivered at a mean 34.3 weeks gestational age, compared with 27.5 weeks for those receiving progesterone alone (P less than .001).
There were 13 neonatal ICU admissions for infants born to the 36 patients in the cerclage group, compared with 23 for the 39 women receiving progesterone alone (P = .009). And there were seven perinatal or neonatal deaths among the group who did not receive cerclage; no deaths occurred in the cerclage group.
“Premature cervical ripening plays a significant role in spontaneous preterm birth,” said Dr. Enakpene. “And studies have shown that, the shorter the cervix, the higher the risk of spontaneous preterm birth.”
Preterm birth, said Dr. Enakpene, is the top cause of neonatal morbidity and mortality both in the United States and worldwide; it is associated with 70% of neonatal deaths and half of all neurodevelopmental delay, he said.
At the University of Illinois at Chicago, where Dr. Enakpene is a maternal-fetal medicine fellow in the department of obstetrics and gynecology, all pregnant women are screened for cervical length by transvaginal ultrasound during their second trimester.
If screening reveals cervical length of less than 20 mm, the patient receives vaginal progesterone, “the current standard of care in singleton pregnancy with incidental short cervix,” said Dr. Enakpene. Vaginal progesterone can reduce the risk of spontaneous preterm birth by about half, he said.
At his facility, women with a short cervix then receive serial cervical length assessments every week or 2 until 24 weeks’ gestation, to identify women whose cervixes continue to shorten. For these women, it’s usually physician preference that determines whether cerclage is placed to reinforce the progressively shortening cervix, said Dr. Enakpene.
There had been previous retrospective work showing that cerclage was more effective at preventing spontaneous preterm birth than was doing nothing when a woman with a singleton pregnancy had a short cervix. However, Dr. Enakpene said that vaginal progesterone alone had not been compared with continuing progesterone and adding a cerclage.
During the study period, 310 women with cervical length of less than 20 mm were placed on progesterone. These women were included in the study cohort if, over the course of at least two cervical length measurements, their cervix shortened to less than 10 mm while they were on vaginal progesterone. They could not have indications that delivery was imminent when the 10 mm threshold was met, said Dr. Enakpene.
Women with known intrauterine fetal death, an undesired pregnancy, or any sign of intra-amniotic infection or fetal anomalies were excluded from the study.
A total of 75 women met final inclusion criteria, and received cerclage (n = 36), or not (n = 39) according to physician judgment. Demographic and pregnancy-specific characteristics were generally similar between the two groups.
In their statistical analysis, Dr. Enakpene and his colleagues used Kaplan-Meier survival analysis to look at pregnancy latency over time for women who did – or didn’t – receive a cerclage. There were significantly fewer spontaneous preterm births before 24, 28, and 34 weeks gestational age in the cerclage group (P less than .001 for all).
Dr. Enakpene acknowledged the study’s limitations, including its retrospective nature, the small sample size, and the fact that cerclage placement was done by the preference of the attending physician. However, this study was the first to examine rescue cerclage as add-on to vaginal progesterone, he said, adding, “Following this study, we are designing a prospective randomized interventional study to address this important topic.”
Dr. Enakpene reported that he had no conflicts of interest, and reported no outside sources of funding.
SOURCE: Enakpene C et al. Am J Obstet Gynecol. 2018 Jan;218:S72-S73.
DALLAS – Placing a cerclage conferred additional benefit over vaginal progesterone alone for women with extreme short cervixes and singleton pregnancies, in a recent study. Those who received rescue cerclage in addition to vaginal progesterone had a 92% overall reduction in spontaneous preterm birth rates, and infants had fewer neonatal ICU admissions and neonatal complications.
The single-center retrospective cohort study of 75 women with cervical length less than 10 cm who were receiving vaginal progesterone was presented by Christopher Enakpene, MD, at the meeting sponsored by the Society for Maternal-Fetal Medicine.
Women who received rescue cerclage in addition to progesterone delivered at a mean 34.3 weeks gestational age, compared with 27.5 weeks for those receiving progesterone alone (P less than .001).
There were 13 neonatal ICU admissions for infants born to the 36 patients in the cerclage group, compared with 23 for the 39 women receiving progesterone alone (P = .009). And there were seven perinatal or neonatal deaths among the group who did not receive cerclage; no deaths occurred in the cerclage group.
“Premature cervical ripening plays a significant role in spontaneous preterm birth,” said Dr. Enakpene. “And studies have shown that, the shorter the cervix, the higher the risk of spontaneous preterm birth.”
Preterm birth, said Dr. Enakpene, is the top cause of neonatal morbidity and mortality both in the United States and worldwide; it is associated with 70% of neonatal deaths and half of all neurodevelopmental delay, he said.
At the University of Illinois at Chicago, where Dr. Enakpene is a maternal-fetal medicine fellow in the department of obstetrics and gynecology, all pregnant women are screened for cervical length by transvaginal ultrasound during their second trimester.
If screening reveals cervical length of less than 20 mm, the patient receives vaginal progesterone, “the current standard of care in singleton pregnancy with incidental short cervix,” said Dr. Enakpene. Vaginal progesterone can reduce the risk of spontaneous preterm birth by about half, he said.
At his facility, women with a short cervix then receive serial cervical length assessments every week or 2 until 24 weeks’ gestation, to identify women whose cervixes continue to shorten. For these women, it’s usually physician preference that determines whether cerclage is placed to reinforce the progressively shortening cervix, said Dr. Enakpene.
There had been previous retrospective work showing that cerclage was more effective at preventing spontaneous preterm birth than was doing nothing when a woman with a singleton pregnancy had a short cervix. However, Dr. Enakpene said that vaginal progesterone alone had not been compared with continuing progesterone and adding a cerclage.
During the study period, 310 women with cervical length of less than 20 mm were placed on progesterone. These women were included in the study cohort if, over the course of at least two cervical length measurements, their cervix shortened to less than 10 mm while they were on vaginal progesterone. They could not have indications that delivery was imminent when the 10 mm threshold was met, said Dr. Enakpene.
Women with known intrauterine fetal death, an undesired pregnancy, or any sign of intra-amniotic infection or fetal anomalies were excluded from the study.
A total of 75 women met final inclusion criteria, and received cerclage (n = 36), or not (n = 39) according to physician judgment. Demographic and pregnancy-specific characteristics were generally similar between the two groups.
In their statistical analysis, Dr. Enakpene and his colleagues used Kaplan-Meier survival analysis to look at pregnancy latency over time for women who did – or didn’t – receive a cerclage. There were significantly fewer spontaneous preterm births before 24, 28, and 34 weeks gestational age in the cerclage group (P less than .001 for all).
Dr. Enakpene acknowledged the study’s limitations, including its retrospective nature, the small sample size, and the fact that cerclage placement was done by the preference of the attending physician. However, this study was the first to examine rescue cerclage as add-on to vaginal progesterone, he said, adding, “Following this study, we are designing a prospective randomized interventional study to address this important topic.”
Dr. Enakpene reported that he had no conflicts of interest, and reported no outside sources of funding.
SOURCE: Enakpene C et al. Am J Obstet Gynecol. 2018 Jan;218:S72-S73.
REPORTING FROM THE PREGNANCY MEETING
Key clinical point: Women receiving rescue cerclage plus progesterone had fewer spontaneous preterm births.
Major finding: Those who also received cerclage delivered at 34.3 weeks gestational age, compared with 27.5 weeks for those on progesterone alone (P less than .001).
Study details: Retrospective cohort study of 75 women with singleton pregnancies and very short cervixes.
Disclosures: Dr. Enakpene reported no outside sources of funding and had no conflicts of interest.
Source: Enakpene C et al. Am J Obstet Gynecol. 2018 Jan;218:S72-S73.
Adil Harroud, MD
Katharina Eikermann-Haerter, MD
Jes Olesen, MD
States show large disparities in lung cancer mortality
, with the highest rate in West Virginia and the lowest in Utah.
Approximately 154,050 deaths from lung cancer – three times as many as any other cancer – are predicted for the year in the United States by the American Cancer Society in its Cancer Facts & Figures 2018, based on analysis of 2001-2015 data from the National Center for Health Statistics. That figure is down from the 155,870 predicted for 2017, as the most recent trend (2011-2015) in the death rate has been a decline of about 2.3% per year for women and 3.8% per year for men, the ACS noted.
The expected number of deaths for 2018, coupled with a current population estimate of nearly 326 million, works out to an expected death rate of 47.3 per a population of 100,000. The Census Bureau estimates for the state populations and the deaths projected by the ACS produce expected death rates of 80.8 per 100,000 for West Virginia and 15.2 for Utah. Kentucky’s rate of 79.3 is just behind West Virginia, but Colorado, the next-lowest state after Utah, has an estimated rate that’s almost twice as high at 28.5.
Nationally, death rates for lung cancer were 53.8 per 100,000 for males and 35.4 for females for 2011-2015, and incidence rates were 73 per 100,000 for males and 52.8 for females for 2010-2014, the ACS reported.
Among racial and ethnic groups, in men, the mortality was highest for those who were both non-Hispanic and black (66.9 per 100,00) during 2011-2015. Of the racial and ethnic groups of women for the same period, white women had the highest death rate (39). Hispanic/Latino men (26.4) and Hispanic/Latino women (13.3) had the lowest deaths rates, according to the report.
, with the highest rate in West Virginia and the lowest in Utah.
Approximately 154,050 deaths from lung cancer – three times as many as any other cancer – are predicted for the year in the United States by the American Cancer Society in its Cancer Facts & Figures 2018, based on analysis of 2001-2015 data from the National Center for Health Statistics. That figure is down from the 155,870 predicted for 2017, as the most recent trend (2011-2015) in the death rate has been a decline of about 2.3% per year for women and 3.8% per year for men, the ACS noted.
The expected number of deaths for 2018, coupled with a current population estimate of nearly 326 million, works out to an expected death rate of 47.3 per a population of 100,000. The Census Bureau estimates for the state populations and the deaths projected by the ACS produce expected death rates of 80.8 per 100,000 for West Virginia and 15.2 for Utah. Kentucky’s rate of 79.3 is just behind West Virginia, but Colorado, the next-lowest state after Utah, has an estimated rate that’s almost twice as high at 28.5.
Nationally, death rates for lung cancer were 53.8 per 100,000 for males and 35.4 for females for 2011-2015, and incidence rates were 73 per 100,000 for males and 52.8 for females for 2010-2014, the ACS reported.
Among racial and ethnic groups, in men, the mortality was highest for those who were both non-Hispanic and black (66.9 per 100,00) during 2011-2015. Of the racial and ethnic groups of women for the same period, white women had the highest death rate (39). Hispanic/Latino men (26.4) and Hispanic/Latino women (13.3) had the lowest deaths rates, according to the report.
, with the highest rate in West Virginia and the lowest in Utah.
Approximately 154,050 deaths from lung cancer – three times as many as any other cancer – are predicted for the year in the United States by the American Cancer Society in its Cancer Facts & Figures 2018, based on analysis of 2001-2015 data from the National Center for Health Statistics. That figure is down from the 155,870 predicted for 2017, as the most recent trend (2011-2015) in the death rate has been a decline of about 2.3% per year for women and 3.8% per year for men, the ACS noted.
The expected number of deaths for 2018, coupled with a current population estimate of nearly 326 million, works out to an expected death rate of 47.3 per a population of 100,000. The Census Bureau estimates for the state populations and the deaths projected by the ACS produce expected death rates of 80.8 per 100,000 for West Virginia and 15.2 for Utah. Kentucky’s rate of 79.3 is just behind West Virginia, but Colorado, the next-lowest state after Utah, has an estimated rate that’s almost twice as high at 28.5.
Nationally, death rates for lung cancer were 53.8 per 100,000 for males and 35.4 for females for 2011-2015, and incidence rates were 73 per 100,000 for males and 52.8 for females for 2010-2014, the ACS reported.
Among racial and ethnic groups, in men, the mortality was highest for those who were both non-Hispanic and black (66.9 per 100,00) during 2011-2015. Of the racial and ethnic groups of women for the same period, white women had the highest death rate (39). Hispanic/Latino men (26.4) and Hispanic/Latino women (13.3) had the lowest deaths rates, according to the report.
Jeffrey S. Mogil, PhD
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
T-cell lymphoma therapies on the horizon
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018
Prazosin falls short for veterans’ PTSD-related sleep problems
The alpha-1 adrenergic receptor prazosin failed to improve recurring nightmares or sleep quality compared with placebo in veterans with PTSD in a 26-week randomized trial of 304 adult veterans.
In several previous randomized trials lasting fewer than 15 weeks, veterans with PTSD and recurring nightmares who received prazosin showed benefits, including improved sleep quality and PTSD symptoms, compared with placebo patients, wrote Murray A. Raskind, MD, of the Department of Veterans Affairs Puget Sound Health Care System, Seattle, and his colleagues.
In a study published in the New England Journal of Medicine, the researchers randomized 152 veterans with sleep problems and PTSD to prazosin and 152 to a placebo. The participants were recruited from 12 VA medical centers. The average age of the participants was 52 years, more than 96% were male, and about two-thirds were white. Demographics were similar between the two groups.
After 10 weeks and after 26 weeks, there were no significant differences between the two groups in changes from baseline measures of recurring nightmares, using the mean change from baseline in Clinician-Administered PTSD Score item B2 (recurrent distressing dreams). Similarly, no significant differences appeared between the two groups based on Pittsburgh Sleep Quality Index scores.
“A possible explanation for these negative results is selection bias resulting from recruitment of patients who were mainly in clinically stable condition, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment,” reported Dr. Raskind and his colleagues.
The average maintenance dose of prazosin was 14.8 mg, compared with 16.4 mg in the placebo group; 187 male study participants reached the maximum dose of 20 mg/day (54% of the prazosin group and 70% of the placebo group).
After 10 weeks, no significant differences were found between the two groups in changes from baseline measures of “recurring distressing dreams,” using the mean change from baseline in Clinician-Administered PTSD Score item B2 (recurrent distressing dreams). The between group difference was 0.2. In addition, no significant differences were found at 10 weeks in the average change from baseline Pittsburgh Sleep Quality Index scores.
Similarly, no significant differences appeared between the two groups at 26 weeks. “ since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment,” the researchers said.
On average, patients in the prazosin group had significantly greater decreases in blood pressure, compared with the placebo group. In addition, they had fewer reports of new or worsening suicidal ideation, compared with the placebo group (8% vs.15%).
“Given the concern about suicide among veterans, it is noteworthy that the specifically solicited adverse event of new or worsening suicidal ideation was less common in the prazosin group than in the placebo group, but the absolute number of events was small; this issue warrants further study,” the researchers said.
The study was limited by several factors, including the absence of screening for sleep apnea or sleep-disordered breathing, Dr. Raskind and his colleagues noted. However, the results suggest that “further studies with more refined characterization of autonomic nervous system activity and nocturnal behaviors are needed to determine whether there might be subgroups of veterans with PTSD who can benefit from prazosin.”
Dr. Raskind had no financial conflicts to disclose. The study was supported by the Department of Veterans Affairs Cooperative Studies Program.
SOURCE: Raskind MA et al. N Engl J Med. 2018 Feb 8;378:507-17. doi: 10.1056/NEJMoa1507598.
The alpha-1 adrenergic receptor prazosin failed to improve recurring nightmares or sleep quality compared with placebo in veterans with PTSD in a 26-week randomized trial of 304 adult veterans.
In several previous randomized trials lasting fewer than 15 weeks, veterans with PTSD and recurring nightmares who received prazosin showed benefits, including improved sleep quality and PTSD symptoms, compared with placebo patients, wrote Murray A. Raskind, MD, of the Department of Veterans Affairs Puget Sound Health Care System, Seattle, and his colleagues.
In a study published in the New England Journal of Medicine, the researchers randomized 152 veterans with sleep problems and PTSD to prazosin and 152 to a placebo. The participants were recruited from 12 VA medical centers. The average age of the participants was 52 years, more than 96% were male, and about two-thirds were white. Demographics were similar between the two groups.
After 10 weeks and after 26 weeks, there were no significant differences between the two groups in changes from baseline measures of recurring nightmares, using the mean change from baseline in Clinician-Administered PTSD Score item B2 (recurrent distressing dreams). Similarly, no significant differences appeared between the two groups based on Pittsburgh Sleep Quality Index scores.
“A possible explanation for these negative results is selection bias resulting from recruitment of patients who were mainly in clinically stable condition, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment,” reported Dr. Raskind and his colleagues.
The average maintenance dose of prazosin was 14.8 mg, compared with 16.4 mg in the placebo group; 187 male study participants reached the maximum dose of 20 mg/day (54% of the prazosin group and 70% of the placebo group).
After 10 weeks, no significant differences were found between the two groups in changes from baseline measures of “recurring distressing dreams,” using the mean change from baseline in Clinician-Administered PTSD Score item B2 (recurrent distressing dreams). The between group difference was 0.2. In addition, no significant differences were found at 10 weeks in the average change from baseline Pittsburgh Sleep Quality Index scores.
Similarly, no significant differences appeared between the two groups at 26 weeks. “ since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment,” the researchers said.
On average, patients in the prazosin group had significantly greater decreases in blood pressure, compared with the placebo group. In addition, they had fewer reports of new or worsening suicidal ideation, compared with the placebo group (8% vs.15%).
“Given the concern about suicide among veterans, it is noteworthy that the specifically solicited adverse event of new or worsening suicidal ideation was less common in the prazosin group than in the placebo group, but the absolute number of events was small; this issue warrants further study,” the researchers said.
The study was limited by several factors, including the absence of screening for sleep apnea or sleep-disordered breathing, Dr. Raskind and his colleagues noted. However, the results suggest that “further studies with more refined characterization of autonomic nervous system activity and nocturnal behaviors are needed to determine whether there might be subgroups of veterans with PTSD who can benefit from prazosin.”
Dr. Raskind had no financial conflicts to disclose. The study was supported by the Department of Veterans Affairs Cooperative Studies Program.
SOURCE: Raskind MA et al. N Engl J Med. 2018 Feb 8;378:507-17. doi: 10.1056/NEJMoa1507598.
The alpha-1 adrenergic receptor prazosin failed to improve recurring nightmares or sleep quality compared with placebo in veterans with PTSD in a 26-week randomized trial of 304 adult veterans.
In several previous randomized trials lasting fewer than 15 weeks, veterans with PTSD and recurring nightmares who received prazosin showed benefits, including improved sleep quality and PTSD symptoms, compared with placebo patients, wrote Murray A. Raskind, MD, of the Department of Veterans Affairs Puget Sound Health Care System, Seattle, and his colleagues.
In a study published in the New England Journal of Medicine, the researchers randomized 152 veterans with sleep problems and PTSD to prazosin and 152 to a placebo. The participants were recruited from 12 VA medical centers. The average age of the participants was 52 years, more than 96% were male, and about two-thirds were white. Demographics were similar between the two groups.
After 10 weeks and after 26 weeks, there were no significant differences between the two groups in changes from baseline measures of recurring nightmares, using the mean change from baseline in Clinician-Administered PTSD Score item B2 (recurrent distressing dreams). Similarly, no significant differences appeared between the two groups based on Pittsburgh Sleep Quality Index scores.
“A possible explanation for these negative results is selection bias resulting from recruitment of patients who were mainly in clinically stable condition, since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment,” reported Dr. Raskind and his colleagues.
The average maintenance dose of prazosin was 14.8 mg, compared with 16.4 mg in the placebo group; 187 male study participants reached the maximum dose of 20 mg/day (54% of the prazosin group and 70% of the placebo group).
After 10 weeks, no significant differences were found between the two groups in changes from baseline measures of “recurring distressing dreams,” using the mean change from baseline in Clinician-Administered PTSD Score item B2 (recurrent distressing dreams). The between group difference was 0.2. In addition, no significant differences were found at 10 weeks in the average change from baseline Pittsburgh Sleep Quality Index scores.
Similarly, no significant differences appeared between the two groups at 26 weeks. “ since symptoms in such patients were less likely to be ameliorated with antiadrenergic treatment,” the researchers said.
On average, patients in the prazosin group had significantly greater decreases in blood pressure, compared with the placebo group. In addition, they had fewer reports of new or worsening suicidal ideation, compared with the placebo group (8% vs.15%).
“Given the concern about suicide among veterans, it is noteworthy that the specifically solicited adverse event of new or worsening suicidal ideation was less common in the prazosin group than in the placebo group, but the absolute number of events was small; this issue warrants further study,” the researchers said.
The study was limited by several factors, including the absence of screening for sleep apnea or sleep-disordered breathing, Dr. Raskind and his colleagues noted. However, the results suggest that “further studies with more refined characterization of autonomic nervous system activity and nocturnal behaviors are needed to determine whether there might be subgroups of veterans with PTSD who can benefit from prazosin.”
Dr. Raskind had no financial conflicts to disclose. The study was supported by the Department of Veterans Affairs Cooperative Studies Program.
SOURCE: Raskind MA et al. N Engl J Med. 2018 Feb 8;378:507-17. doi: 10.1056/NEJMoa1507598.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Prazosin had no apparent effect on recurrent distressing dreams or sleep quality in veterans with PTSD.
Major finding: The between-group difference in scores on a measure of “recurrent distressing dreams” between the prazosin and placebo groups was a nonsignificant 0.2.
Study details: The data come from a randomized trial of 304 military veterans with PTSD who reported frequent nightmares.
Disclosures: Dr. Raskind had no financial conflicts to disclose. The study was supported by the Department of Veterans Affairs Cooperative Studies Program.
Source: Raskind MA et al. N Engl J Med. 2018;378:507-17.
Panniculitis, Pancreatitis, and Polyarthritis: A Rare Clinical Syndrome
Pancreatic panniculitis is a rare disease contributing to widespread fat necrosis in patients with underlying pancreatic disorders. This entity was first described in 1883,1 but it was not until 1947 that it was reported in the English-language literature.2 Patients with pancreatitis infrequently develop extrapancreatic manifestations. It has been estimated that only 2% to 3% of patients worldwide with an underlying pancreatic disease develop cutaneous lesions.3 Patients who develop pancreatic panniculitis typically present with tender, edematous, erythematous to brown, subcutaneous nodules on the lower legs with the tendency for spontaneous ulceration. Lesions tend to exude a viscous, yellow-brown, oily substance that represents liquefactive necrosis of enzymatic fat in subcutaneous tissue. Cutaneous lesions may precede, occur simultaneously, or follow the development of an underlying pancreatic disorder. Rarely, patients may develop inflammatory arthritis secondary to intraosseous fat necrosis, completing the triad of findings diagnostic for panniculitis, pancreatitis, and polyarthritis (PPP) syndrome. Although the underlying pancreatic pathology may vary, roughly 80% of cases worldwide have acute/chronic pancreatitis or pancreatic carcinoma, most commonly acinar cell carcinoma.4-6 Less common pancreatic disorders include pancreatic pseudocyst, pancreatic divisum, and vascular pancreatic fistulas.7 Narváez et al8 found that of the 25 cases of PPP syndrome reported in the literature, 68% (17/25) were men, 32% (8/25) were women, 56% (14/25) were younger than 50 years, and 64% (16/25) had a history of prior or current alcohol abuse.
Case Report
A 68-year-old man with a history of hypertension, gastroesophageal reflux disease, chronic pancreatitis of unknown etiology, and arthritis presented to our clinic for evaluation of painful skin nodules on the lower legs of 8 months’ duration, in addition to joint pain and swelling of the metacarpophalangeal (MCP), metatarsophalangeal, and ankle joints. He had a history of numerous hospital admissions over the last 2 years for pancreatitis and was being managed by the rheumatology department for arthritic symptoms.
Physical examination revealed multiple 1- to 4-cm, ill-defined, erythematous to brown, subcutaneous nodules on the bilateral lower legs (Figure 1) and right inferomedial thigh that were tender to palpation. Marked erythema and edema of the MCP and metatarsophalangeal joints (Figure 2) and bilateral ankles were observed. Diffuse 2+ pitting edema was present in the bilateral lower extremities, along with areas of hyperpigmentation overlying resolving lesions.
Laboratory data revealed an elevated lipase level (>16,000 U/L [reference range, 31–186 U/L]), amylase level (>4700 U/L [reference range, 27–131 U/L]), erythrocyte sedimentation rate (94 mm/h [reference range, 0–20 mm/h]), and C-reactive protein level (93.5 mg/L [0.08–3.1 mg/L]). The patient had more than 6 episodes of recurrent idiopathic pancreatitis over the last 2 years, though symptoms of abdominal pain were minimal to nonexistent. Liver function tests and alcohol, calcium, and triglyceride levels all were within reference range. Rheumatoid factor and antinuclear antibodies were negative.
Ultrasonography showed no evidence of cholelithiasis. Computed tomography of the abdomen and pelvis demonstrated a 1.8×1.4-cm hypodense lesion within the pancreatic head with calcifications and mild proximal pancreatic ductal dilatation (Figure 3). However, multiple magnetic resonance cholangiopancreatography examinations and endoscopic ultrasounds with fine-needle aspiration specimens were performed, all negative for malignancy. Computed tomography of the left ankle demonstrated evidence of bony cortical destruction in the lateral aspect of the posterior calcaneus. Bone biopsy specimens demonstrated mild chronic inflammation with no evidence of osteomyelitis. A serum uric acid level was found to be 4.4 mg/dL (reference range, 4.0–8.0 mg/dL) and a joint aspirate demonstrated turbid fluid with lipoid material and no evidence of crystals or organisms on culture. Furthermore, a 4-mm punch biopsy of a nodule on the right leg revealed extensive lobular and septal liquefactive adipocyte necrosis with scattered neutrophils and lymphocytes (Figure 4). Aggregates of fine granular basophilic material were observed with prominent adipocyte degeneration and calcification.
Symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) along with intralesional, topical, and oral corticosteroids had proven ineffective in the management of this patient. He was subsequently referred to the surgery department for a pancreaticoduodenectomy (Whipple procedure) with notable improvement in pancreatic enzyme levels, lower leg subcutaneous nodules, and arthritis weeks after surgery.
Comment
A triad of pancreatic panniculitis, pancreatitis, and polyarthritis characterizes a rare entity known as PPP syndrome. Pancreatic panniculitis is a rare form of subcutaneous lobular fat necrosis associated with various underlying pancreatic disorders. Approximately 0.3% to 3.0% of patients with an underlying pancreatic disorder are affected with pancreatic panniculitis.9 Pancreatic panniculitis has been found in roughly 2% to 3% of patients with acute or chronic pancreatitis and pancreatic carcinoma, most commonly the acinar cell type.10 Narváez et al8 reported that nearly two-thirds of patients diagnosed with PPP syndrome have minimal to absent abdominal symptoms that often lead to misdiagnosis and affect the overall prognosis of patients with pancreatic disease. Any delay in the diagnosis of PPP syndrome leads to a worse prognosis, with a mortality rate reported to be approximately 24%.8 Potts et al5 provided a review of 27 patients with pancreatic panniculitis in which all 8 patients with pancreatic carcinoma and 42% (8/19) of patients with pancreatitis died.
Pancreatic panniculitis in the setting of PPP syndrome commonly presents with erythematous to brown, exquisitely tender, edematous, subcutaneous nodules on the lower legs. Lesions can range in size from several millimeters to 5 cm. The subcutaneous nodules may spontaneously ulcerate and exude oily viscous material from the liquefactive necrosis of adipocytes. In approximately 40% of patients, skin lesions are the presenting feature.11 Lesions typically resolve only after the pancreatic inflammation regresses, leaving behind atrophic hyperpigmented scars.3 Other presenting symptoms may include joint pain, pitting edema, and subcutaneous nodules, which can precede the diagnosis by up to 9 months.
The exact pathogenesis of PPP syndrome remains unclear. The most widely recognized hypothesis suggests that pancreatic enzymes (eg, trypsin, amylase, lipase, phospholipase A) released from the damaged pancreas are transported through the bloodstream to distant visceral and soft tissue sites, leading to lipolysis and inflammation to the surrounding subcutis and bone marrow.3 Ferrari et al12 reported this effect as a product of the accumulation of high levels of free fatty acids within the joint space by the action of lipolytic pancreatic enzymes on adipose cell membranes, resulting in acute arthritis.
Histopathologic findings of pancreatic panniculitis vary based on the acuity of the disease. Acute lesions typically demonstrate lobular and septal panniculitis. Szymanski and Bluefarb13 described the pathognomonic histologic findings of focal liquefactive necrosis and anucleate necrotic adipocytes surrounded by a shadowy and thickened cell membrane signifying the characteristic ghost cells. Fine basophilic material also may be seen intermixed with the necrotic adipocytes, representing saponified calcium. A brisk inflammatory infiltrate involving lymphocytes, macrophages, and neutrophils tends to surround the areas of necrotic adipocytes. Chronic lesions often demonstrate a paucity of fat necrosis and ghost cells and more granulomatous infiltrate. Langerhans giant cells, macrophages, and lymphocytes predominate in the subcutaneous fat.
Laboratory findings associated with pancreatic panniculitis may include elevated serum amylase, lipase, and/or trypsin levels. Not all the enzymes have to be elevated simultaneously. On occasion, one enzyme may be within reference range while the others are elevated. Rarely, patients may have an elevated lipase level with no signs of underlying pancreatic disease, which demonstrates that panniculitis does not correlate with the enzyme levels. In all cases of suspected pancreatic panniculitis, a complete laboratory workup is recommended including lipase, amylase, and trypsin serum levels. Eosinophilia may be a prominent finding in patients with pancreatic panniculitis and tends to occur in association with an underlying pancreatic carcinoma. Patients with pancreatic panniculitis associated with pancreatic carcinoma tend to have more severe, diffuse, and persistent subcutaneous nodules that often are refractory to treatment with frequent recurrence. A rare constellation of findings known as Schmid triad is comprised of panniculitis, polyarthritis, and eosinophilia and typically portends a poor prognosis secondary to an underlying pancreatic tumor.14 Cutaneous nodules may predate the diagnosis of pancreatic carcinoma by several months, thus signifying the need for a high index of suspicion in patients with lower leg subcutaneous nodules.
Joint disease most commonly involves the ankles, knees, wrists, and MCP joints.5,6,11 It has been suggested that arthritic symptoms are from periarticular fat necrosis or a direct extension from the necrotic subcutaneous tissue to the adjacent joint space.15 Dahl et al3 reported the composition of joint effusion fluid in 3 patients with PPP syndrome. The aspirate in all 3 patients contained viscous yellow material similar to the necrotic adipose tissue seen draining from subcutaneous nodules. Joint aspirate analysis demonstrated increased concentration of free fatty acids in the joint fluid consistent with severe lipolysis.3
The PPP syndrome acronym may be misleading to physicians, as arthritis is not always polyarticular. Dahl et al3 reported that monoarticular or oligoarticular arthritic symptoms were present in 56% of patients studied. In rare cases, the arthritic symptoms antedated the diagnosis of clinically asymptomatic pancreatic disease. Arthritis can be either symmetric or asymmetric and infrequently follows a chronic course, leading to radiographic lytic lesions and symptoms that often are unresponsive to conventional therapy.16
Treatment of PPP syndrome is largely supportive, with a focus on correcting the underlying pancreatic disease. It is imperative to identify any complicating factors contributing to high levels of circulating pancreatic enzymes. Pseudocysts must be addressed if discovered in these patients, as they often perpetuate the substantial release of pancreatic enzymes into the serum, leading to characteristic subcutaneous fat necrosis and arthritis. Sepsis also is a concern, likely secondary to bacterial colonization of the ulcerated subcutaneous nodules and compromised skin barrier. Nonsteroidal anti-inflammatory drugs and corticosteroids have been used for symptomatic relief but usually are ineffective and have not been shown to reduce the duration of the disease.12,16 Octreotide has been utilized and may potentially reduce pancreatic enzyme secretion leading to improvement in cutaneous and musculoskeletal lesions.17 Plasmapheresis has been used as an adjuvant treatment in patients with persistent hyperamylasemia and hyperlipasemia, but reports are anecdotal. Often reserved for severe disease, cholecystectomy, pancreatic duct removal, and pancreaticoduodenectomy have demonstrated success in the management of chronic pancreatitis and panniculitis. Dahl et al3 reported 2 cases in which cholecystectomy was performed with complete resolution of the skin and pancreatic disease. Our patient was initially treated symptomatically with NSAIDs and corticosteroids but there was no clinical response. The patient eventually underwent a pancreaticoduodenectomy 9 months after the onset of symptoms with complete resolution of joint pain and swelling, greater than 50% resolution of his lower leg subcutaneous nodules, and remarkable reduction in amylase and lipase levels on 1-month follow-up.
Conclusion
Panniculitis, pancreatitis, and polyarthritis syndrome is a rare diagnosis characterized by a triad of pancreatic panniculitis, pancreatitis, and polyarthritis. Adjuvant therapies for PPP syndrome, such as NSAIDs, corticosteroids, plasmapheresis, and octreotide, have been used with equivocal results, but definitive treatment requires correction of the primary pancreatic disorder. More importantly, many pancreatic diseases can cause pancreatic panniculitis, but extensive, refractory, or ulcerated cases could be an early indicator of an occult pancreatic malignancy and should prompt early evaluation with a multidisciplinary approach. This approach should incorporate management from dermatology, internal medicine, rheumatology, gastroenterology, surgery, and primary care.
- Chiari H. Uber die Sogenannte Fettnekrose. Prag Med Wochenschr. 1883;8:285-286, 299-301.
- Blauvelt H. Case of acute pancreatitis with subcutaneous fat necrosis. Br J Surg. 1946;34:207-208.
- Dahl PR, Su D, Cullimore KC, et al. Pancreatic panniculitis. J Am Acad Dermatol. 1995;33:413-417.
- Mullen GT, Caperton EM Jr, Crespin SR, et al. Arthritis and skin lesions resembling erythema nodosum in pancreatic disease. Ann Intern Med. 1968;68:75-87.
- Potts DE, Mass MF, Iseman MD. Syndrome and pancreatic disease, subcutaneous fat necrosis and polyserositis: case report and review of literature. Am J Med. 1975;58:417-423.
- Sorensen EV. Subcutaneous fat necrosis in pancreatic disease: a review and two new case reports. J Clin Gastroenterol. 1988;10:71-75.
- García-Romero D, Vanaclocha F. Pancreatic panniculitis. Dermatol Clin. 2008;26:465-470.
- Narváez J, Bianchi M, Santo P, et al. Pancreatitis, panniculitis, and polyarthritis. Semin Arthritis Rheum. 2010;39:417-423.
- Rongioetti F, Caputo V. Pancreatic panniculitis. G Ital Dermatol Venereol. 2013;148:419-425.
- Poelman SM, Nguyen K. Pancreatic panniculitis associated with acinar cell pancreatic carcinoma. J Cutan Med Surg. 2008;12:38-42.
- Hughes SH, Apisarnthanarax P, Mullins F. Subcutaneous fat necrosis associated with pancreatic disease. Arch Dermatol. 1975:111:506-510.
- Ferrari R, Wendelboe M, Ford PM, et al. Pancreatitis arthritis with periarticular fat necrosis. J Rheumatol. 1993;20:1436-1437.
- Szymanski FJ, Bluefarb SM. Nodular fat necrosis and pancreatic diseases. Arch Dermatol. 1961;83:224-229.
- Beltraminelly HS, Buechner SA, Hausermann P. Pancreatic panniculitis in a patient with an acinar cell cystadenocarcinoma of the pancreas. Dermatology. 2004;208:265-267.
- Burns WA, Matthews MJ, Hamosh M, et al. Lipase-secreting acinar cell carcinoma of the pancreas with polyarthropathy: a light and electron microscopic, histochemical, and biochemical study. Cancer. 1974;33:1002-1009.
- Baron M, Paltiel H, Lander P. Aseptic necrosis of the talus and calcaneal insufficiency fractures in a patient with pancreatitis, subcutaneous fat necrosis, and arthritis. Arthritis Rheum. 1984;27:1309-1313.
- Zundler S, Erber R, Agaimy A, et al. Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver—case report and review of literature. BMC Cancer. 2016;16:130.
Pancreatic panniculitis is a rare disease contributing to widespread fat necrosis in patients with underlying pancreatic disorders. This entity was first described in 1883,1 but it was not until 1947 that it was reported in the English-language literature.2 Patients with pancreatitis infrequently develop extrapancreatic manifestations. It has been estimated that only 2% to 3% of patients worldwide with an underlying pancreatic disease develop cutaneous lesions.3 Patients who develop pancreatic panniculitis typically present with tender, edematous, erythematous to brown, subcutaneous nodules on the lower legs with the tendency for spontaneous ulceration. Lesions tend to exude a viscous, yellow-brown, oily substance that represents liquefactive necrosis of enzymatic fat in subcutaneous tissue. Cutaneous lesions may precede, occur simultaneously, or follow the development of an underlying pancreatic disorder. Rarely, patients may develop inflammatory arthritis secondary to intraosseous fat necrosis, completing the triad of findings diagnostic for panniculitis, pancreatitis, and polyarthritis (PPP) syndrome. Although the underlying pancreatic pathology may vary, roughly 80% of cases worldwide have acute/chronic pancreatitis or pancreatic carcinoma, most commonly acinar cell carcinoma.4-6 Less common pancreatic disorders include pancreatic pseudocyst, pancreatic divisum, and vascular pancreatic fistulas.7 Narváez et al8 found that of the 25 cases of PPP syndrome reported in the literature, 68% (17/25) were men, 32% (8/25) were women, 56% (14/25) were younger than 50 years, and 64% (16/25) had a history of prior or current alcohol abuse.
Case Report
A 68-year-old man with a history of hypertension, gastroesophageal reflux disease, chronic pancreatitis of unknown etiology, and arthritis presented to our clinic for evaluation of painful skin nodules on the lower legs of 8 months’ duration, in addition to joint pain and swelling of the metacarpophalangeal (MCP), metatarsophalangeal, and ankle joints. He had a history of numerous hospital admissions over the last 2 years for pancreatitis and was being managed by the rheumatology department for arthritic symptoms.
Physical examination revealed multiple 1- to 4-cm, ill-defined, erythematous to brown, subcutaneous nodules on the bilateral lower legs (Figure 1) and right inferomedial thigh that were tender to palpation. Marked erythema and edema of the MCP and metatarsophalangeal joints (Figure 2) and bilateral ankles were observed. Diffuse 2+ pitting edema was present in the bilateral lower extremities, along with areas of hyperpigmentation overlying resolving lesions.
Laboratory data revealed an elevated lipase level (>16,000 U/L [reference range, 31–186 U/L]), amylase level (>4700 U/L [reference range, 27–131 U/L]), erythrocyte sedimentation rate (94 mm/h [reference range, 0–20 mm/h]), and C-reactive protein level (93.5 mg/L [0.08–3.1 mg/L]). The patient had more than 6 episodes of recurrent idiopathic pancreatitis over the last 2 years, though symptoms of abdominal pain were minimal to nonexistent. Liver function tests and alcohol, calcium, and triglyceride levels all were within reference range. Rheumatoid factor and antinuclear antibodies were negative.
Ultrasonography showed no evidence of cholelithiasis. Computed tomography of the abdomen and pelvis demonstrated a 1.8×1.4-cm hypodense lesion within the pancreatic head with calcifications and mild proximal pancreatic ductal dilatation (Figure 3). However, multiple magnetic resonance cholangiopancreatography examinations and endoscopic ultrasounds with fine-needle aspiration specimens were performed, all negative for malignancy. Computed tomography of the left ankle demonstrated evidence of bony cortical destruction in the lateral aspect of the posterior calcaneus. Bone biopsy specimens demonstrated mild chronic inflammation with no evidence of osteomyelitis. A serum uric acid level was found to be 4.4 mg/dL (reference range, 4.0–8.0 mg/dL) and a joint aspirate demonstrated turbid fluid with lipoid material and no evidence of crystals or organisms on culture. Furthermore, a 4-mm punch biopsy of a nodule on the right leg revealed extensive lobular and septal liquefactive adipocyte necrosis with scattered neutrophils and lymphocytes (Figure 4). Aggregates of fine granular basophilic material were observed with prominent adipocyte degeneration and calcification.
Symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) along with intralesional, topical, and oral corticosteroids had proven ineffective in the management of this patient. He was subsequently referred to the surgery department for a pancreaticoduodenectomy (Whipple procedure) with notable improvement in pancreatic enzyme levels, lower leg subcutaneous nodules, and arthritis weeks after surgery.
Comment
A triad of pancreatic panniculitis, pancreatitis, and polyarthritis characterizes a rare entity known as PPP syndrome. Pancreatic panniculitis is a rare form of subcutaneous lobular fat necrosis associated with various underlying pancreatic disorders. Approximately 0.3% to 3.0% of patients with an underlying pancreatic disorder are affected with pancreatic panniculitis.9 Pancreatic panniculitis has been found in roughly 2% to 3% of patients with acute or chronic pancreatitis and pancreatic carcinoma, most commonly the acinar cell type.10 Narváez et al8 reported that nearly two-thirds of patients diagnosed with PPP syndrome have minimal to absent abdominal symptoms that often lead to misdiagnosis and affect the overall prognosis of patients with pancreatic disease. Any delay in the diagnosis of PPP syndrome leads to a worse prognosis, with a mortality rate reported to be approximately 24%.8 Potts et al5 provided a review of 27 patients with pancreatic panniculitis in which all 8 patients with pancreatic carcinoma and 42% (8/19) of patients with pancreatitis died.
Pancreatic panniculitis in the setting of PPP syndrome commonly presents with erythematous to brown, exquisitely tender, edematous, subcutaneous nodules on the lower legs. Lesions can range in size from several millimeters to 5 cm. The subcutaneous nodules may spontaneously ulcerate and exude oily viscous material from the liquefactive necrosis of adipocytes. In approximately 40% of patients, skin lesions are the presenting feature.11 Lesions typically resolve only after the pancreatic inflammation regresses, leaving behind atrophic hyperpigmented scars.3 Other presenting symptoms may include joint pain, pitting edema, and subcutaneous nodules, which can precede the diagnosis by up to 9 months.
The exact pathogenesis of PPP syndrome remains unclear. The most widely recognized hypothesis suggests that pancreatic enzymes (eg, trypsin, amylase, lipase, phospholipase A) released from the damaged pancreas are transported through the bloodstream to distant visceral and soft tissue sites, leading to lipolysis and inflammation to the surrounding subcutis and bone marrow.3 Ferrari et al12 reported this effect as a product of the accumulation of high levels of free fatty acids within the joint space by the action of lipolytic pancreatic enzymes on adipose cell membranes, resulting in acute arthritis.
Histopathologic findings of pancreatic panniculitis vary based on the acuity of the disease. Acute lesions typically demonstrate lobular and septal panniculitis. Szymanski and Bluefarb13 described the pathognomonic histologic findings of focal liquefactive necrosis and anucleate necrotic adipocytes surrounded by a shadowy and thickened cell membrane signifying the characteristic ghost cells. Fine basophilic material also may be seen intermixed with the necrotic adipocytes, representing saponified calcium. A brisk inflammatory infiltrate involving lymphocytes, macrophages, and neutrophils tends to surround the areas of necrotic adipocytes. Chronic lesions often demonstrate a paucity of fat necrosis and ghost cells and more granulomatous infiltrate. Langerhans giant cells, macrophages, and lymphocytes predominate in the subcutaneous fat.
Laboratory findings associated with pancreatic panniculitis may include elevated serum amylase, lipase, and/or trypsin levels. Not all the enzymes have to be elevated simultaneously. On occasion, one enzyme may be within reference range while the others are elevated. Rarely, patients may have an elevated lipase level with no signs of underlying pancreatic disease, which demonstrates that panniculitis does not correlate with the enzyme levels. In all cases of suspected pancreatic panniculitis, a complete laboratory workup is recommended including lipase, amylase, and trypsin serum levels. Eosinophilia may be a prominent finding in patients with pancreatic panniculitis and tends to occur in association with an underlying pancreatic carcinoma. Patients with pancreatic panniculitis associated with pancreatic carcinoma tend to have more severe, diffuse, and persistent subcutaneous nodules that often are refractory to treatment with frequent recurrence. A rare constellation of findings known as Schmid triad is comprised of panniculitis, polyarthritis, and eosinophilia and typically portends a poor prognosis secondary to an underlying pancreatic tumor.14 Cutaneous nodules may predate the diagnosis of pancreatic carcinoma by several months, thus signifying the need for a high index of suspicion in patients with lower leg subcutaneous nodules.
Joint disease most commonly involves the ankles, knees, wrists, and MCP joints.5,6,11 It has been suggested that arthritic symptoms are from periarticular fat necrosis or a direct extension from the necrotic subcutaneous tissue to the adjacent joint space.15 Dahl et al3 reported the composition of joint effusion fluid in 3 patients with PPP syndrome. The aspirate in all 3 patients contained viscous yellow material similar to the necrotic adipose tissue seen draining from subcutaneous nodules. Joint aspirate analysis demonstrated increased concentration of free fatty acids in the joint fluid consistent with severe lipolysis.3
The PPP syndrome acronym may be misleading to physicians, as arthritis is not always polyarticular. Dahl et al3 reported that monoarticular or oligoarticular arthritic symptoms were present in 56% of patients studied. In rare cases, the arthritic symptoms antedated the diagnosis of clinically asymptomatic pancreatic disease. Arthritis can be either symmetric or asymmetric and infrequently follows a chronic course, leading to radiographic lytic lesions and symptoms that often are unresponsive to conventional therapy.16
Treatment of PPP syndrome is largely supportive, with a focus on correcting the underlying pancreatic disease. It is imperative to identify any complicating factors contributing to high levels of circulating pancreatic enzymes. Pseudocysts must be addressed if discovered in these patients, as they often perpetuate the substantial release of pancreatic enzymes into the serum, leading to characteristic subcutaneous fat necrosis and arthritis. Sepsis also is a concern, likely secondary to bacterial colonization of the ulcerated subcutaneous nodules and compromised skin barrier. Nonsteroidal anti-inflammatory drugs and corticosteroids have been used for symptomatic relief but usually are ineffective and have not been shown to reduce the duration of the disease.12,16 Octreotide has been utilized and may potentially reduce pancreatic enzyme secretion leading to improvement in cutaneous and musculoskeletal lesions.17 Plasmapheresis has been used as an adjuvant treatment in patients with persistent hyperamylasemia and hyperlipasemia, but reports are anecdotal. Often reserved for severe disease, cholecystectomy, pancreatic duct removal, and pancreaticoduodenectomy have demonstrated success in the management of chronic pancreatitis and panniculitis. Dahl et al3 reported 2 cases in which cholecystectomy was performed with complete resolution of the skin and pancreatic disease. Our patient was initially treated symptomatically with NSAIDs and corticosteroids but there was no clinical response. The patient eventually underwent a pancreaticoduodenectomy 9 months after the onset of symptoms with complete resolution of joint pain and swelling, greater than 50% resolution of his lower leg subcutaneous nodules, and remarkable reduction in amylase and lipase levels on 1-month follow-up.
Conclusion
Panniculitis, pancreatitis, and polyarthritis syndrome is a rare diagnosis characterized by a triad of pancreatic panniculitis, pancreatitis, and polyarthritis. Adjuvant therapies for PPP syndrome, such as NSAIDs, corticosteroids, plasmapheresis, and octreotide, have been used with equivocal results, but definitive treatment requires correction of the primary pancreatic disorder. More importantly, many pancreatic diseases can cause pancreatic panniculitis, but extensive, refractory, or ulcerated cases could be an early indicator of an occult pancreatic malignancy and should prompt early evaluation with a multidisciplinary approach. This approach should incorporate management from dermatology, internal medicine, rheumatology, gastroenterology, surgery, and primary care.
Pancreatic panniculitis is a rare disease contributing to widespread fat necrosis in patients with underlying pancreatic disorders. This entity was first described in 1883,1 but it was not until 1947 that it was reported in the English-language literature.2 Patients with pancreatitis infrequently develop extrapancreatic manifestations. It has been estimated that only 2% to 3% of patients worldwide with an underlying pancreatic disease develop cutaneous lesions.3 Patients who develop pancreatic panniculitis typically present with tender, edematous, erythematous to brown, subcutaneous nodules on the lower legs with the tendency for spontaneous ulceration. Lesions tend to exude a viscous, yellow-brown, oily substance that represents liquefactive necrosis of enzymatic fat in subcutaneous tissue. Cutaneous lesions may precede, occur simultaneously, or follow the development of an underlying pancreatic disorder. Rarely, patients may develop inflammatory arthritis secondary to intraosseous fat necrosis, completing the triad of findings diagnostic for panniculitis, pancreatitis, and polyarthritis (PPP) syndrome. Although the underlying pancreatic pathology may vary, roughly 80% of cases worldwide have acute/chronic pancreatitis or pancreatic carcinoma, most commonly acinar cell carcinoma.4-6 Less common pancreatic disorders include pancreatic pseudocyst, pancreatic divisum, and vascular pancreatic fistulas.7 Narváez et al8 found that of the 25 cases of PPP syndrome reported in the literature, 68% (17/25) were men, 32% (8/25) were women, 56% (14/25) were younger than 50 years, and 64% (16/25) had a history of prior or current alcohol abuse.
Case Report
A 68-year-old man with a history of hypertension, gastroesophageal reflux disease, chronic pancreatitis of unknown etiology, and arthritis presented to our clinic for evaluation of painful skin nodules on the lower legs of 8 months’ duration, in addition to joint pain and swelling of the metacarpophalangeal (MCP), metatarsophalangeal, and ankle joints. He had a history of numerous hospital admissions over the last 2 years for pancreatitis and was being managed by the rheumatology department for arthritic symptoms.
Physical examination revealed multiple 1- to 4-cm, ill-defined, erythematous to brown, subcutaneous nodules on the bilateral lower legs (Figure 1) and right inferomedial thigh that were tender to palpation. Marked erythema and edema of the MCP and metatarsophalangeal joints (Figure 2) and bilateral ankles were observed. Diffuse 2+ pitting edema was present in the bilateral lower extremities, along with areas of hyperpigmentation overlying resolving lesions.
Laboratory data revealed an elevated lipase level (>16,000 U/L [reference range, 31–186 U/L]), amylase level (>4700 U/L [reference range, 27–131 U/L]), erythrocyte sedimentation rate (94 mm/h [reference range, 0–20 mm/h]), and C-reactive protein level (93.5 mg/L [0.08–3.1 mg/L]). The patient had more than 6 episodes of recurrent idiopathic pancreatitis over the last 2 years, though symptoms of abdominal pain were minimal to nonexistent. Liver function tests and alcohol, calcium, and triglyceride levels all were within reference range. Rheumatoid factor and antinuclear antibodies were negative.
Ultrasonography showed no evidence of cholelithiasis. Computed tomography of the abdomen and pelvis demonstrated a 1.8×1.4-cm hypodense lesion within the pancreatic head with calcifications and mild proximal pancreatic ductal dilatation (Figure 3). However, multiple magnetic resonance cholangiopancreatography examinations and endoscopic ultrasounds with fine-needle aspiration specimens were performed, all negative for malignancy. Computed tomography of the left ankle demonstrated evidence of bony cortical destruction in the lateral aspect of the posterior calcaneus. Bone biopsy specimens demonstrated mild chronic inflammation with no evidence of osteomyelitis. A serum uric acid level was found to be 4.4 mg/dL (reference range, 4.0–8.0 mg/dL) and a joint aspirate demonstrated turbid fluid with lipoid material and no evidence of crystals or organisms on culture. Furthermore, a 4-mm punch biopsy of a nodule on the right leg revealed extensive lobular and septal liquefactive adipocyte necrosis with scattered neutrophils and lymphocytes (Figure 4). Aggregates of fine granular basophilic material were observed with prominent adipocyte degeneration and calcification.
Symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) along with intralesional, topical, and oral corticosteroids had proven ineffective in the management of this patient. He was subsequently referred to the surgery department for a pancreaticoduodenectomy (Whipple procedure) with notable improvement in pancreatic enzyme levels, lower leg subcutaneous nodules, and arthritis weeks after surgery.
Comment
A triad of pancreatic panniculitis, pancreatitis, and polyarthritis characterizes a rare entity known as PPP syndrome. Pancreatic panniculitis is a rare form of subcutaneous lobular fat necrosis associated with various underlying pancreatic disorders. Approximately 0.3% to 3.0% of patients with an underlying pancreatic disorder are affected with pancreatic panniculitis.9 Pancreatic panniculitis has been found in roughly 2% to 3% of patients with acute or chronic pancreatitis and pancreatic carcinoma, most commonly the acinar cell type.10 Narváez et al8 reported that nearly two-thirds of patients diagnosed with PPP syndrome have minimal to absent abdominal symptoms that often lead to misdiagnosis and affect the overall prognosis of patients with pancreatic disease. Any delay in the diagnosis of PPP syndrome leads to a worse prognosis, with a mortality rate reported to be approximately 24%.8 Potts et al5 provided a review of 27 patients with pancreatic panniculitis in which all 8 patients with pancreatic carcinoma and 42% (8/19) of patients with pancreatitis died.
Pancreatic panniculitis in the setting of PPP syndrome commonly presents with erythematous to brown, exquisitely tender, edematous, subcutaneous nodules on the lower legs. Lesions can range in size from several millimeters to 5 cm. The subcutaneous nodules may spontaneously ulcerate and exude oily viscous material from the liquefactive necrosis of adipocytes. In approximately 40% of patients, skin lesions are the presenting feature.11 Lesions typically resolve only after the pancreatic inflammation regresses, leaving behind atrophic hyperpigmented scars.3 Other presenting symptoms may include joint pain, pitting edema, and subcutaneous nodules, which can precede the diagnosis by up to 9 months.
The exact pathogenesis of PPP syndrome remains unclear. The most widely recognized hypothesis suggests that pancreatic enzymes (eg, trypsin, amylase, lipase, phospholipase A) released from the damaged pancreas are transported through the bloodstream to distant visceral and soft tissue sites, leading to lipolysis and inflammation to the surrounding subcutis and bone marrow.3 Ferrari et al12 reported this effect as a product of the accumulation of high levels of free fatty acids within the joint space by the action of lipolytic pancreatic enzymes on adipose cell membranes, resulting in acute arthritis.
Histopathologic findings of pancreatic panniculitis vary based on the acuity of the disease. Acute lesions typically demonstrate lobular and septal panniculitis. Szymanski and Bluefarb13 described the pathognomonic histologic findings of focal liquefactive necrosis and anucleate necrotic adipocytes surrounded by a shadowy and thickened cell membrane signifying the characteristic ghost cells. Fine basophilic material also may be seen intermixed with the necrotic adipocytes, representing saponified calcium. A brisk inflammatory infiltrate involving lymphocytes, macrophages, and neutrophils tends to surround the areas of necrotic adipocytes. Chronic lesions often demonstrate a paucity of fat necrosis and ghost cells and more granulomatous infiltrate. Langerhans giant cells, macrophages, and lymphocytes predominate in the subcutaneous fat.
Laboratory findings associated with pancreatic panniculitis may include elevated serum amylase, lipase, and/or trypsin levels. Not all the enzymes have to be elevated simultaneously. On occasion, one enzyme may be within reference range while the others are elevated. Rarely, patients may have an elevated lipase level with no signs of underlying pancreatic disease, which demonstrates that panniculitis does not correlate with the enzyme levels. In all cases of suspected pancreatic panniculitis, a complete laboratory workup is recommended including lipase, amylase, and trypsin serum levels. Eosinophilia may be a prominent finding in patients with pancreatic panniculitis and tends to occur in association with an underlying pancreatic carcinoma. Patients with pancreatic panniculitis associated with pancreatic carcinoma tend to have more severe, diffuse, and persistent subcutaneous nodules that often are refractory to treatment with frequent recurrence. A rare constellation of findings known as Schmid triad is comprised of panniculitis, polyarthritis, and eosinophilia and typically portends a poor prognosis secondary to an underlying pancreatic tumor.14 Cutaneous nodules may predate the diagnosis of pancreatic carcinoma by several months, thus signifying the need for a high index of suspicion in patients with lower leg subcutaneous nodules.
Joint disease most commonly involves the ankles, knees, wrists, and MCP joints.5,6,11 It has been suggested that arthritic symptoms are from periarticular fat necrosis or a direct extension from the necrotic subcutaneous tissue to the adjacent joint space.15 Dahl et al3 reported the composition of joint effusion fluid in 3 patients with PPP syndrome. The aspirate in all 3 patients contained viscous yellow material similar to the necrotic adipose tissue seen draining from subcutaneous nodules. Joint aspirate analysis demonstrated increased concentration of free fatty acids in the joint fluid consistent with severe lipolysis.3
The PPP syndrome acronym may be misleading to physicians, as arthritis is not always polyarticular. Dahl et al3 reported that monoarticular or oligoarticular arthritic symptoms were present in 56% of patients studied. In rare cases, the arthritic symptoms antedated the diagnosis of clinically asymptomatic pancreatic disease. Arthritis can be either symmetric or asymmetric and infrequently follows a chronic course, leading to radiographic lytic lesions and symptoms that often are unresponsive to conventional therapy.16
Treatment of PPP syndrome is largely supportive, with a focus on correcting the underlying pancreatic disease. It is imperative to identify any complicating factors contributing to high levels of circulating pancreatic enzymes. Pseudocysts must be addressed if discovered in these patients, as they often perpetuate the substantial release of pancreatic enzymes into the serum, leading to characteristic subcutaneous fat necrosis and arthritis. Sepsis also is a concern, likely secondary to bacterial colonization of the ulcerated subcutaneous nodules and compromised skin barrier. Nonsteroidal anti-inflammatory drugs and corticosteroids have been used for symptomatic relief but usually are ineffective and have not been shown to reduce the duration of the disease.12,16 Octreotide has been utilized and may potentially reduce pancreatic enzyme secretion leading to improvement in cutaneous and musculoskeletal lesions.17 Plasmapheresis has been used as an adjuvant treatment in patients with persistent hyperamylasemia and hyperlipasemia, but reports are anecdotal. Often reserved for severe disease, cholecystectomy, pancreatic duct removal, and pancreaticoduodenectomy have demonstrated success in the management of chronic pancreatitis and panniculitis. Dahl et al3 reported 2 cases in which cholecystectomy was performed with complete resolution of the skin and pancreatic disease. Our patient was initially treated symptomatically with NSAIDs and corticosteroids but there was no clinical response. The patient eventually underwent a pancreaticoduodenectomy 9 months after the onset of symptoms with complete resolution of joint pain and swelling, greater than 50% resolution of his lower leg subcutaneous nodules, and remarkable reduction in amylase and lipase levels on 1-month follow-up.
Conclusion
Panniculitis, pancreatitis, and polyarthritis syndrome is a rare diagnosis characterized by a triad of pancreatic panniculitis, pancreatitis, and polyarthritis. Adjuvant therapies for PPP syndrome, such as NSAIDs, corticosteroids, plasmapheresis, and octreotide, have been used with equivocal results, but definitive treatment requires correction of the primary pancreatic disorder. More importantly, many pancreatic diseases can cause pancreatic panniculitis, but extensive, refractory, or ulcerated cases could be an early indicator of an occult pancreatic malignancy and should prompt early evaluation with a multidisciplinary approach. This approach should incorporate management from dermatology, internal medicine, rheumatology, gastroenterology, surgery, and primary care.
- Chiari H. Uber die Sogenannte Fettnekrose. Prag Med Wochenschr. 1883;8:285-286, 299-301.
- Blauvelt H. Case of acute pancreatitis with subcutaneous fat necrosis. Br J Surg. 1946;34:207-208.
- Dahl PR, Su D, Cullimore KC, et al. Pancreatic panniculitis. J Am Acad Dermatol. 1995;33:413-417.
- Mullen GT, Caperton EM Jr, Crespin SR, et al. Arthritis and skin lesions resembling erythema nodosum in pancreatic disease. Ann Intern Med. 1968;68:75-87.
- Potts DE, Mass MF, Iseman MD. Syndrome and pancreatic disease, subcutaneous fat necrosis and polyserositis: case report and review of literature. Am J Med. 1975;58:417-423.
- Sorensen EV. Subcutaneous fat necrosis in pancreatic disease: a review and two new case reports. J Clin Gastroenterol. 1988;10:71-75.
- García-Romero D, Vanaclocha F. Pancreatic panniculitis. Dermatol Clin. 2008;26:465-470.
- Narváez J, Bianchi M, Santo P, et al. Pancreatitis, panniculitis, and polyarthritis. Semin Arthritis Rheum. 2010;39:417-423.
- Rongioetti F, Caputo V. Pancreatic panniculitis. G Ital Dermatol Venereol. 2013;148:419-425.
- Poelman SM, Nguyen K. Pancreatic panniculitis associated with acinar cell pancreatic carcinoma. J Cutan Med Surg. 2008;12:38-42.
- Hughes SH, Apisarnthanarax P, Mullins F. Subcutaneous fat necrosis associated with pancreatic disease. Arch Dermatol. 1975:111:506-510.
- Ferrari R, Wendelboe M, Ford PM, et al. Pancreatitis arthritis with periarticular fat necrosis. J Rheumatol. 1993;20:1436-1437.
- Szymanski FJ, Bluefarb SM. Nodular fat necrosis and pancreatic diseases. Arch Dermatol. 1961;83:224-229.
- Beltraminelly HS, Buechner SA, Hausermann P. Pancreatic panniculitis in a patient with an acinar cell cystadenocarcinoma of the pancreas. Dermatology. 2004;208:265-267.
- Burns WA, Matthews MJ, Hamosh M, et al. Lipase-secreting acinar cell carcinoma of the pancreas with polyarthropathy: a light and electron microscopic, histochemical, and biochemical study. Cancer. 1974;33:1002-1009.
- Baron M, Paltiel H, Lander P. Aseptic necrosis of the talus and calcaneal insufficiency fractures in a patient with pancreatitis, subcutaneous fat necrosis, and arthritis. Arthritis Rheum. 1984;27:1309-1313.
- Zundler S, Erber R, Agaimy A, et al. Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver—case report and review of literature. BMC Cancer. 2016;16:130.
- Chiari H. Uber die Sogenannte Fettnekrose. Prag Med Wochenschr. 1883;8:285-286, 299-301.
- Blauvelt H. Case of acute pancreatitis with subcutaneous fat necrosis. Br J Surg. 1946;34:207-208.
- Dahl PR, Su D, Cullimore KC, et al. Pancreatic panniculitis. J Am Acad Dermatol. 1995;33:413-417.
- Mullen GT, Caperton EM Jr, Crespin SR, et al. Arthritis and skin lesions resembling erythema nodosum in pancreatic disease. Ann Intern Med. 1968;68:75-87.
- Potts DE, Mass MF, Iseman MD. Syndrome and pancreatic disease, subcutaneous fat necrosis and polyserositis: case report and review of literature. Am J Med. 1975;58:417-423.
- Sorensen EV. Subcutaneous fat necrosis in pancreatic disease: a review and two new case reports. J Clin Gastroenterol. 1988;10:71-75.
- García-Romero D, Vanaclocha F. Pancreatic panniculitis. Dermatol Clin. 2008;26:465-470.
- Narváez J, Bianchi M, Santo P, et al. Pancreatitis, panniculitis, and polyarthritis. Semin Arthritis Rheum. 2010;39:417-423.
- Rongioetti F, Caputo V. Pancreatic panniculitis. G Ital Dermatol Venereol. 2013;148:419-425.
- Poelman SM, Nguyen K. Pancreatic panniculitis associated with acinar cell pancreatic carcinoma. J Cutan Med Surg. 2008;12:38-42.
- Hughes SH, Apisarnthanarax P, Mullins F. Subcutaneous fat necrosis associated with pancreatic disease. Arch Dermatol. 1975:111:506-510.
- Ferrari R, Wendelboe M, Ford PM, et al. Pancreatitis arthritis with periarticular fat necrosis. J Rheumatol. 1993;20:1436-1437.
- Szymanski FJ, Bluefarb SM. Nodular fat necrosis and pancreatic diseases. Arch Dermatol. 1961;83:224-229.
- Beltraminelly HS, Buechner SA, Hausermann P. Pancreatic panniculitis in a patient with an acinar cell cystadenocarcinoma of the pancreas. Dermatology. 2004;208:265-267.
- Burns WA, Matthews MJ, Hamosh M, et al. Lipase-secreting acinar cell carcinoma of the pancreas with polyarthropathy: a light and electron microscopic, histochemical, and biochemical study. Cancer. 1974;33:1002-1009.
- Baron M, Paltiel H, Lander P. Aseptic necrosis of the talus and calcaneal insufficiency fractures in a patient with pancreatitis, subcutaneous fat necrosis, and arthritis. Arthritis Rheum. 1984;27:1309-1313.
- Zundler S, Erber R, Agaimy A, et al. Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver—case report and review of literature. BMC Cancer. 2016;16:130.
Practice Points
- Recognition of skin lesions in a patient with a history of pancreatitis may represent a rare entity known as pancreatic panniculitis.
- Panniculitis, pancreatitis, and polyarthritis (PPP) syndrome is a rare diagnosis characterized by a triad of pancreatic panniculitis, pancreatitis, and polyarthritis.
- A rare constellation of findings known as Schmid triad is comprised of panniculitis, polyarthritis, and eosinophilia and typically portends a poor prognosis secondary to an underlying pancreatic tumor.
- These findings should prompt early evaluation with a multidisciplinary approach.
COPD in Primary Care: Key Considerations for Optimized Management
Click Here to Read the Supplement
This supplement provides an overview of 4 key topics critical to the effective management of COPD in primary care. The articles in this supplement are:
Dyspnea and Hyperinflation in COPD: Impact on Physical Activity
by Nathaniel Marchetti, DO; and Alan Kaplan, MD
Anxiety and Depression in COPD: Recognition and Management
by Abebaw Mengistu Yohannes, PhD; Alan Kaplan, MD; and Nicola A. Hanania, MD, MS
Considerations for Optimal Inhaler Device Selection in COPD
by Rajiv Dhand, MD; Tricia Cavanaugh, MD; and Neil Skolnik, MD
Treatment Options for Stable COPD: Current Recommendations and Unmet Needs
by Barbara Yawn, MD, MSc, FAAFP; and Victor Kim, MD
Click Here to Read the Supplement
Click Here to Read the Supplement
This supplement provides an overview of 4 key topics critical to the effective management of COPD in primary care. The articles in this supplement are:
Dyspnea and Hyperinflation in COPD: Impact on Physical Activity
by Nathaniel Marchetti, DO; and Alan Kaplan, MD
Anxiety and Depression in COPD: Recognition and Management
by Abebaw Mengistu Yohannes, PhD; Alan Kaplan, MD; and Nicola A. Hanania, MD, MS
Considerations for Optimal Inhaler Device Selection in COPD
by Rajiv Dhand, MD; Tricia Cavanaugh, MD; and Neil Skolnik, MD
Treatment Options for Stable COPD: Current Recommendations and Unmet Needs
by Barbara Yawn, MD, MSc, FAAFP; and Victor Kim, MD
Click Here to Read the Supplement
Click Here to Read the Supplement
This supplement provides an overview of 4 key topics critical to the effective management of COPD in primary care. The articles in this supplement are:
Dyspnea and Hyperinflation in COPD: Impact on Physical Activity
by Nathaniel Marchetti, DO; and Alan Kaplan, MD
Anxiety and Depression in COPD: Recognition and Management
by Abebaw Mengistu Yohannes, PhD; Alan Kaplan, MD; and Nicola A. Hanania, MD, MS
Considerations for Optimal Inhaler Device Selection in COPD
by Rajiv Dhand, MD; Tricia Cavanaugh, MD; and Neil Skolnik, MD
Treatment Options for Stable COPD: Current Recommendations and Unmet Needs
by Barbara Yawn, MD, MSc, FAAFP; and Victor Kim, MD
Click Here to Read the Supplement
