The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.^1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).^3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.⁷ Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).⁸ Effective treatments may considerably improve the QOL of patients with pemphigus.⁶

Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.^9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.⁸ Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.^11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.^11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.

In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.

MATERIALS AND METHODS

Study Design

We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.

Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).

After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.

Patient-Reported Outcome Measures

The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.

The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.⁶

The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.¹⁶ The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.^17,18 In this study, we used an MCD of a 5-point change or more between study groups.

Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).

Statistical Analysis

Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.

RESULTS

Patient Characteristics

A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.

Patient-Reported Outcomes

Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).

Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).

The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).

Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.

COMMENT

Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.^19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.

In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.²¹ The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis⁸ and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.^21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies^19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.

Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.²³ These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.²³

Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.

One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.

Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.

CONCLUSION

The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.

Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.^1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).^3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.⁷ Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).⁸ Effective treatments may considerably improve the QOL of patients with pemphigus.⁶

Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.^9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.⁸ Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.^11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.^11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.

In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.

MATERIALS AND METHODS

Study Design

We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.

Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).

After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.

Patient-Reported Outcome Measures

The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.

The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.⁶

The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.¹⁶ The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.^17,18 In this study, we used an MCD of a 5-point change or more between study groups.

Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).

Statistical Analysis

Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.

RESULTS

Patient Characteristics

A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.

Patient-Reported Outcomes

Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).

Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).

The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).

Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.

COMMENT

Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.^19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.

In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.²¹ The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis⁸ and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.^21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies^19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.

Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.²³ These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.²³

Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.

One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.

Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.

CONCLUSION

The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.

Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.^1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).^3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.⁷ Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).⁸ Effective treatments may considerably improve the QOL of patients with pemphigus.⁶

Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.^9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.⁸ Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.^11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.^11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.

In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.

MATERIALS AND METHODS

Study Design

We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.

Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).

After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.

Patient-Reported Outcome Measures

The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.

The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.⁶

The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.¹⁶ The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.^17,18 In this study, we used an MCD of a 5-point change or more between study groups.

Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).

Statistical Analysis

Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.

RESULTS

Patient Characteristics

A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.

Patient-Reported Outcomes

Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).

Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).

The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).

Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.

COMMENT

Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.^19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.

In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.²¹ The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis⁸ and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.^21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies^19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.

Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.²³ These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.²³

Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.

One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.

Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.

CONCLUSION

The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.

Hereditary alpha tryptasemia (HaT), an autosomal-dominant disorder of tryptase overproduction, was first described in 2014 by Lyons et al.¹ It has been associated with multiple dermatologic, allergic, gastrointestinal (GI) tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities. These multisystem concerns may include cutaneous flushing, chronic pruritus, urticaria, GI tract symptoms, arthralgia, and autonomic dysfunction.² The diverse symptoms and the recent discovery of HaT make recognition of this disorder challenging. Currently, it also is believed that HaT is associated with an elevated risk for anaphylaxis and is a biomarker for severe symptoms in disorders with increased mast cell burden such as mastocytosis.^3-5

Given the potential cutaneous manifestations and the fact that dermatologic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review summarizes the cutaneous presentations consistent with HaT and discusses various conditions that share overlapping dermatologic symptoms with HaT.

Background on HaT

Mast cells are known to secrete several vasoactive mediators including tryptase and histamine when activated by foreign substances, similar to IgE-mediated hypersensitivity reactions. In their baseline state, mast cells continuously secrete immature forms of tryptases called protryptases.⁶ These protryptases come in 2 forms: α and β. Although mature tryptase is acutely elevatedin anaphylaxis, persistently elevated total serum tryptase levels frequently are regarded as indicative of a systemic mast cell disorder such as systemic mastocytosis (SM).³ Despite the wide-ranging phenotype of HaT, all individuals with the disorder have an elevated basal serum tryptase level (>8 ng/mL). Hereditary alpha tryptasemia has been identified as another possible cause of persistently elevated levels.^2,6

Genetics and Epidemiology of HaT—The humantryptase locus at chromosome 16p13.3 is composed of 4 paralog genes: TPSG1, TPSB2, TPSAB1, and TPSD1.⁴ Only TPSAB1 encodes for α-tryptase, while both TPSB2 and TPSAB1 encode for β-tryptase.⁴ Hereditary alpha tryptasemia is an autosomal-dominant disorder resulting from a copy number increase in the α-tryptase encoding sequence within the TPSAB1 gene. Despite the wide-ranging phenotype of HaT, all individuals identified with the disorder have a basal serum tryptase level greater than 8 ng/mL, with mean (SD) levels of 15 (5) ng/mL and 24 (6) ng/mL with gene duplication and triplication, respectively (reference range, 0–11.4 ng/mL).^2,6 Hereditary alpha tryptasemia likely is common and largely undiagnosed, with a recently estimated prevalence of 5% in the United Kingdom⁷ and 5.6% in a cohort of 125 individuals from Italy, Slovenia, and the United States.⁵

Implications of Increased α-tryptase Levels—After an inciting stimulus, the active portions of α-protryptase and β-protryptase are secreted as tetramers by activated mast cells via degranulation. In vitro, β-tryptase homotetramers have been found to play a role in anaphylaxis, while α-homotetramers are nearly inactive.^8,9 Recently, however, it has been discovered that α2β2 tetramers also can form and do so in a higher ratio in individuals with increased α-tryptase–encoding gene copies, such as those with HaT.⁸ These heterotetramers exhibit unique properties compared with the homotetramers and may stimulate epidermal growth factor–like module-containing mucinlike hormone receptor 2 and protease-activated receptor 2 (PAR2). Epidermal growth factor–like module-containing mucinlike hormone receptor 2 activation likely contributes to vibratory urticaria in patients, while activation of PAR2 may have a range of clinical effects, including worsening asthma, inflammatory bowel disease, pruritus, and the exacerbation of dermal inflammation and hyperalgesia.^8,10 Thus, α- and β-tryptase tetramers can be considered mediators that may influence the severity of disorders in which mast cells are naturally prevalent and likely contribute to the phenotype of those with HaT.⁷ Furthermore, these characteristics have been shown to potentially increase in severity with increasing tryptase levels and with increased TPSAB1 duplications.^1,2 In contrast, more than 25% of the population is deficient in α-tryptase without known deleterious effects.⁵

Cutaneous Manifestations of HaT

A case series reported by Lyons et al¹ in 2014 detailed persistent elevated basal serum tryptase levels in 9 families with an autosomal-dominant pattern of inheritance. In this cohort, 31 of 33 (94%) affected individuals had a history of atopic dermatitis (AD), and 26 of 33 (79%) affected individuals reported symptoms consistent with mast cell degranulation, including urticaria; flushing; and/or crampy abdominal pain unprovoked or triggered by heat, exercise, vibration, stress, certain foods, or minor physical stimulation.¹ A later report by Lyons et al² in 2016 identified the TPSAB1 α-tryptase–encoding sequence copy number increase as the causative entity for HaT by examining a group of 96 patients from 35 families with frequent recurrent cutaneous flushing and pruritus, sometimes associated with urticaria and sleep disruption. Flushing and pruritus were found in 45% (33/73) of those with a TPSAB1 duplication and 80% (12/15) of those with a triplication (P=.022), suggesting a gene dose effect regarding α-tryptase encoding sequence copy number and these symptoms.²

A 2019 study further explored the clinical finding of urticaria in patients with HaT by specifically examining if vibration-induced urticaria was affected by TPSAB1 gene dosage.⁸ A cohort of 56 volunteers—35 healthy and 21 with HaT—underwent tryptase genotyping and cutaneous vibratory challenge. The presence of TPSAB1 was significantly correlated with induction of vibration-induced urticaria (P<.01), as the severity and prevalence of the urticarial response increased along with α- and β-tryptase gene ratios.⁸

Urticaria and angioedema also were seen in 51% (36/70) of patients in a cohort of HaT patients in the United Kingdom, in which 41% (29/70) also had skin flushing. In contrast to prior studies, these manifestations were not more common in patients with gene triplications or quintuplications than those with duplications.⁷ In another recent retrospective evaluation conducted at Brigham and Women’s Hospital (Boston, Massachusetts)(N=101), 80% of patients aged 4 to 85 years with confirmed diagnoses of HaT had skin manifestations such as urticaria, flushing, and pruritus.⁴

HaT and Mast Cell Activation Syndrome—In 2019, a Mast Cell Disorders Committee Work Group Report outlined recommendations for diagnosing and treating primary mast cell activation syndrome (MCAS), a disorder in which mast cells seem to be more easily activated. Mast cell activation syndrome is defined as a primary clinical condition in which there are episodic signs and symptoms of systemic anaphylaxis (Table) concurrently affecting at least 2 organ systems, resulting from secreted mast cell mediators.^9,11 The 2019 report also touched on clinical criteria that lack precision for diagnosing MCAS yet are in use, including dermographism and several types of rashes.⁹ Episode triggers frequent in MCAS include hot water, alcohol, stress, exercise, infection, hormonal changes, and physical stimuli.

Hereditary alpha tryptasemia has been suggested to be a risk factor for MCAS, which also can be associated with SM and clonal MCAS.⁹ Patients with MCAS should be tested for increased α-tryptase gene copy number given the overlap in symptoms, the likely predisposition of those with HaT to develop MCAS, and the fact that these patients could be at an increased risk for anaphylaxis.^4,7,9,11 However, the clinical phenotype for HaT includes allergic disorders affecting the skin as well as neuropsychiatric and connective tissue abnormalities that are distinctive from MCAS. Although HaT may be considered a heritable risk factor for MCAS, MCAS is only 1 potential phenotype associated with HaT.⁹

Implications of HaT

Hereditary alpha tryptasemia should be considered in all patients with basal tryptase levels greater than 8 ng/mL. Cutaneous symptoms are among the most common presentations for individuals with HaT and can include AD, chronic or episodic urticaria, pruritus, flushing, and angioedema. However, HaT is unique because of the coupling of these common dermatologic findings with other abnormalities, including abdominal pain and diarrhea, hypermobile joints, and autonomic dysfunction. Patients with HaT also may manifest psychiatric concerns of anxiety, depression, and chronic pain, all of which have been linked to this disorder.

It is unclear in HaT if the presence of extra-allelic copies of tryptase in an individual is directly pathogenic. The effects of increased basal tryptase and α2β2 tetramers have been shown to likely be responsible for some of the clinical features in these individuals but also may magnify other individual underlying disease(s) or diathesis in which mast cells are naturally abundant.⁸ In the skin, this increased mast cell activation and subsequent histamine release frequently are visible as dermatographia and urticaria. However, mast cell numbers also are known to be increased in both psoriatic and AD skin lesions,¹² thus severe presentation of these diseases in conjunction with the other symptoms associated with mast cell activation should prompt suspicion for HaT.

Effects of HaT on Other Cutaneous Disease—Given the increase of mast cells in AD skin lesions and fact that 94% of patients in the 2014 Lyons et al¹ study cited a history of AD, HaT may be a risk factor in the development of AD. Interestingly, in addition to the increased mast cells in AD lesions, PAR2+ nerve fibers also are increased in AD lesions and have been implicated in the nonhistaminergic pruritus experienced by patients with AD.¹² Thus, given the proposed propensity for α2β2 tetramers to activate PAR2, it is possible this mechanism may contribute to severe pruritus in individuals with AD and concurrent HaT, as those with HaT express increased α2β2 tetramers. However, no study to date has directly compared AD symptoms in patients with concurrent HaT vs patients without it. Further research is needed on how HaT impacts other allergic and inflammatory skin diseases such as AD and psoriasis, but one may reasonably consider HaT when treating chronic inflammatory skin diseases refractory to typical interventions and/or severe presentations. Although HaT is an autosomal-dominant disorder, it is not detected by standard whole exome sequencing or microarrays. A commercial test is available, utilizing a buccal swab to test for TPSAB1 copy number.

HaT and Mast Cell Disorders—When evaluating someone with suspected HaT, it is important to screen for other symptoms of mast cell activation. For instance, in the GI tract increased mast cell activation results in activation of motor neurons and nociceptors and increases secretion and peristalsis with consequent bloating, abdominal pain, and diarrhea.¹⁰ Likewise, tryptase also has neuromodulatory effects that amplify the perception of pain and are likely responsible for the feelings of hyperalgesia reported in patients with HaT.¹³

There is substantial overlap in the clinical pictures of HaT and MCAS, and HaT is considered a heritable risk factor for MCAS. Consequently, any patient undergoing workup for MCAS also should be tested for HaT. Although HaT is associated with consistently elevated tryptase, MCAS is episodic in nature, and an increase in tryptase levels of at least 20% plus 2 ng/mL from baseline only in the presence of other symptoms reflective of mast cell activation (Table) is a prerequisite for diagnosis.⁹ Chronic signs and symptoms of atopy, chronic urticaria, and severe asthma are not indicative of MCAS but are frequently seen in HaT.

Another cause of persistently elevated tryptase levels is SM. Systemic mastocytosis is defined by aberrant clonal mast cell expansion and systemic involvement¹¹ and can cause persistent symptoms, unlike MCAS alone. However, SM also can be associated with MCAS.⁹ Notably, a baseline serum tryptase level greater than 20 ng/mL—much higher than the threshold of greater than 8 ng/mL for suspicion of HaT—is seen in 75% of SM cases and is part of the minor diagnostic criteria for the disease.^9,11 However, the 2016 study identifying increased TPSAB1 α-tryptase–encoding sequences as the causative entity for HaT by Lyons et al² found the average (SD) basal serum tryptase level in individuals with α-tryptase–encoding sequence duplications to be 15 (5) ng/mL and 24 (6) ng/mL in those with triplications. Thus, there likely is no threshold for elevated baseline tryptase levels that would indicate SM over HaT as a more likely diagnosis. However, SM will present with new persistently elevated tryptase levels, whereas the elevation in HaT is believed to be lifelong.⁵ Also in contrast to HaT, SM can present with liver, spleen, and lymph node involvement; bone sclerosis; and cytopenia.^11,14

Mastocytosis is much rarer than HaT, with an estimated prevalence of 9 cases per 100,000 individuals in the United States.¹¹ Although HaT diagnostic testing is noninvasive, SM requires a bone marrow biopsy for definitive diagnosis. Given the likely much higher prevalence of HaT than SM and the patient burden of a bone marrow biopsy, HaT should be considered before proceeding with a bone marrow biopsy to evaluate for SM when a patient presents with persistent systemic symptoms of mast cell activation and elevated baseline tryptase levels. Furthermore, it also would be prudent to test for HaT in patients with known SM, as a cohort study by Lyons et al⁵ indicated that HaT is likely more common in those with SM (12.2% [10/82] of cohort with known SM vs 5.3% of 398 controls), and patients with concurrent SM and HaT were at a higher risk for severe anaphylaxis (RR=9.5; P=.007).

Studies thus far surrounding HaT have not evaluated timing of initial symptom onset or age of initial presentation for HaT. Furthermore, there is no guarantee that those with increased TPSAB1 copy number will be symptomatic, as there have been reports of asymptomatic individuals with HaT who had basal serum levels greater than 8 ng/mL.⁷ As research into HaT continues and larger cohorts are evaluated, questions surrounding timing of symptom onset and various factors that may make someone more likely to display a particular phenotype will be answered.

Treatment—Long-term prognosis for individuals with HaT is largely unknown. Unfortunately, there are limited data to support a single effective treatment strategy for managing HaT, and treatment has varied based on predominant symptoms. For cutaneous and GI tract symptoms, trials of maximal H₁ and H₂ antihistamines twice daily have been recommended.⁴ Omalizumab was reported to improve chronic urticaria in 3 of 3 patients, showing potential promise as a treatment.⁴ Mast cell stabilizers, such as oral cromolyn, have been used for severe GI symptoms, while some patients also have reported improvement with oral ketotifen.⁶ Other medications, such as tricyclic antidepressants, clemastine fumarate, and gabapentin, have been beneficial anecdotally.⁶ Given the lack of harmful effects seen in individuals who are α-tryptase deficient, α-tryptase inhibition is an intriguing target for future therapies.

Conclusion

Patients who present with a constellation of dermatologic, allergic, GI tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities consistent with HaT may receive a prompt diagnosis if the association is recognized. The full relationship between HaT and other chronic dermatologic disorders is still unknown. Ultimately, heightened interest and research into HaT will lead to more treatment options available for affected patients.

Hereditary alpha tryptasemia (HaT), an autosomal-dominant disorder of tryptase overproduction, was first described in 2014 by Lyons et al.¹ It has been associated with multiple dermatologic, allergic, gastrointestinal (GI) tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities. These multisystem concerns may include cutaneous flushing, chronic pruritus, urticaria, GI tract symptoms, arthralgia, and autonomic dysfunction.² The diverse symptoms and the recent discovery of HaT make recognition of this disorder challenging. Currently, it also is believed that HaT is associated with an elevated risk for anaphylaxis and is a biomarker for severe symptoms in disorders with increased mast cell burden such as mastocytosis.^3-5

Given the potential cutaneous manifestations and the fact that dermatologic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review summarizes the cutaneous presentations consistent with HaT and discusses various conditions that share overlapping dermatologic symptoms with HaT.

Background on HaT

Mast cells are known to secrete several vasoactive mediators including tryptase and histamine when activated by foreign substances, similar to IgE-mediated hypersensitivity reactions. In their baseline state, mast cells continuously secrete immature forms of tryptases called protryptases.⁶ These protryptases come in 2 forms: α and β. Although mature tryptase is acutely elevatedin anaphylaxis, persistently elevated total serum tryptase levels frequently are regarded as indicative of a systemic mast cell disorder such as systemic mastocytosis (SM).³ Despite the wide-ranging phenotype of HaT, all individuals with the disorder have an elevated basal serum tryptase level (>8 ng/mL). Hereditary alpha tryptasemia has been identified as another possible cause of persistently elevated levels.^2,6

Genetics and Epidemiology of HaT—The humantryptase locus at chromosome 16p13.3 is composed of 4 paralog genes: TPSG1, TPSB2, TPSAB1, and TPSD1.⁴ Only TPSAB1 encodes for α-tryptase, while both TPSB2 and TPSAB1 encode for β-tryptase.⁴ Hereditary alpha tryptasemia is an autosomal-dominant disorder resulting from a copy number increase in the α-tryptase encoding sequence within the TPSAB1 gene. Despite the wide-ranging phenotype of HaT, all individuals identified with the disorder have a basal serum tryptase level greater than 8 ng/mL, with mean (SD) levels of 15 (5) ng/mL and 24 (6) ng/mL with gene duplication and triplication, respectively (reference range, 0–11.4 ng/mL).^2,6 Hereditary alpha tryptasemia likely is common and largely undiagnosed, with a recently estimated prevalence of 5% in the United Kingdom⁷ and 5.6% in a cohort of 125 individuals from Italy, Slovenia, and the United States.⁵

Implications of Increased α-tryptase Levels—After an inciting stimulus, the active portions of α-protryptase and β-protryptase are secreted as tetramers by activated mast cells via degranulation. In vitro, β-tryptase homotetramers have been found to play a role in anaphylaxis, while α-homotetramers are nearly inactive.^8,9 Recently, however, it has been discovered that α2β2 tetramers also can form and do so in a higher ratio in individuals with increased α-tryptase–encoding gene copies, such as those with HaT.⁸ These heterotetramers exhibit unique properties compared with the homotetramers and may stimulate epidermal growth factor–like module-containing mucinlike hormone receptor 2 and protease-activated receptor 2 (PAR2). Epidermal growth factor–like module-containing mucinlike hormone receptor 2 activation likely contributes to vibratory urticaria in patients, while activation of PAR2 may have a range of clinical effects, including worsening asthma, inflammatory bowel disease, pruritus, and the exacerbation of dermal inflammation and hyperalgesia.^8,10 Thus, α- and β-tryptase tetramers can be considered mediators that may influence the severity of disorders in which mast cells are naturally prevalent and likely contribute to the phenotype of those with HaT.⁷ Furthermore, these characteristics have been shown to potentially increase in severity with increasing tryptase levels and with increased TPSAB1 duplications.^1,2 In contrast, more than 25% of the population is deficient in α-tryptase without known deleterious effects.⁵

Cutaneous Manifestations of HaT

A case series reported by Lyons et al¹ in 2014 detailed persistent elevated basal serum tryptase levels in 9 families with an autosomal-dominant pattern of inheritance. In this cohort, 31 of 33 (94%) affected individuals had a history of atopic dermatitis (AD), and 26 of 33 (79%) affected individuals reported symptoms consistent with mast cell degranulation, including urticaria; flushing; and/or crampy abdominal pain unprovoked or triggered by heat, exercise, vibration, stress, certain foods, or minor physical stimulation.¹ A later report by Lyons et al² in 2016 identified the TPSAB1 α-tryptase–encoding sequence copy number increase as the causative entity for HaT by examining a group of 96 patients from 35 families with frequent recurrent cutaneous flushing and pruritus, sometimes associated with urticaria and sleep disruption. Flushing and pruritus were found in 45% (33/73) of those with a TPSAB1 duplication and 80% (12/15) of those with a triplication (P=.022), suggesting a gene dose effect regarding α-tryptase encoding sequence copy number and these symptoms.²

A 2019 study further explored the clinical finding of urticaria in patients with HaT by specifically examining if vibration-induced urticaria was affected by TPSAB1 gene dosage.⁸ A cohort of 56 volunteers—35 healthy and 21 with HaT—underwent tryptase genotyping and cutaneous vibratory challenge. The presence of TPSAB1 was significantly correlated with induction of vibration-induced urticaria (P<.01), as the severity and prevalence of the urticarial response increased along with α- and β-tryptase gene ratios.⁸

Urticaria and angioedema also were seen in 51% (36/70) of patients in a cohort of HaT patients in the United Kingdom, in which 41% (29/70) also had skin flushing. In contrast to prior studies, these manifestations were not more common in patients with gene triplications or quintuplications than those with duplications.⁷ In another recent retrospective evaluation conducted at Brigham and Women’s Hospital (Boston, Massachusetts)(N=101), 80% of patients aged 4 to 85 years with confirmed diagnoses of HaT had skin manifestations such as urticaria, flushing, and pruritus.⁴

HaT and Mast Cell Activation Syndrome—In 2019, a Mast Cell Disorders Committee Work Group Report outlined recommendations for diagnosing and treating primary mast cell activation syndrome (MCAS), a disorder in which mast cells seem to be more easily activated. Mast cell activation syndrome is defined as a primary clinical condition in which there are episodic signs and symptoms of systemic anaphylaxis (Table) concurrently affecting at least 2 organ systems, resulting from secreted mast cell mediators.^9,11 The 2019 report also touched on clinical criteria that lack precision for diagnosing MCAS yet are in use, including dermographism and several types of rashes.⁹ Episode triggers frequent in MCAS include hot water, alcohol, stress, exercise, infection, hormonal changes, and physical stimuli.

Hereditary alpha tryptasemia has been suggested to be a risk factor for MCAS, which also can be associated with SM and clonal MCAS.⁹ Patients with MCAS should be tested for increased α-tryptase gene copy number given the overlap in symptoms, the likely predisposition of those with HaT to develop MCAS, and the fact that these patients could be at an increased risk for anaphylaxis.^4,7,9,11 However, the clinical phenotype for HaT includes allergic disorders affecting the skin as well as neuropsychiatric and connective tissue abnormalities that are distinctive from MCAS. Although HaT may be considered a heritable risk factor for MCAS, MCAS is only 1 potential phenotype associated with HaT.⁹

Implications of HaT

Hereditary alpha tryptasemia should be considered in all patients with basal tryptase levels greater than 8 ng/mL. Cutaneous symptoms are among the most common presentations for individuals with HaT and can include AD, chronic or episodic urticaria, pruritus, flushing, and angioedema. However, HaT is unique because of the coupling of these common dermatologic findings with other abnormalities, including abdominal pain and diarrhea, hypermobile joints, and autonomic dysfunction. Patients with HaT also may manifest psychiatric concerns of anxiety, depression, and chronic pain, all of which have been linked to this disorder.

It is unclear in HaT if the presence of extra-allelic copies of tryptase in an individual is directly pathogenic. The effects of increased basal tryptase and α2β2 tetramers have been shown to likely be responsible for some of the clinical features in these individuals but also may magnify other individual underlying disease(s) or diathesis in which mast cells are naturally abundant.⁸ In the skin, this increased mast cell activation and subsequent histamine release frequently are visible as dermatographia and urticaria. However, mast cell numbers also are known to be increased in both psoriatic and AD skin lesions,¹² thus severe presentation of these diseases in conjunction with the other symptoms associated with mast cell activation should prompt suspicion for HaT.

Effects of HaT on Other Cutaneous Disease—Given the increase of mast cells in AD skin lesions and fact that 94% of patients in the 2014 Lyons et al¹ study cited a history of AD, HaT may be a risk factor in the development of AD. Interestingly, in addition to the increased mast cells in AD lesions, PAR2+ nerve fibers also are increased in AD lesions and have been implicated in the nonhistaminergic pruritus experienced by patients with AD.¹² Thus, given the proposed propensity for α2β2 tetramers to activate PAR2, it is possible this mechanism may contribute to severe pruritus in individuals with AD and concurrent HaT, as those with HaT express increased α2β2 tetramers. However, no study to date has directly compared AD symptoms in patients with concurrent HaT vs patients without it. Further research is needed on how HaT impacts other allergic and inflammatory skin diseases such as AD and psoriasis, but one may reasonably consider HaT when treating chronic inflammatory skin diseases refractory to typical interventions and/or severe presentations. Although HaT is an autosomal-dominant disorder, it is not detected by standard whole exome sequencing or microarrays. A commercial test is available, utilizing a buccal swab to test for TPSAB1 copy number.

HaT and Mast Cell Disorders—When evaluating someone with suspected HaT, it is important to screen for other symptoms of mast cell activation. For instance, in the GI tract increased mast cell activation results in activation of motor neurons and nociceptors and increases secretion and peristalsis with consequent bloating, abdominal pain, and diarrhea.¹⁰ Likewise, tryptase also has neuromodulatory effects that amplify the perception of pain and are likely responsible for the feelings of hyperalgesia reported in patients with HaT.¹³

There is substantial overlap in the clinical pictures of HaT and MCAS, and HaT is considered a heritable risk factor for MCAS. Consequently, any patient undergoing workup for MCAS also should be tested for HaT. Although HaT is associated with consistently elevated tryptase, MCAS is episodic in nature, and an increase in tryptase levels of at least 20% plus 2 ng/mL from baseline only in the presence of other symptoms reflective of mast cell activation (Table) is a prerequisite for diagnosis.⁹ Chronic signs and symptoms of atopy, chronic urticaria, and severe asthma are not indicative of MCAS but are frequently seen in HaT.

Another cause of persistently elevated tryptase levels is SM. Systemic mastocytosis is defined by aberrant clonal mast cell expansion and systemic involvement¹¹ and can cause persistent symptoms, unlike MCAS alone. However, SM also can be associated with MCAS.⁹ Notably, a baseline serum tryptase level greater than 20 ng/mL—much higher than the threshold of greater than 8 ng/mL for suspicion of HaT—is seen in 75% of SM cases and is part of the minor diagnostic criteria for the disease.^9,11 However, the 2016 study identifying increased TPSAB1 α-tryptase–encoding sequences as the causative entity for HaT by Lyons et al² found the average (SD) basal serum tryptase level in individuals with α-tryptase–encoding sequence duplications to be 15 (5) ng/mL and 24 (6) ng/mL in those with triplications. Thus, there likely is no threshold for elevated baseline tryptase levels that would indicate SM over HaT as a more likely diagnosis. However, SM will present with new persistently elevated tryptase levels, whereas the elevation in HaT is believed to be lifelong.⁵ Also in contrast to HaT, SM can present with liver, spleen, and lymph node involvement; bone sclerosis; and cytopenia.^11,14

Mastocytosis is much rarer than HaT, with an estimated prevalence of 9 cases per 100,000 individuals in the United States.¹¹ Although HaT diagnostic testing is noninvasive, SM requires a bone marrow biopsy for definitive diagnosis. Given the likely much higher prevalence of HaT than SM and the patient burden of a bone marrow biopsy, HaT should be considered before proceeding with a bone marrow biopsy to evaluate for SM when a patient presents with persistent systemic symptoms of mast cell activation and elevated baseline tryptase levels. Furthermore, it also would be prudent to test for HaT in patients with known SM, as a cohort study by Lyons et al⁵ indicated that HaT is likely more common in those with SM (12.2% [10/82] of cohort with known SM vs 5.3% of 398 controls), and patients with concurrent SM and HaT were at a higher risk for severe anaphylaxis (RR=9.5; P=.007).

Studies thus far surrounding HaT have not evaluated timing of initial symptom onset or age of initial presentation for HaT. Furthermore, there is no guarantee that those with increased TPSAB1 copy number will be symptomatic, as there have been reports of asymptomatic individuals with HaT who had basal serum levels greater than 8 ng/mL.⁷ As research into HaT continues and larger cohorts are evaluated, questions surrounding timing of symptom onset and various factors that may make someone more likely to display a particular phenotype will be answered.

Treatment—Long-term prognosis for individuals with HaT is largely unknown. Unfortunately, there are limited data to support a single effective treatment strategy for managing HaT, and treatment has varied based on predominant symptoms. For cutaneous and GI tract symptoms, trials of maximal H₁ and H₂ antihistamines twice daily have been recommended.⁴ Omalizumab was reported to improve chronic urticaria in 3 of 3 patients, showing potential promise as a treatment.⁴ Mast cell stabilizers, such as oral cromolyn, have been used for severe GI symptoms, while some patients also have reported improvement with oral ketotifen.⁶ Other medications, such as tricyclic antidepressants, clemastine fumarate, and gabapentin, have been beneficial anecdotally.⁶ Given the lack of harmful effects seen in individuals who are α-tryptase deficient, α-tryptase inhibition is an intriguing target for future therapies.

Conclusion

Patients who present with a constellation of dermatologic, allergic, GI tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities consistent with HaT may receive a prompt diagnosis if the association is recognized. The full relationship between HaT and other chronic dermatologic disorders is still unknown. Ultimately, heightened interest and research into HaT will lead to more treatment options available for affected patients.

Hereditary alpha tryptasemia (HaT), an autosomal-dominant disorder of tryptase overproduction, was first described in 2014 by Lyons et al.¹ It has been associated with multiple dermatologic, allergic, gastrointestinal (GI) tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities. These multisystem concerns may include cutaneous flushing, chronic pruritus, urticaria, GI tract symptoms, arthralgia, and autonomic dysfunction.² The diverse symptoms and the recent discovery of HaT make recognition of this disorder challenging. Currently, it also is believed that HaT is associated with an elevated risk for anaphylaxis and is a biomarker for severe symptoms in disorders with increased mast cell burden such as mastocytosis.^3-5

Given the potential cutaneous manifestations and the fact that dermatologic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review summarizes the cutaneous presentations consistent with HaT and discusses various conditions that share overlapping dermatologic symptoms with HaT.

Background on HaT

Mast cells are known to secrete several vasoactive mediators including tryptase and histamine when activated by foreign substances, similar to IgE-mediated hypersensitivity reactions. In their baseline state, mast cells continuously secrete immature forms of tryptases called protryptases.⁶ These protryptases come in 2 forms: α and β. Although mature tryptase is acutely elevatedin anaphylaxis, persistently elevated total serum tryptase levels frequently are regarded as indicative of a systemic mast cell disorder such as systemic mastocytosis (SM).³ Despite the wide-ranging phenotype of HaT, all individuals with the disorder have an elevated basal serum tryptase level (>8 ng/mL). Hereditary alpha tryptasemia has been identified as another possible cause of persistently elevated levels.^2,6

Genetics and Epidemiology of HaT—The humantryptase locus at chromosome 16p13.3 is composed of 4 paralog genes: TPSG1, TPSB2, TPSAB1, and TPSD1.⁴ Only TPSAB1 encodes for α-tryptase, while both TPSB2 and TPSAB1 encode for β-tryptase.⁴ Hereditary alpha tryptasemia is an autosomal-dominant disorder resulting from a copy number increase in the α-tryptase encoding sequence within the TPSAB1 gene. Despite the wide-ranging phenotype of HaT, all individuals identified with the disorder have a basal serum tryptase level greater than 8 ng/mL, with mean (SD) levels of 15 (5) ng/mL and 24 (6) ng/mL with gene duplication and triplication, respectively (reference range, 0–11.4 ng/mL).^2,6 Hereditary alpha tryptasemia likely is common and largely undiagnosed, with a recently estimated prevalence of 5% in the United Kingdom⁷ and 5.6% in a cohort of 125 individuals from Italy, Slovenia, and the United States.⁵

Implications of Increased α-tryptase Levels—After an inciting stimulus, the active portions of α-protryptase and β-protryptase are secreted as tetramers by activated mast cells via degranulation. In vitro, β-tryptase homotetramers have been found to play a role in anaphylaxis, while α-homotetramers are nearly inactive.^8,9 Recently, however, it has been discovered that α2β2 tetramers also can form and do so in a higher ratio in individuals with increased α-tryptase–encoding gene copies, such as those with HaT.⁸ These heterotetramers exhibit unique properties compared with the homotetramers and may stimulate epidermal growth factor–like module-containing mucinlike hormone receptor 2 and protease-activated receptor 2 (PAR2). Epidermal growth factor–like module-containing mucinlike hormone receptor 2 activation likely contributes to vibratory urticaria in patients, while activation of PAR2 may have a range of clinical effects, including worsening asthma, inflammatory bowel disease, pruritus, and the exacerbation of dermal inflammation and hyperalgesia.^8,10 Thus, α- and β-tryptase tetramers can be considered mediators that may influence the severity of disorders in which mast cells are naturally prevalent and likely contribute to the phenotype of those with HaT.⁷ Furthermore, these characteristics have been shown to potentially increase in severity with increasing tryptase levels and with increased TPSAB1 duplications.^1,2 In contrast, more than 25% of the population is deficient in α-tryptase without known deleterious effects.⁵

Cutaneous Manifestations of HaT

A case series reported by Lyons et al¹ in 2014 detailed persistent elevated basal serum tryptase levels in 9 families with an autosomal-dominant pattern of inheritance. In this cohort, 31 of 33 (94%) affected individuals had a history of atopic dermatitis (AD), and 26 of 33 (79%) affected individuals reported symptoms consistent with mast cell degranulation, including urticaria; flushing; and/or crampy abdominal pain unprovoked or triggered by heat, exercise, vibration, stress, certain foods, or minor physical stimulation.¹ A later report by Lyons et al² in 2016 identified the TPSAB1 α-tryptase–encoding sequence copy number increase as the causative entity for HaT by examining a group of 96 patients from 35 families with frequent recurrent cutaneous flushing and pruritus, sometimes associated with urticaria and sleep disruption. Flushing and pruritus were found in 45% (33/73) of those with a TPSAB1 duplication and 80% (12/15) of those with a triplication (P=.022), suggesting a gene dose effect regarding α-tryptase encoding sequence copy number and these symptoms.²

A 2019 study further explored the clinical finding of urticaria in patients with HaT by specifically examining if vibration-induced urticaria was affected by TPSAB1 gene dosage.⁸ A cohort of 56 volunteers—35 healthy and 21 with HaT—underwent tryptase genotyping and cutaneous vibratory challenge. The presence of TPSAB1 was significantly correlated with induction of vibration-induced urticaria (P<.01), as the severity and prevalence of the urticarial response increased along with α- and β-tryptase gene ratios.⁸

Urticaria and angioedema also were seen in 51% (36/70) of patients in a cohort of HaT patients in the United Kingdom, in which 41% (29/70) also had skin flushing. In contrast to prior studies, these manifestations were not more common in patients with gene triplications or quintuplications than those with duplications.⁷ In another recent retrospective evaluation conducted at Brigham and Women’s Hospital (Boston, Massachusetts)(N=101), 80% of patients aged 4 to 85 years with confirmed diagnoses of HaT had skin manifestations such as urticaria, flushing, and pruritus.⁴

HaT and Mast Cell Activation Syndrome—In 2019, a Mast Cell Disorders Committee Work Group Report outlined recommendations for diagnosing and treating primary mast cell activation syndrome (MCAS), a disorder in which mast cells seem to be more easily activated. Mast cell activation syndrome is defined as a primary clinical condition in which there are episodic signs and symptoms of systemic anaphylaxis (Table) concurrently affecting at least 2 organ systems, resulting from secreted mast cell mediators.^9,11 The 2019 report also touched on clinical criteria that lack precision for diagnosing MCAS yet are in use, including dermographism and several types of rashes.⁹ Episode triggers frequent in MCAS include hot water, alcohol, stress, exercise, infection, hormonal changes, and physical stimuli.

Hereditary alpha tryptasemia has been suggested to be a risk factor for MCAS, which also can be associated with SM and clonal MCAS.⁹ Patients with MCAS should be tested for increased α-tryptase gene copy number given the overlap in symptoms, the likely predisposition of those with HaT to develop MCAS, and the fact that these patients could be at an increased risk for anaphylaxis.^4,7,9,11 However, the clinical phenotype for HaT includes allergic disorders affecting the skin as well as neuropsychiatric and connective tissue abnormalities that are distinctive from MCAS. Although HaT may be considered a heritable risk factor for MCAS, MCAS is only 1 potential phenotype associated with HaT.⁹

Implications of HaT

Hereditary alpha tryptasemia should be considered in all patients with basal tryptase levels greater than 8 ng/mL. Cutaneous symptoms are among the most common presentations for individuals with HaT and can include AD, chronic or episodic urticaria, pruritus, flushing, and angioedema. However, HaT is unique because of the coupling of these common dermatologic findings with other abnormalities, including abdominal pain and diarrhea, hypermobile joints, and autonomic dysfunction. Patients with HaT also may manifest psychiatric concerns of anxiety, depression, and chronic pain, all of which have been linked to this disorder.

It is unclear in HaT if the presence of extra-allelic copies of tryptase in an individual is directly pathogenic. The effects of increased basal tryptase and α2β2 tetramers have been shown to likely be responsible for some of the clinical features in these individuals but also may magnify other individual underlying disease(s) or diathesis in which mast cells are naturally abundant.⁸ In the skin, this increased mast cell activation and subsequent histamine release frequently are visible as dermatographia and urticaria. However, mast cell numbers also are known to be increased in both psoriatic and AD skin lesions,¹² thus severe presentation of these diseases in conjunction with the other symptoms associated with mast cell activation should prompt suspicion for HaT.

Effects of HaT on Other Cutaneous Disease—Given the increase of mast cells in AD skin lesions and fact that 94% of patients in the 2014 Lyons et al¹ study cited a history of AD, HaT may be a risk factor in the development of AD. Interestingly, in addition to the increased mast cells in AD lesions, PAR2+ nerve fibers also are increased in AD lesions and have been implicated in the nonhistaminergic pruritus experienced by patients with AD.¹² Thus, given the proposed propensity for α2β2 tetramers to activate PAR2, it is possible this mechanism may contribute to severe pruritus in individuals with AD and concurrent HaT, as those with HaT express increased α2β2 tetramers. However, no study to date has directly compared AD symptoms in patients with concurrent HaT vs patients without it. Further research is needed on how HaT impacts other allergic and inflammatory skin diseases such as AD and psoriasis, but one may reasonably consider HaT when treating chronic inflammatory skin diseases refractory to typical interventions and/or severe presentations. Although HaT is an autosomal-dominant disorder, it is not detected by standard whole exome sequencing or microarrays. A commercial test is available, utilizing a buccal swab to test for TPSAB1 copy number.

HaT and Mast Cell Disorders—When evaluating someone with suspected HaT, it is important to screen for other symptoms of mast cell activation. For instance, in the GI tract increased mast cell activation results in activation of motor neurons and nociceptors and increases secretion and peristalsis with consequent bloating, abdominal pain, and diarrhea.¹⁰ Likewise, tryptase also has neuromodulatory effects that amplify the perception of pain and are likely responsible for the feelings of hyperalgesia reported in patients with HaT.¹³

There is substantial overlap in the clinical pictures of HaT and MCAS, and HaT is considered a heritable risk factor for MCAS. Consequently, any patient undergoing workup for MCAS also should be tested for HaT. Although HaT is associated with consistently elevated tryptase, MCAS is episodic in nature, and an increase in tryptase levels of at least 20% plus 2 ng/mL from baseline only in the presence of other symptoms reflective of mast cell activation (Table) is a prerequisite for diagnosis.⁹ Chronic signs and symptoms of atopy, chronic urticaria, and severe asthma are not indicative of MCAS but are frequently seen in HaT.

Another cause of persistently elevated tryptase levels is SM. Systemic mastocytosis is defined by aberrant clonal mast cell expansion and systemic involvement¹¹ and can cause persistent symptoms, unlike MCAS alone. However, SM also can be associated with MCAS.⁹ Notably, a baseline serum tryptase level greater than 20 ng/mL—much higher than the threshold of greater than 8 ng/mL for suspicion of HaT—is seen in 75% of SM cases and is part of the minor diagnostic criteria for the disease.^9,11 However, the 2016 study identifying increased TPSAB1 α-tryptase–encoding sequences as the causative entity for HaT by Lyons et al² found the average (SD) basal serum tryptase level in individuals with α-tryptase–encoding sequence duplications to be 15 (5) ng/mL and 24 (6) ng/mL in those with triplications. Thus, there likely is no threshold for elevated baseline tryptase levels that would indicate SM over HaT as a more likely diagnosis. However, SM will present with new persistently elevated tryptase levels, whereas the elevation in HaT is believed to be lifelong.⁵ Also in contrast to HaT, SM can present with liver, spleen, and lymph node involvement; bone sclerosis; and cytopenia.^11,14

Mastocytosis is much rarer than HaT, with an estimated prevalence of 9 cases per 100,000 individuals in the United States.¹¹ Although HaT diagnostic testing is noninvasive, SM requires a bone marrow biopsy for definitive diagnosis. Given the likely much higher prevalence of HaT than SM and the patient burden of a bone marrow biopsy, HaT should be considered before proceeding with a bone marrow biopsy to evaluate for SM when a patient presents with persistent systemic symptoms of mast cell activation and elevated baseline tryptase levels. Furthermore, it also would be prudent to test for HaT in patients with known SM, as a cohort study by Lyons et al⁵ indicated that HaT is likely more common in those with SM (12.2% [10/82] of cohort with known SM vs 5.3% of 398 controls), and patients with concurrent SM and HaT were at a higher risk for severe anaphylaxis (RR=9.5; P=.007).

Studies thus far surrounding HaT have not evaluated timing of initial symptom onset or age of initial presentation for HaT. Furthermore, there is no guarantee that those with increased TPSAB1 copy number will be symptomatic, as there have been reports of asymptomatic individuals with HaT who had basal serum levels greater than 8 ng/mL.⁷ As research into HaT continues and larger cohorts are evaluated, questions surrounding timing of symptom onset and various factors that may make someone more likely to display a particular phenotype will be answered.

Treatment—Long-term prognosis for individuals with HaT is largely unknown. Unfortunately, there are limited data to support a single effective treatment strategy for managing HaT, and treatment has varied based on predominant symptoms. For cutaneous and GI tract symptoms, trials of maximal H₁ and H₂ antihistamines twice daily have been recommended.⁴ Omalizumab was reported to improve chronic urticaria in 3 of 3 patients, showing potential promise as a treatment.⁴ Mast cell stabilizers, such as oral cromolyn, have been used for severe GI symptoms, while some patients also have reported improvement with oral ketotifen.⁶ Other medications, such as tricyclic antidepressants, clemastine fumarate, and gabapentin, have been beneficial anecdotally.⁶ Given the lack of harmful effects seen in individuals who are α-tryptase deficient, α-tryptase inhibition is an intriguing target for future therapies.

Conclusion

Patients who present with a constellation of dermatologic, allergic, GI tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities consistent with HaT may receive a prompt diagnosis if the association is recognized. The full relationship between HaT and other chronic dermatologic disorders is still unknown. Ultimately, heightened interest and research into HaT will lead to more treatment options available for affected patients.

The Diagnosis: Pigmented Fungiform Papillae of the Tongue

Our patient’s hyperpigmentation was confined to the fungiform papillae, leading to a diagnosis of pigmented fungiform papillae of the tongue (PFPT). A biopsy was not performed, and reassurance was provided regarding the benign nature of this finding, which did not require treatment.

Pigmented fungiform papillae of the tongue is a benign, nonprogressive, asymptomatic pigmentary condition that is most common among patients with skin of color and typically develops within the second or third decade of life.^1,2 The pathogenesis is unclear, but activation of subepithelial melanophages without evidence of inflammation has been implicated.² Although no standard treatment exists, cosmetic improvement with the use of the Q-switched ruby laser has been reported.^3,4 Clinically, PFPT presents as asymptomatic hyperpigmentation confined to the fungiform papillae along the anterior and lateral portions of the tongue.^1,2

Pigmented fungiform papillae of the tongue typically is an isolated finding but rarely can be associated with hyperpigmentation of the nails (as in our patient) or gingiva.² Three different clinical patterns of presentation have been described: (1) a single well-circumscribed collection of pigmented fungiform papillae, (2) few scattered pigmented fungiform papillae admixed with many nonpigmented fungiform papillae, or (3) pigmentation of all fungiform papillae on the dorsal aspect of the tongue.^2,5,6 Pigmented fungiform papillae of the tongue is a clinical diagnosis based on visual recognition. Dermoscopic examination revealing a cobblestonelike or rose petal–like pattern may be helpful in diagnosing PFPT.^2,5-7 Although not typically recommended in the evaluation of PFPT, a biopsy will reveal papillary structures with hyperpigmentation of basilar keratinocytes as well as melanophages in the lamina propria.8 The latter finding suggests a transient inflammatory process despite the hallmark absence of inflammation.⁵ Melanocytic neoplasia and exogenous granules of pigment typically are not seen.⁸

Other conditions that may present with dark-colored macules or papules on the tongue should be considered in the evaluation of a patient with these clinical findings. Black hairy tongue (BHT), or lingua villosa nigra, is a benign finding due to filiform papillae hypertrophy on the dorsum of the tongue.⁹ Food particle debris caught in BHT can lead to porphyrin production by chromogenic bacteria and fungi. These porphyrins result in discoloration ranging from brown-black to yellow and green occurring anteriorly to the circumvallate papillae while usually sparing the tip and lateral sides of the tongue. Dermoscopy can show thin discolored fibers with a hairy appearance. Although normal filiform papillae are less than 1-mm long, 3-mm long papillae are considered diagnostic of BHT.⁹ Treatment includes effective oral hygiene and desquamation measures, which can lead to complete resolution.10

Peutz-Jeghers syndrome is a rare genodermatosis that is characterized by focal hyperpigmentation and multiple gastrointestinal mucosal hamartomatous polyps. Peutz-Jeghers syndrome should be suspected in a patient with discrete, 1- to 5-mm, brown to black macules on the perioral or periocular skin, tongue, genitals, palms, soles, and buccal mucosa with a history of abdominal symptoms.^11,12

Addison disease, or primary adrenal insufficiency, may present with brown hyperpigmentation on chronically sun-exposed areas; regions of friction or pressure; surrounding scar tissue; and mucosal surfaces such as the tongue, inner surface of the lip, and buccal and gingival mucosa.¹³ Addison disease is differentiated from PFPT by a more generalized hyperpigmentation due to increased melanin production as well as the presence of systemic symptoms related to hypocortisolism. The pigmentation seen on the buccal mucosa in Addison disease is patchy and diffuse, and histology reveals basal melanin hyperpigmentation with superficial dermal melanophages.¹³

Hereditary hemorrhagic telangiectasia is an inherited disorder featuring telangiectasia and generally appears in the third decade of life.¹⁴ Telangiectases classically are 1 to 3 mm in diameter with or without slight elevation. Dermoscopic findings include small red clots, lacunae, and serpentine or linear vessels arranged in a radial conformation surrounding a homogenous pink center.¹⁵ These telangiectases typically occur on the skin or mucosa, particularly the face, lips, tongue, nail beds, and nasal mucosa; however, any organ can be affected with arteriovenous malformations. Recurrent epistaxis occurs in more than half of patients with hereditary hemorrhagic telangiectasia.¹⁴ Histopathology reveals dilated vessels and lacunae near the dermoepidermal junction displacing the epidermis and papillary dermis.¹⁵ It is distinguished from PFPT by the vascular nature of the lesions and by the presence of other characteristic symptoms such as recurrent epistaxis and visceral arteriovenous malformations.

The Diagnosis: Pigmented Fungiform Papillae of the Tongue

Our patient’s hyperpigmentation was confined to the fungiform papillae, leading to a diagnosis of pigmented fungiform papillae of the tongue (PFPT). A biopsy was not performed, and reassurance was provided regarding the benign nature of this finding, which did not require treatment.

Pigmented fungiform papillae of the tongue is a benign, nonprogressive, asymptomatic pigmentary condition that is most common among patients with skin of color and typically develops within the second or third decade of life.^1,2 The pathogenesis is unclear, but activation of subepithelial melanophages without evidence of inflammation has been implicated.² Although no standard treatment exists, cosmetic improvement with the use of the Q-switched ruby laser has been reported.^3,4 Clinically, PFPT presents as asymptomatic hyperpigmentation confined to the fungiform papillae along the anterior and lateral portions of the tongue.^1,2

Pigmented fungiform papillae of the tongue typically is an isolated finding but rarely can be associated with hyperpigmentation of the nails (as in our patient) or gingiva.² Three different clinical patterns of presentation have been described: (1) a single well-circumscribed collection of pigmented fungiform papillae, (2) few scattered pigmented fungiform papillae admixed with many nonpigmented fungiform papillae, or (3) pigmentation of all fungiform papillae on the dorsal aspect of the tongue.^2,5,6 Pigmented fungiform papillae of the tongue is a clinical diagnosis based on visual recognition. Dermoscopic examination revealing a cobblestonelike or rose petal–like pattern may be helpful in diagnosing PFPT.^2,5-7 Although not typically recommended in the evaluation of PFPT, a biopsy will reveal papillary structures with hyperpigmentation of basilar keratinocytes as well as melanophages in the lamina propria.8 The latter finding suggests a transient inflammatory process despite the hallmark absence of inflammation.⁵ Melanocytic neoplasia and exogenous granules of pigment typically are not seen.⁸

Other conditions that may present with dark-colored macules or papules on the tongue should be considered in the evaluation of a patient with these clinical findings. Black hairy tongue (BHT), or lingua villosa nigra, is a benign finding due to filiform papillae hypertrophy on the dorsum of the tongue.⁹ Food particle debris caught in BHT can lead to porphyrin production by chromogenic bacteria and fungi. These porphyrins result in discoloration ranging from brown-black to yellow and green occurring anteriorly to the circumvallate papillae while usually sparing the tip and lateral sides of the tongue. Dermoscopy can show thin discolored fibers with a hairy appearance. Although normal filiform papillae are less than 1-mm long, 3-mm long papillae are considered diagnostic of BHT.⁹ Treatment includes effective oral hygiene and desquamation measures, which can lead to complete resolution.10

Peutz-Jeghers syndrome is a rare genodermatosis that is characterized by focal hyperpigmentation and multiple gastrointestinal mucosal hamartomatous polyps. Peutz-Jeghers syndrome should be suspected in a patient with discrete, 1- to 5-mm, brown to black macules on the perioral or periocular skin, tongue, genitals, palms, soles, and buccal mucosa with a history of abdominal symptoms.^11,12

Addison disease, or primary adrenal insufficiency, may present with brown hyperpigmentation on chronically sun-exposed areas; regions of friction or pressure; surrounding scar tissue; and mucosal surfaces such as the tongue, inner surface of the lip, and buccal and gingival mucosa.¹³ Addison disease is differentiated from PFPT by a more generalized hyperpigmentation due to increased melanin production as well as the presence of systemic symptoms related to hypocortisolism. The pigmentation seen on the buccal mucosa in Addison disease is patchy and diffuse, and histology reveals basal melanin hyperpigmentation with superficial dermal melanophages.¹³

Hereditary hemorrhagic telangiectasia is an inherited disorder featuring telangiectasia and generally appears in the third decade of life.¹⁴ Telangiectases classically are 1 to 3 mm in diameter with or without slight elevation. Dermoscopic findings include small red clots, lacunae, and serpentine or linear vessels arranged in a radial conformation surrounding a homogenous pink center.¹⁵ These telangiectases typically occur on the skin or mucosa, particularly the face, lips, tongue, nail beds, and nasal mucosa; however, any organ can be affected with arteriovenous malformations. Recurrent epistaxis occurs in more than half of patients with hereditary hemorrhagic telangiectasia.¹⁴ Histopathology reveals dilated vessels and lacunae near the dermoepidermal junction displacing the epidermis and papillary dermis.¹⁵ It is distinguished from PFPT by the vascular nature of the lesions and by the presence of other characteristic symptoms such as recurrent epistaxis and visceral arteriovenous malformations.

The Diagnosis: Pigmented Fungiform Papillae of the Tongue

Our patient’s hyperpigmentation was confined to the fungiform papillae, leading to a diagnosis of pigmented fungiform papillae of the tongue (PFPT). A biopsy was not performed, and reassurance was provided regarding the benign nature of this finding, which did not require treatment.

Pigmented fungiform papillae of the tongue is a benign, nonprogressive, asymptomatic pigmentary condition that is most common among patients with skin of color and typically develops within the second or third decade of life.^1,2 The pathogenesis is unclear, but activation of subepithelial melanophages without evidence of inflammation has been implicated.² Although no standard treatment exists, cosmetic improvement with the use of the Q-switched ruby laser has been reported.^3,4 Clinically, PFPT presents as asymptomatic hyperpigmentation confined to the fungiform papillae along the anterior and lateral portions of the tongue.^1,2

Pigmented fungiform papillae of the tongue typically is an isolated finding but rarely can be associated with hyperpigmentation of the nails (as in our patient) or gingiva.² Three different clinical patterns of presentation have been described: (1) a single well-circumscribed collection of pigmented fungiform papillae, (2) few scattered pigmented fungiform papillae admixed with many nonpigmented fungiform papillae, or (3) pigmentation of all fungiform papillae on the dorsal aspect of the tongue.^2,5,6 Pigmented fungiform papillae of the tongue is a clinical diagnosis based on visual recognition. Dermoscopic examination revealing a cobblestonelike or rose petal–like pattern may be helpful in diagnosing PFPT.^2,5-7 Although not typically recommended in the evaluation of PFPT, a biopsy will reveal papillary structures with hyperpigmentation of basilar keratinocytes as well as melanophages in the lamina propria.8 The latter finding suggests a transient inflammatory process despite the hallmark absence of inflammation.⁵ Melanocytic neoplasia and exogenous granules of pigment typically are not seen.⁸

Other conditions that may present with dark-colored macules or papules on the tongue should be considered in the evaluation of a patient with these clinical findings. Black hairy tongue (BHT), or lingua villosa nigra, is a benign finding due to filiform papillae hypertrophy on the dorsum of the tongue.⁹ Food particle debris caught in BHT can lead to porphyrin production by chromogenic bacteria and fungi. These porphyrins result in discoloration ranging from brown-black to yellow and green occurring anteriorly to the circumvallate papillae while usually sparing the tip and lateral sides of the tongue. Dermoscopy can show thin discolored fibers with a hairy appearance. Although normal filiform papillae are less than 1-mm long, 3-mm long papillae are considered diagnostic of BHT.⁹ Treatment includes effective oral hygiene and desquamation measures, which can lead to complete resolution.10

Peutz-Jeghers syndrome is a rare genodermatosis that is characterized by focal hyperpigmentation and multiple gastrointestinal mucosal hamartomatous polyps. Peutz-Jeghers syndrome should be suspected in a patient with discrete, 1- to 5-mm, brown to black macules on the perioral or periocular skin, tongue, genitals, palms, soles, and buccal mucosa with a history of abdominal symptoms.^11,12

Addison disease, or primary adrenal insufficiency, may present with brown hyperpigmentation on chronically sun-exposed areas; regions of friction or pressure; surrounding scar tissue; and mucosal surfaces such as the tongue, inner surface of the lip, and buccal and gingival mucosa.¹³ Addison disease is differentiated from PFPT by a more generalized hyperpigmentation due to increased melanin production as well as the presence of systemic symptoms related to hypocortisolism. The pigmentation seen on the buccal mucosa in Addison disease is patchy and diffuse, and histology reveals basal melanin hyperpigmentation with superficial dermal melanophages.¹³

Hereditary hemorrhagic telangiectasia is an inherited disorder featuring telangiectasia and generally appears in the third decade of life.¹⁴ Telangiectases classically are 1 to 3 mm in diameter with or without slight elevation. Dermoscopic findings include small red clots, lacunae, and serpentine or linear vessels arranged in a radial conformation surrounding a homogenous pink center.¹⁵ These telangiectases typically occur on the skin or mucosa, particularly the face, lips, tongue, nail beds, and nasal mucosa; however, any organ can be affected with arteriovenous malformations. Recurrent epistaxis occurs in more than half of patients with hereditary hemorrhagic telangiectasia.¹⁴ Histopathology reveals dilated vessels and lacunae near the dermoepidermal junction displacing the epidermis and papillary dermis.¹⁵ It is distinguished from PFPT by the vascular nature of the lesions and by the presence of other characteristic symptoms such as recurrent epistaxis and visceral arteriovenous malformations.

“More than Jews have kept Shabbat, Shabbat has kept the Jews.” – Ahad Ha’am

You should all be well rested by now. After all, we’ve just come through the festive shutdown of the holiday season where all of your pumpkin/peppermint/marshmallow flavored coffees were sipped while walking around in your jimjams at 10 a.m. It was the time of year for you to take time off to get a proper rest and be energized to get back to work. Yet, I’m not feeling it from you.

So let’s talk about burnout – just kidding, that would only make it worse. “Burned-out’’ is a hackneyed and defective phrase to describe what many of us are feeling. We are not “destroyed, gutted by fire or by overheating.” No, we are, as one of our docs put it to me: “Just tired.” Ah, a much better Old English word! “Tired” captures it. It means to feel “in need of rest.” We are not ruined, we are just depleted. We don’t need discarding. We need some rest.

Ironically, this column, like most of mine, comes to you after my having written it on a Saturday and Sunday. I also just logged on to my EMR and checked results, renewed a few prescriptions, and answered a couple messages. If I didn’t, my Monday’s work would be crushingly heavy.

Maybe I need to be more efficient and finish my work during the week. Or maybe I need to realize that work has not let up since about 600 BCE and taking one day off each week to rest is an obligation to myself, my family and my community.

I wonder if I can choose Mondays.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

“More than Jews have kept Shabbat, Shabbat has kept the Jews.” – Ahad Ha’am

You should all be well rested by now. After all, we’ve just come through the festive shutdown of the holiday season where all of your pumpkin/peppermint/marshmallow flavored coffees were sipped while walking around in your jimjams at 10 a.m. It was the time of year for you to take time off to get a proper rest and be energized to get back to work. Yet, I’m not feeling it from you.

So let’s talk about burnout – just kidding, that would only make it worse. “Burned-out’’ is a hackneyed and defective phrase to describe what many of us are feeling. We are not “destroyed, gutted by fire or by overheating.” No, we are, as one of our docs put it to me: “Just tired.” Ah, a much better Old English word! “Tired” captures it. It means to feel “in need of rest.” We are not ruined, we are just depleted. We don’t need discarding. We need some rest.

Ironically, this column, like most of mine, comes to you after my having written it on a Saturday and Sunday. I also just logged on to my EMR and checked results, renewed a few prescriptions, and answered a couple messages. If I didn’t, my Monday’s work would be crushingly heavy.

Maybe I need to be more efficient and finish my work during the week. Or maybe I need to realize that work has not let up since about 600 BCE and taking one day off each week to rest is an obligation to myself, my family and my community.

I wonder if I can choose Mondays.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

“More than Jews have kept Shabbat, Shabbat has kept the Jews.” – Ahad Ha’am

You should all be well rested by now. After all, we’ve just come through the festive shutdown of the holiday season where all of your pumpkin/peppermint/marshmallow flavored coffees were sipped while walking around in your jimjams at 10 a.m. It was the time of year for you to take time off to get a proper rest and be energized to get back to work. Yet, I’m not feeling it from you.

So let’s talk about burnout – just kidding, that would only make it worse. “Burned-out’’ is a hackneyed and defective phrase to describe what many of us are feeling. We are not “destroyed, gutted by fire or by overheating.” No, we are, as one of our docs put it to me: “Just tired.” Ah, a much better Old English word! “Tired” captures it. It means to feel “in need of rest.” We are not ruined, we are just depleted. We don’t need discarding. We need some rest.

Ironically, this column, like most of mine, comes to you after my having written it on a Saturday and Sunday. I also just logged on to my EMR and checked results, renewed a few prescriptions, and answered a couple messages. If I didn’t, my Monday’s work would be crushingly heavy.

Maybe I need to be more efficient and finish my work during the week. Or maybe I need to realize that work has not let up since about 600 BCE and taking one day off each week to rest is an obligation to myself, my family and my community.

I wonder if I can choose Mondays.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.

Though rheumatoid arthritis (RA)–associated interstitial lung disease (RA-ILD) is a feared complication that can significantly affect morbidity and mortality, the role of methotrexate in treatment and its possible contribution to ILD is yet unknown. Kim and colleagues performed a retrospective analysis of a series of 170 patients with RA-ILD to try to identify risk factors and protective factors for mortality and decline of lung function. Previously known risk factors included older age, smoking, and seropositivity for cyclic citrullinated peptide (CCP). In this series, patients who had exposure to methotrexate after a diagnosis of RA-ILD were found to have less progression of decline in lung function and decreased mortality compared with those who did not, which is a finding that warrants further examination. On the other hand, there was a suggestion that sulfasalazine use is associated with increased mortality, though this finding was not borne out in multivariate analysis.

A different group of authors also examined the association with conventional disease-modifying antirheumatic drugs (DMARD) with ILD progression in a prospective analysis of 143 patients in the multicenter Korean RA-ILD cohort. Patients were classified regarding exposure to methotrexate, leflunomide, or tacrolimus as well as biologic DMARD and glucocorticoid exposure, with a primary outcome of ILD progression based on pulmonary function tests or mortality. The study did not detect any difference in time to ILD progression with methotrexate exposure, though it is not clear that the study would be able to detect a protective effect as was possible in the prior study. However, patients who were exposed to leflunomide had a shorter time to ILD progression than did those who were not, though this did not persist in multivariate analysis, and tacrolimus exposure had a statistically insignificant impact on ILD progression. Because the study is small, other associations which could affect use of leflunomide in these patients were not examined, though prior studies have suggested an association with leflunomide in ILD progression in patients with existing RA-ILD.

Li and colleagues addressed the characteristics and prognosis of late-onset RA (LORA) in people 60 years or older compared with younger-onset RA (YORA) in a prospective cohort study using a Canadian RA registry. Patients in the registry were enrolled early in the course of their illness and clinical characteristics as well as time to Disease Activity Score (DAS28) remission were analyzed. Of note, YORA and LORA patients had similar times to remission but were on less aggressive medication regimens, such as conventional DMARD without biologic DMARD or Janus kinase (JAK) inhibitors. In this registry, a smaller percentage of LORA patients compared with YORA patients were seropositive, which, given the enrollment of patients early in their disease course, may affect the use of biologic DMARD and JAK inhibitors.

Finally, the issue of noninflammatory pain contributing to disease activity and quality of life in RA has received increased scrutiny recently. Choy and colleagues studied disproportionate articular pain (DP) and its response to sarilumab, adalimumab, or placebo in a post hoc analysis of data from prior randomized clinical trials. DP was defined as a tender joint count that exceeded swollen joint count by seven and was present in about 20% of patients in the three randomized clinical trials examined. In these studies, DP was reduced in patients treated with sarilumab compared with placebo or adalimumab. Although this finding is exciting in raising the possibility of an immunologic explanation for DP via interleukin 6 (IL-6), the results should be considered carefully in the context of this post hoc analysis, especially before considering sarilumab or other IL-6 inhibitors as viable treatment options for DP in RA.

ILLUSTRATION: PAUL ZWOLAK

While many anticipated the fall of Roe v Wade after the leaked Supreme Court of the United States (SCOTUS) decision in the Dobbs v Jackson case, few may have fully comprehended the myriad of ways this ruling would create a national health care crisis overnight. Since the ruling, abortion has been banned, or a 6-week gestational age limit has been implemented, in a total of 13 states, all within the South and Midwest regions of the country.¹ Many additional states will almost assuredly enact bans on access to reproductive health care in the near future. While the specific case of the 10-year-old rape victim in Ohio and her gynecologic care by Dr. Caitlin Bernard, an Indiana ObGyn, has garnered national attention, most of the devastating effects have not yet been realized.² Recent published data highlights the substantially negative impact these legislative changes already have had regarding the treatment of early spontaneous abortions and premature rupture of membranes.^3,4 Physicians could face legal consequences for treating emergencies, such as ectopic pregnancies, in some states.⁵

The 2022 American College of Obstetricians and Gynecologists (ACOG) Annual Clinical and Scientific Meeting, held shortly after the leaked SCOTUS opinion, was unlike most others. ACOG staff appropriately recognized the vastly different ways this ruling would affect patients and providers alike, simply based on the states in which they reside. ACOG staff organized the large group of attendees according to self-identified status (ie, whether they worked in states with protected, restricted, or threatened access to abortion care). Since this is such a vast topic, attendees also were asked to identify an area upon which to focus, such as the provision of health care, advocacy, or education. As a clinician practicing in Massachusetts, Dr. Bradley found herself meeting with an ACOG leader from California as they brainstormed how to best help our own communities. In conversing with attendees from other parts of the country, it became apparent the challenges others would be facing elsewhere were far more substantive than those we would be facing in “blue states.” After the Dobbs ruling, those predictions became harsh realities.

As we begin to see and hear reports of the devastating consequences of this ruling in “red states,” those of us in protected states have been struggling to try and ascertain how to help. Many of us have worked with our own legislatures to further enshrine protections for our patients and clinicians. New York and Massachusetts exemplify these efforts.^6,7 These legislative efforts have included liability protections for patients and their clinicians who care for those who travel from restricted to protected states. Others involve codifying the principles of Roe and clarifying existing law to improve access. An online fundraiser organized by physicians to assist Dr. Bernard with her legal costs as she faces politically motivated investigation by Indiana state authorities has raised more than $260,000.⁸ Many expressed the potential legal and medical peril for examiners and examinees if the American Board of Obstetrics and Gynecology held in-person oral examinations in Texas as previously scheduled.⁹ An online petition to change the format to virtual had 728 signatories, and the format was changed back to virtual.¹⁰

The implications on medical schools, residencies, and fellowships cannot be overstated. The Dobbs ruling almost immediately affected nearly half of the training programs, which is particularly problematic given the Accreditation Council for Graduate Medical Education requirement that all ObGyn residents have access to abortion training.¹¹ Other programs already are starting to try to meet this vast training need. The University of California San Francisco started offering training to physicians from Texas who were affected by the strict restrictions that predated Dobbs in the SB8 legislation, which turned ordinary citizens into vigilantes.¹²

ACOG has created an online resource (https://www.acog.org/advocacy/abortion-is-essential) with a number of different sections regarding clinical care, education and training, advocacy at the state level, and how to use effective language when talking about abortion in our communities. Planned Parenthood also suggests a myriad of ways those directly and indirectly affected could get involved:

1. Donate to the National Network of Abortion Funds. This fund (https://secure.actblue.com/donate/fundabortionnow) facilitates care for those without the financial means to obtain it, supporting travel, lodging, and child care.
2. Share #AbortionAccess posts on social media. These stories are a powerful reminder of the incredibly harmful impact this legislation can have on our patients.
3. Donate to the If When How’s Legal Repro Defense Fund (https:/www.ifwhenhow.org/), which helps cover legal costs for those facing state persecution related to reproductive health care.
4. Volunteer to help protect abortion health care at the state level.
5. Engage with members of Congress in their home districts. (https://www.congress.gov/members/find-your-member)
6. Contact the Planned Parenthood Local Engagement Team to facilitate your group, business, or organization’s involvement.
7. Partner. Facilitate your organization and other companies to partner with Planned Parenthood and sign up for Bans off our Bodies (https://docs.google.com/forms/d/e/1FAIpQLSdrmxwMcwNXJ8I NE8S2gYjDDXuT76ws_Fr7CLm3 qbtR8dcZHw/viewform).
8. Record your perspective about abortion (https://www.together.plannedparenthood.org/articles/6-share-abortion-story), whether it’s having had one, supported someone who had one, or advocated for others to have access to the procedure.¹³

ACOG also outlines several ways those of us in protected states could help shape the landscape in other communities in addition to advocating for state medical society resolutions, writing op-eds and letters to the editor, and utilizing ACOG’s social media graphics.¹⁴ In recognition of the often sensitive, polarizing nature of these discussions, ACOG is offering a workshop entitled “Building Evidence-Based Skills for Effective Conversations about Abortion.”¹⁵

Abortion traditionally was a policy issue other medical organizations shied away from developing official policy on and speaking out in support of, but recognizing the devastating scope of the public health crisis, 75 medical professional organizations recently released a strongly worded joint statement noting, “As leading medical and health care organizations dedicated to patient care and public health, we condemn this and all interference in the patient–clinician relationship.”¹⁶ Clinicians could work to expand this list to include all aspects of organized medicine. Initiatives to get out the vote may be helpful in vulnerable states, as well.

Clinicians in protected states are not necessarily directly affected in our daily interactions with patients, but we stand in solidarity with those who are. We must remain united as a profession as different state legislatures seek to divide us. We must support those who are struggling every day. Our colleagues and fellow citizens deserve nothing less. ●

ILLUSTRATION: PAUL ZWOLAK

While many anticipated the fall of Roe v Wade after the leaked Supreme Court of the United States (SCOTUS) decision in the Dobbs v Jackson case, few may have fully comprehended the myriad of ways this ruling would create a national health care crisis overnight. Since the ruling, abortion has been banned, or a 6-week gestational age limit has been implemented, in a total of 13 states, all within the South and Midwest regions of the country.¹ Many additional states will almost assuredly enact bans on access to reproductive health care in the near future. While the specific case of the 10-year-old rape victim in Ohio and her gynecologic care by Dr. Caitlin Bernard, an Indiana ObGyn, has garnered national attention, most of the devastating effects have not yet been realized.² Recent published data highlights the substantially negative impact these legislative changes already have had regarding the treatment of early spontaneous abortions and premature rupture of membranes.^3,4 Physicians could face legal consequences for treating emergencies, such as ectopic pregnancies, in some states.⁵

The 2022 American College of Obstetricians and Gynecologists (ACOG) Annual Clinical and Scientific Meeting, held shortly after the leaked SCOTUS opinion, was unlike most others. ACOG staff appropriately recognized the vastly different ways this ruling would affect patients and providers alike, simply based on the states in which they reside. ACOG staff organized the large group of attendees according to self-identified status (ie, whether they worked in states with protected, restricted, or threatened access to abortion care). Since this is such a vast topic, attendees also were asked to identify an area upon which to focus, such as the provision of health care, advocacy, or education. As a clinician practicing in Massachusetts, Dr. Bradley found herself meeting with an ACOG leader from California as they brainstormed how to best help our own communities. In conversing with attendees from other parts of the country, it became apparent the challenges others would be facing elsewhere were far more substantive than those we would be facing in “blue states.” After the Dobbs ruling, those predictions became harsh realities.

As we begin to see and hear reports of the devastating consequences of this ruling in “red states,” those of us in protected states have been struggling to try and ascertain how to help. Many of us have worked with our own legislatures to further enshrine protections for our patients and clinicians. New York and Massachusetts exemplify these efforts.^6,7 These legislative efforts have included liability protections for patients and their clinicians who care for those who travel from restricted to protected states. Others involve codifying the principles of Roe and clarifying existing law to improve access. An online fundraiser organized by physicians to assist Dr. Bernard with her legal costs as she faces politically motivated investigation by Indiana state authorities has raised more than $260,000.⁸ Many expressed the potential legal and medical peril for examiners and examinees if the American Board of Obstetrics and Gynecology held in-person oral examinations in Texas as previously scheduled.⁹ An online petition to change the format to virtual had 728 signatories, and the format was changed back to virtual.¹⁰

The implications on medical schools, residencies, and fellowships cannot be overstated. The Dobbs ruling almost immediately affected nearly half of the training programs, which is particularly problematic given the Accreditation Council for Graduate Medical Education requirement that all ObGyn residents have access to abortion training.¹¹ Other programs already are starting to try to meet this vast training need. The University of California San Francisco started offering training to physicians from Texas who were affected by the strict restrictions that predated Dobbs in the SB8 legislation, which turned ordinary citizens into vigilantes.¹²

ACOG has created an online resource (https://www.acog.org/advocacy/abortion-is-essential) with a number of different sections regarding clinical care, education and training, advocacy at the state level, and how to use effective language when talking about abortion in our communities. Planned Parenthood also suggests a myriad of ways those directly and indirectly affected could get involved:

1. Donate to the National Network of Abortion Funds. This fund (https://secure.actblue.com/donate/fundabortionnow) facilitates care for those without the financial means to obtain it, supporting travel, lodging, and child care.
2. Share #AbortionAccess posts on social media. These stories are a powerful reminder of the incredibly harmful impact this legislation can have on our patients.
3. Donate to the If When How’s Legal Repro Defense Fund (https:/www.ifwhenhow.org/), which helps cover legal costs for those facing state persecution related to reproductive health care.
4. Volunteer to help protect abortion health care at the state level.
5. Engage with members of Congress in their home districts. (https://www.congress.gov/members/find-your-member)
6. Contact the Planned Parenthood Local Engagement Team to facilitate your group, business, or organization’s involvement.
7. Partner. Facilitate your organization and other companies to partner with Planned Parenthood and sign up for Bans off our Bodies (https://docs.google.com/forms/d/e/1FAIpQLSdrmxwMcwNXJ8I NE8S2gYjDDXuT76ws_Fr7CLm3 qbtR8dcZHw/viewform).
8. Record your perspective about abortion (https://www.together.plannedparenthood.org/articles/6-share-abortion-story), whether it’s having had one, supported someone who had one, or advocated for others to have access to the procedure.¹³

ACOG also outlines several ways those of us in protected states could help shape the landscape in other communities in addition to advocating for state medical society resolutions, writing op-eds and letters to the editor, and utilizing ACOG’s social media graphics.¹⁴ In recognition of the often sensitive, polarizing nature of these discussions, ACOG is offering a workshop entitled “Building Evidence-Based Skills for Effective Conversations about Abortion.”¹⁵

Abortion traditionally was a policy issue other medical organizations shied away from developing official policy on and speaking out in support of, but recognizing the devastating scope of the public health crisis, 75 medical professional organizations recently released a strongly worded joint statement noting, “As leading medical and health care organizations dedicated to patient care and public health, we condemn this and all interference in the patient–clinician relationship.”¹⁶ Clinicians could work to expand this list to include all aspects of organized medicine. Initiatives to get out the vote may be helpful in vulnerable states, as well.

Clinicians in protected states are not necessarily directly affected in our daily interactions with patients, but we stand in solidarity with those who are. We must remain united as a profession as different state legislatures seek to divide us. We must support those who are struggling every day. Our colleagues and fellow citizens deserve nothing less. ●

ILLUSTRATION: PAUL ZWOLAK

While many anticipated the fall of Roe v Wade after the leaked Supreme Court of the United States (SCOTUS) decision in the Dobbs v Jackson case, few may have fully comprehended the myriad of ways this ruling would create a national health care crisis overnight. Since the ruling, abortion has been banned, or a 6-week gestational age limit has been implemented, in a total of 13 states, all within the South and Midwest regions of the country.¹ Many additional states will almost assuredly enact bans on access to reproductive health care in the near future. While the specific case of the 10-year-old rape victim in Ohio and her gynecologic care by Dr. Caitlin Bernard, an Indiana ObGyn, has garnered national attention, most of the devastating effects have not yet been realized.² Recent published data highlights the substantially negative impact these legislative changes already have had regarding the treatment of early spontaneous abortions and premature rupture of membranes.^3,4 Physicians could face legal consequences for treating emergencies, such as ectopic pregnancies, in some states.⁵

The 2022 American College of Obstetricians and Gynecologists (ACOG) Annual Clinical and Scientific Meeting, held shortly after the leaked SCOTUS opinion, was unlike most others. ACOG staff appropriately recognized the vastly different ways this ruling would affect patients and providers alike, simply based on the states in which they reside. ACOG staff organized the large group of attendees according to self-identified status (ie, whether they worked in states with protected, restricted, or threatened access to abortion care). Since this is such a vast topic, attendees also were asked to identify an area upon which to focus, such as the provision of health care, advocacy, or education. As a clinician practicing in Massachusetts, Dr. Bradley found herself meeting with an ACOG leader from California as they brainstormed how to best help our own communities. In conversing with attendees from other parts of the country, it became apparent the challenges others would be facing elsewhere were far more substantive than those we would be facing in “blue states.” After the Dobbs ruling, those predictions became harsh realities.

As we begin to see and hear reports of the devastating consequences of this ruling in “red states,” those of us in protected states have been struggling to try and ascertain how to help. Many of us have worked with our own legislatures to further enshrine protections for our patients and clinicians. New York and Massachusetts exemplify these efforts.^6,7 These legislative efforts have included liability protections for patients and their clinicians who care for those who travel from restricted to protected states. Others involve codifying the principles of Roe and clarifying existing law to improve access. An online fundraiser organized by physicians to assist Dr. Bernard with her legal costs as she faces politically motivated investigation by Indiana state authorities has raised more than $260,000.⁸ Many expressed the potential legal and medical peril for examiners and examinees if the American Board of Obstetrics and Gynecology held in-person oral examinations in Texas as previously scheduled.⁹ An online petition to change the format to virtual had 728 signatories, and the format was changed back to virtual.¹⁰

The implications on medical schools, residencies, and fellowships cannot be overstated. The Dobbs ruling almost immediately affected nearly half of the training programs, which is particularly problematic given the Accreditation Council for Graduate Medical Education requirement that all ObGyn residents have access to abortion training.¹¹ Other programs already are starting to try to meet this vast training need. The University of California San Francisco started offering training to physicians from Texas who were affected by the strict restrictions that predated Dobbs in the SB8 legislation, which turned ordinary citizens into vigilantes.¹²

ACOG has created an online resource (https://www.acog.org/advocacy/abortion-is-essential) with a number of different sections regarding clinical care, education and training, advocacy at the state level, and how to use effective language when talking about abortion in our communities. Planned Parenthood also suggests a myriad of ways those directly and indirectly affected could get involved:

1. Donate to the National Network of Abortion Funds. This fund (https://secure.actblue.com/donate/fundabortionnow) facilitates care for those without the financial means to obtain it, supporting travel, lodging, and child care.
2. Share #AbortionAccess posts on social media. These stories are a powerful reminder of the incredibly harmful impact this legislation can have on our patients.
3. Donate to the If When How’s Legal Repro Defense Fund (https:/www.ifwhenhow.org/), which helps cover legal costs for those facing state persecution related to reproductive health care.
4. Volunteer to help protect abortion health care at the state level.
5. Engage with members of Congress in their home districts. (https://www.congress.gov/members/find-your-member)
6. Contact the Planned Parenthood Local Engagement Team to facilitate your group, business, or organization’s involvement.
7. Partner. Facilitate your organization and other companies to partner with Planned Parenthood and sign up for Bans off our Bodies (https://docs.google.com/forms/d/e/1FAIpQLSdrmxwMcwNXJ8I NE8S2gYjDDXuT76ws_Fr7CLm3 qbtR8dcZHw/viewform).
8. Record your perspective about abortion (https://www.together.plannedparenthood.org/articles/6-share-abortion-story), whether it’s having had one, supported someone who had one, or advocated for others to have access to the procedure.¹³

ACOG also outlines several ways those of us in protected states could help shape the landscape in other communities in addition to advocating for state medical society resolutions, writing op-eds and letters to the editor, and utilizing ACOG’s social media graphics.¹⁴ In recognition of the often sensitive, polarizing nature of these discussions, ACOG is offering a workshop entitled “Building Evidence-Based Skills for Effective Conversations about Abortion.”¹⁵

Abortion traditionally was a policy issue other medical organizations shied away from developing official policy on and speaking out in support of, but recognizing the devastating scope of the public health crisis, 75 medical professional organizations recently released a strongly worded joint statement noting, “As leading medical and health care organizations dedicated to patient care and public health, we condemn this and all interference in the patient–clinician relationship.”¹⁶ Clinicians could work to expand this list to include all aspects of organized medicine. Initiatives to get out the vote may be helpful in vulnerable states, as well.

Clinicians in protected states are not necessarily directly affected in our daily interactions with patients, but we stand in solidarity with those who are. We must remain united as a profession as different state legislatures seek to divide us. We must support those who are struggling every day. Our colleagues and fellow citizens deserve nothing less. ●

Dear colleagues,

Treating obesity easily falls under our purview as gastroenterologists. But like the mouse who would bell the cat, our direct involvement has been limited. However, over the past decade, advances in endobariatrics and medical management have given us many options. But how do we choose from this growing armamentarium of minimally invasive procedures and weight loss medicines? What combination is best? And what about the standard “diet and exercise”?

In this issue of perspectives, Carolyn Newberry, MD, director of GI nutrition at Innovation Center for Health and Nutrition in Gastroenterology, Weill Cornell Medicine, New York, will emphasize the benefits of medical and lifestyle management. Pichamol Jirapinyo, MD, MPH, ABOM, director of bariatric endoscopy fellowship at Brigham and Women’s Hospital/Harvard Medical School, Boston, responds with robust data for endoscopic therapies. We hope that their expert perspectives will help guide you in your own approach to obesity management – certainly no one size fits all. I welcome your thoughts on this growing field in gastroenterology – share with us on Twitter @AGA_GIHN.

Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, Conn., and chief of endoscopy at West Haven (Conn.) VA Medical Center. He is an associate editor for GI & Hepatology News.

Exciting time for endoscopic bariatric and metabolic therapies (EBMTs)

BY PICHAMOL JIRAPINYO, MD, MPH, ABOM

2022 was an exciting year for our field of endoscopic bariatric and metabolic therapy (EBMT). Not only did it mark the 10th year anniversary since the very first-in-human endoscopic sleeve gastroplasty (ESG) performed by Christopher Thompson and Robert Hawes in India, but also the MERIT trial (a randomized-controlled trial on ESG) was published.¹ This decade of work led to the OverStitch Endoscopic Suturing System (Apollo Endosurgery, Austin, Tex.) being granted de novo authorization from the Food and Drug Administration for the treatment of obesity and weight regain following bariatric surgery.

Currently, at our institution, we offer four primary EBMTs for patients who are seeking endoscopic weight loss therapy and have not yet undergone prior bariatric surgery. These include the Orbera intragastric balloon (IGB) (Apollo Endosurgery), ESG (Apollo Endosurgery), primary obesity surgery endoluminal (POSE: USGI Medical, San Clemente, Calif.), and a gastric plication procedure using Endomina (Endo Tools Therapeutics, Gosselies, Belgium). While the former two have FDA approval, the latter two devices have FDA clearance for tissue approximation. The indication for primary EBMTs includes having a body mass index of at least 30 kg/m².

From our experience, patients who present to our bariatric endoscopy clinic consist of three groups. First are those who have tried several anti-obesity medications (AOMs), but are unable to tolerate the side effects or their BMI remains greater than 30 kg/m². Second are those who have heard about EBMTs and are interested in the procedures. Usually, these patients are either too light to qualify for bariatric surgery (BMI 30-35 kg/m² or 35-40 kg/m² without an obesity-related comorbidity) or are not interested in bariatric surgery for a variety of reasons, including its perceived invasiveness. The last group are those whose BMI falls within the “super obese” category, defined as a BMI ≥ 50 kg/m², who are deemed too high risk to undergo medically necessary procedures, such as an orthopedic, colorectal, or transplant surgery.

During the initial consultation, I always discuss pros and cons of all treatment modalities for obesity with the patients, ranging from lifestyle modification to AOMs, EBMTs, and bariatric surgeries. While the data on AOMs are promising, especially with the most recent FDA-approved semaglutide (Wegovy: Novo Nordisk, Bagsvaerd, Denmark) yielding 14.9% total weight loss (TWL) at 1 year, in reality, the starting doses of this medication have been out of stock for over a year.² Other AOMs, on the other hand, are associated with 6%-8% TWL and are frequently associated with intolerance due to side effects. In comparison, meta-analyses demonstrate that an IGB is associated with 11.3% TWL and ESG with 16.5% TWL at 1 year. Our recent publication describing a new technique for POSE, also known as a distal POSE procedure with a double-helix technique, demonstrates a 20.3% TWL at 1 year.³ The rate of serious adverse events for EBMTs is low with 0.1% for IGB and 1%-2% for ESG/POSE.

The question regarding a comparison between AOMs and EBMTs comes up quite frequently in clinical practice. In reality, I often encourage my patients to consider combination therapy where I prescribe an AOM at 3-6 months following EBMTs to augment the amount of weight loss. However, since this is a debate, I will highlight a few advantages of EBMTs. First, the amount of weight loss following EBMTs, especially with ESG/POSE (which is currently the most commonly-requested procedure in our practice), tends to be higher than that of most AOMs. Second, while we are eagerly awaiting the long-term safety and efficacy data for semaglutide, ESG has been shown to be durable with the patients maintaining 15.9% TWL at 5 years.⁴ Third, an EBMT is a one-time procedure. In contrast, AOMs rely on patients’ compliance with taking the medication(s) reliably and indefinitely. A study based on HMO pharmacy data of over a million patients who were prescribed AOMs showed that fewer than 2% completed 12 months of weight loss medication therapy.⁵ The long-term use of AOMs also has cost implications. Specifically, a month supply of semaglutide costs about $1,400, which translates to $16,800 in 1 year and $84,000 in 5 years, which clearly outweighs the cost of ESG/POSE that has been demonstrated to be durable up to at least 5 years. IGBs have limitations similar to those of AOMs upon removal. Nevertheless, with the average cost of an IGB being $8,000, placing one every year would still be less costly, although this would likely be unnecessary considering the weight loss trend after IGB.

There are a few hurdles that need to be overcome before EBMTs are widely adopted. Reimbursement remains a major issue at most centers in the United States. Currently, most EBMTs are offered as a self-pay procedure, making the majority of patients who are otherwise eligible and interested not able to afford the procedure. With the recently published MERIT trial, long-term data on ESG as well as several upcoming society guidelines on EBMTs, we are hopeful that insurance coverage for EBMTs is nearing. Another important aspect is training. While IGB placement and removal are simple procedures, performing a high-quality ESG/POSE requires rigorous training to ensure safety and optimal outcomes. Several professional societies are working hard to develop curriculums on EBMTs with a focus on hands-on training to ensure endoscopists are properly trained prior to starting their bariatric endoscopy program. At our institution, we have a dedicated training program focusing on bariatric endoscopy (i.e. separate from the traditional advanced endoscopy fellowship), where fellows learn advanced bariatric suturing and plication as well as multidisciplinary care for this patient population. I am hopeful that this kind of training will become more prevalent in the near future.

With mounting evidence supporting the benefits of EBMTs, bariatric endoscopy has revolutionized the care of patients suffering from obesity and its related comorbidities. Moving forward, the field will continue to evolve, and EBMT procedures will only become simpler, safer, and more effective. It is an exciting time for gastroenterologists to get involved.
 

Dr. Jirapinyo is the director of bariatric endoscopy fellowship at Brigham and Women’s Hospital/Harvard Medical School, Boston. She is board certified in internal medicine, gastroenterology, and obesity medicine and completed her bariatric endoscopy and advanced endoscopy fellowships at Brigham and Women’s Hospital. She serves as a consultant for Apollo Endosurgery, Spatz Medical, and ERBE, and she receives research support from USGI Medical, GI Dynamics, and Fractyl.

References

1. Abu Dayyeh BK et al. Lancet. 2022;400(10350):441-51.

2. Wilding JPH et al. N Engl J Med. 2021;384:989-1002.

3. Jirapinyo P and Thompson CC. Gastrointest Endosc. 2022;96(3):479-86.

4. Sharaiha RZ et al. Clin Gastroenterol Hepatol. 2021;19(5):1051-57.

5. Hemo B et al. Diabetes Res Clin Pract. 2011;94(2):269-75.

A new frontier for weight management: Assess your options carefully

BY CAROLYN NEWBERRY, MD

Considering the continued rise in obesity rates in this country coupled with an increase in associated digestive disease burden from conditions such as nonalcoholic fatty liver disease (NAFLD), gastroesophageal reflux disease (GERD), and select gastrointestinal malignancies, I believe it is now more important than ever for gastroenterologists to familiarize themselves with weight management principles and incorporation into clinical practice. A growing arsenal of tools is available for addressing excess weight, including medications and novel endobariatric techniques. Although the latter is an important consideration in patients with obesity, lifestyle counseling with or without weight loss medications sets the stage for sustainable weight loss success and may eliminate the need for procedural intervention. As such, current guidelines set forth by multiple societies, including the American Gastroenterological Association (AGA), emphasize the importance of lifestyle counseling targeting caloric restriction and increased physical activity along with medical augmentation via pharmacological agents in eligible patients.^1,2 These guidelines underline the importance of medical weight management prior to consideration of procedural options, including both endobariatrics and more classic bariatric surgeries. This ensures patients understand approaches to weight loss via noninvasive means, reduces risk of weight regain by building foundational habits, and enhances overall success of procedures long term if they are pursued. In addition, newer pharmacological agents are now approaching total body weight loss percentages of currently available endobariatric techniques while still showing high tolerance rates and long-term efficacy, indicating some patients who previously would require procedures to meet weight loss goals may no longer need them.³ Alternatively, these medications may augment efforts prior to procedures, enhancing overall total body weight loss achieved. If patients are not introduced to such options initially and as a part of comprehensive care management planning, they may not achieve the same degree of weight loss success and metabolic optimization.

As a gastroenterologist co-leading a multidisciplinary weight management and lifestyle clinic, I have witnessed firsthand the enhanced outcomes in patients who pursue endobariatric procedures after establishing care with a clinical team and attempting (and succeeding) in weight loss via changes in diet, physical activity, and medication use. Patients should be encouraged to gain understanding of one’s own “personal relationship” with food and/or address medical and social barriers to weight loss maintenance prior to procedural intervention, which requires some lead time and ideally professional expertise from multiple team members, including a dietitian. Weight regain after anti-obesity surgery is common, with significant gain occurring in up to half of patients. Several factors have been associated with weight regain, including lack of consistent follow-up, excess calorie and simple carbohydrate intake, and inconsistent physical activity.⁴ As such, most insurance companies mandate a trial of at least 6 months of lifestyle and/or medical weight management prior to considering procedural reimbursement. Although robust longitudinal data for endobariatric outcomes is not yet available, it is reasonable to believe similar concepts may be in play. In fact, since endobariatric procedures are less invasive but also therefore more temporal (as in the case of endoscopic balloon placement, which is only approved for 6 months of continuous use), behavioral modification and medical management to reduce risk of significant weight regain is even more imperative. Even in the case of more durable procedures, such as endoscopic gastroplasty, lack of compliance with recommended dietary protocols can reduce efficacy by loosening and even ripping sutures prior to establishment of bridging fibrotic mucosal changes, which enhance longevity of the procedure and support continued gastric restriction and reduction in motility. Some patients who undergo endoscopic gastroplasty end up seeking out revision and repeat procedure later due to lack of results, which may be avoided with alternative dietary and lifestyle decisions in the postprocedural state.

The landscape of non-procedural weight management tools has changed in the last 1-2 years with the approval of newer injectable medications that disrupt insulin and hormonal pathways and produce sustainable weight loss similar to reported outcomes achieved with endobariatric procedures. These medications are becoming increasingly accessible and of interest to patients, with continued destigmatization of the use of weight loss drugs in practice, which had previous negative connotations and concerns regarding safety. New guidelines put forth by the AGA recommend adding pharmacological agents to lifestyle interventions over continuing lifestyle interventions alone if adequate weight loss has not been achieved with the latter.³ This further exemplifies the importance of a multifaceted approach to optimize medical weight management as first-line therapy for obesity and associated comorbidities.

In summary, although endobariatric procedures are an important tool for gastroenterologists to incorporate into their weight management plans, they must be implemented with care and only after lifestyle and medical interventions have failed to produce desired results. Shared decision making among providers and patients enhances weight loss efforts and augments sustainability of outcomes. Considering the rapidly evolving landscape of obesity medicine, gastroenterologists need to continue to stay up to date on best practices to improve patient care, reduce associated morbidity, and enhance outcomes of novel endobariatric procedures.
 

Dr. Newberry is with the Innovative Center for Health and Nutrition in Gastroenterology (ICHANGE), division of gastroenterology, Weill Cornell Medical Center, New York. She disclosed receiving speaker honorariums from Baxter International and InBody USA.

References

1. Acosta et al. Clin Gastroenterol Hepatol. 2017 May;15(5):631-49.

2. Jensen et al. Circulation. 2014;129:S102-38.

3. Grunvald et al. Gastroenterology. 2022;163(5):1198-225.

4. Athansiadis et al. Surg Endosc. 2021 Aug;35(8):4069-84.

Dear colleagues,

Treating obesity easily falls under our purview as gastroenterologists. But like the mouse who would bell the cat, our direct involvement has been limited. However, over the past decade, advances in endobariatrics and medical management have given us many options. But how do we choose from this growing armamentarium of minimally invasive procedures and weight loss medicines? What combination is best? And what about the standard “diet and exercise”?

In this issue of perspectives, Carolyn Newberry, MD, director of GI nutrition at Innovation Center for Health and Nutrition in Gastroenterology, Weill Cornell Medicine, New York, will emphasize the benefits of medical and lifestyle management. Pichamol Jirapinyo, MD, MPH, ABOM, director of bariatric endoscopy fellowship at Brigham and Women’s Hospital/Harvard Medical School, Boston, responds with robust data for endoscopic therapies. We hope that their expert perspectives will help guide you in your own approach to obesity management – certainly no one size fits all. I welcome your thoughts on this growing field in gastroenterology – share with us on Twitter @AGA_GIHN.

Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, Conn., and chief of endoscopy at West Haven (Conn.) VA Medical Center. He is an associate editor for GI & Hepatology News.

Exciting time for endoscopic bariatric and metabolic therapies (EBMTs)

BY PICHAMOL JIRAPINYO, MD, MPH, ABOM

2022 was an exciting year for our field of endoscopic bariatric and metabolic therapy (EBMT). Not only did it mark the 10th year anniversary since the very first-in-human endoscopic sleeve gastroplasty (ESG) performed by Christopher Thompson and Robert Hawes in India, but also the MERIT trial (a randomized-controlled trial on ESG) was published.¹ This decade of work led to the OverStitch Endoscopic Suturing System (Apollo Endosurgery, Austin, Tex.) being granted de novo authorization from the Food and Drug Administration for the treatment of obesity and weight regain following bariatric surgery.

Currently, at our institution, we offer four primary EBMTs for patients who are seeking endoscopic weight loss therapy and have not yet undergone prior bariatric surgery. These include the Orbera intragastric balloon (IGB) (Apollo Endosurgery), ESG (Apollo Endosurgery), primary obesity surgery endoluminal (POSE: USGI Medical, San Clemente, Calif.), and a gastric plication procedure using Endomina (Endo Tools Therapeutics, Gosselies, Belgium). While the former two have FDA approval, the latter two devices have FDA clearance for tissue approximation. The indication for primary EBMTs includes having a body mass index of at least 30 kg/m².

From our experience, patients who present to our bariatric endoscopy clinic consist of three groups. First are those who have tried several anti-obesity medications (AOMs), but are unable to tolerate the side effects or their BMI remains greater than 30 kg/m². Second are those who have heard about EBMTs and are interested in the procedures. Usually, these patients are either too light to qualify for bariatric surgery (BMI 30-35 kg/m² or 35-40 kg/m² without an obesity-related comorbidity) or are not interested in bariatric surgery for a variety of reasons, including its perceived invasiveness. The last group are those whose BMI falls within the “super obese” category, defined as a BMI ≥ 50 kg/m², who are deemed too high risk to undergo medically necessary procedures, such as an orthopedic, colorectal, or transplant surgery.

During the initial consultation, I always discuss pros and cons of all treatment modalities for obesity with the patients, ranging from lifestyle modification to AOMs, EBMTs, and bariatric surgeries. While the data on AOMs are promising, especially with the most recent FDA-approved semaglutide (Wegovy: Novo Nordisk, Bagsvaerd, Denmark) yielding 14.9% total weight loss (TWL) at 1 year, in reality, the starting doses of this medication have been out of stock for over a year.² Other AOMs, on the other hand, are associated with 6%-8% TWL and are frequently associated with intolerance due to side effects. In comparison, meta-analyses demonstrate that an IGB is associated with 11.3% TWL and ESG with 16.5% TWL at 1 year. Our recent publication describing a new technique for POSE, also known as a distal POSE procedure with a double-helix technique, demonstrates a 20.3% TWL at 1 year.³ The rate of serious adverse events for EBMTs is low with 0.1% for IGB and 1%-2% for ESG/POSE.

The question regarding a comparison between AOMs and EBMTs comes up quite frequently in clinical practice. In reality, I often encourage my patients to consider combination therapy where I prescribe an AOM at 3-6 months following EBMTs to augment the amount of weight loss. However, since this is a debate, I will highlight a few advantages of EBMTs. First, the amount of weight loss following EBMTs, especially with ESG/POSE (which is currently the most commonly-requested procedure in our practice), tends to be higher than that of most AOMs. Second, while we are eagerly awaiting the long-term safety and efficacy data for semaglutide, ESG has been shown to be durable with the patients maintaining 15.9% TWL at 5 years.⁴ Third, an EBMT is a one-time procedure. In contrast, AOMs rely on patients’ compliance with taking the medication(s) reliably and indefinitely. A study based on HMO pharmacy data of over a million patients who were prescribed AOMs showed that fewer than 2% completed 12 months of weight loss medication therapy.⁵ The long-term use of AOMs also has cost implications. Specifically, a month supply of semaglutide costs about $1,400, which translates to $16,800 in 1 year and $84,000 in 5 years, which clearly outweighs the cost of ESG/POSE that has been demonstrated to be durable up to at least 5 years. IGBs have limitations similar to those of AOMs upon removal. Nevertheless, with the average cost of an IGB being $8,000, placing one every year would still be less costly, although this would likely be unnecessary considering the weight loss trend after IGB.

There are a few hurdles that need to be overcome before EBMTs are widely adopted. Reimbursement remains a major issue at most centers in the United States. Currently, most EBMTs are offered as a self-pay procedure, making the majority of patients who are otherwise eligible and interested not able to afford the procedure. With the recently published MERIT trial, long-term data on ESG as well as several upcoming society guidelines on EBMTs, we are hopeful that insurance coverage for EBMTs is nearing. Another important aspect is training. While IGB placement and removal are simple procedures, performing a high-quality ESG/POSE requires rigorous training to ensure safety and optimal outcomes. Several professional societies are working hard to develop curriculums on EBMTs with a focus on hands-on training to ensure endoscopists are properly trained prior to starting their bariatric endoscopy program. At our institution, we have a dedicated training program focusing on bariatric endoscopy (i.e. separate from the traditional advanced endoscopy fellowship), where fellows learn advanced bariatric suturing and plication as well as multidisciplinary care for this patient population. I am hopeful that this kind of training will become more prevalent in the near future.

With mounting evidence supporting the benefits of EBMTs, bariatric endoscopy has revolutionized the care of patients suffering from obesity and its related comorbidities. Moving forward, the field will continue to evolve, and EBMT procedures will only become simpler, safer, and more effective. It is an exciting time for gastroenterologists to get involved.
 

Dr. Jirapinyo is the director of bariatric endoscopy fellowship at Brigham and Women’s Hospital/Harvard Medical School, Boston. She is board certified in internal medicine, gastroenterology, and obesity medicine and completed her bariatric endoscopy and advanced endoscopy fellowships at Brigham and Women’s Hospital. She serves as a consultant for Apollo Endosurgery, Spatz Medical, and ERBE, and she receives research support from USGI Medical, GI Dynamics, and Fractyl.

References

1. Abu Dayyeh BK et al. Lancet. 2022;400(10350):441-51.

2. Wilding JPH et al. N Engl J Med. 2021;384:989-1002.

3. Jirapinyo P and Thompson CC. Gastrointest Endosc. 2022;96(3):479-86.

4. Sharaiha RZ et al. Clin Gastroenterol Hepatol. 2021;19(5):1051-57.

5. Hemo B et al. Diabetes Res Clin Pract. 2011;94(2):269-75.

A new frontier for weight management: Assess your options carefully

BY CAROLYN NEWBERRY, MD

Considering the continued rise in obesity rates in this country coupled with an increase in associated digestive disease burden from conditions such as nonalcoholic fatty liver disease (NAFLD), gastroesophageal reflux disease (GERD), and select gastrointestinal malignancies, I believe it is now more important than ever for gastroenterologists to familiarize themselves with weight management principles and incorporation into clinical practice. A growing arsenal of tools is available for addressing excess weight, including medications and novel endobariatric techniques. Although the latter is an important consideration in patients with obesity, lifestyle counseling with or without weight loss medications sets the stage for sustainable weight loss success and may eliminate the need for procedural intervention. As such, current guidelines set forth by multiple societies, including the American Gastroenterological Association (AGA), emphasize the importance of lifestyle counseling targeting caloric restriction and increased physical activity along with medical augmentation via pharmacological agents in eligible patients.^1,2 These guidelines underline the importance of medical weight management prior to consideration of procedural options, including both endobariatrics and more classic bariatric surgeries. This ensures patients understand approaches to weight loss via noninvasive means, reduces risk of weight regain by building foundational habits, and enhances overall success of procedures long term if they are pursued. In addition, newer pharmacological agents are now approaching total body weight loss percentages of currently available endobariatric techniques while still showing high tolerance rates and long-term efficacy, indicating some patients who previously would require procedures to meet weight loss goals may no longer need them.³ Alternatively, these medications may augment efforts prior to procedures, enhancing overall total body weight loss achieved. If patients are not introduced to such options initially and as a part of comprehensive care management planning, they may not achieve the same degree of weight loss success and metabolic optimization.

As a gastroenterologist co-leading a multidisciplinary weight management and lifestyle clinic, I have witnessed firsthand the enhanced outcomes in patients who pursue endobariatric procedures after establishing care with a clinical team and attempting (and succeeding) in weight loss via changes in diet, physical activity, and medication use. Patients should be encouraged to gain understanding of one’s own “personal relationship” with food and/or address medical and social barriers to weight loss maintenance prior to procedural intervention, which requires some lead time and ideally professional expertise from multiple team members, including a dietitian. Weight regain after anti-obesity surgery is common, with significant gain occurring in up to half of patients. Several factors have been associated with weight regain, including lack of consistent follow-up, excess calorie and simple carbohydrate intake, and inconsistent physical activity.⁴ As such, most insurance companies mandate a trial of at least 6 months of lifestyle and/or medical weight management prior to considering procedural reimbursement. Although robust longitudinal data for endobariatric outcomes is not yet available, it is reasonable to believe similar concepts may be in play. In fact, since endobariatric procedures are less invasive but also therefore more temporal (as in the case of endoscopic balloon placement, which is only approved for 6 months of continuous use), behavioral modification and medical management to reduce risk of significant weight regain is even more imperative. Even in the case of more durable procedures, such as endoscopic gastroplasty, lack of compliance with recommended dietary protocols can reduce efficacy by loosening and even ripping sutures prior to establishment of bridging fibrotic mucosal changes, which enhance longevity of the procedure and support continued gastric restriction and reduction in motility. Some patients who undergo endoscopic gastroplasty end up seeking out revision and repeat procedure later due to lack of results, which may be avoided with alternative dietary and lifestyle decisions in the postprocedural state.

The landscape of non-procedural weight management tools has changed in the last 1-2 years with the approval of newer injectable medications that disrupt insulin and hormonal pathways and produce sustainable weight loss similar to reported outcomes achieved with endobariatric procedures. These medications are becoming increasingly accessible and of interest to patients, with continued destigmatization of the use of weight loss drugs in practice, which had previous negative connotations and concerns regarding safety. New guidelines put forth by the AGA recommend adding pharmacological agents to lifestyle interventions over continuing lifestyle interventions alone if adequate weight loss has not been achieved with the latter.³ This further exemplifies the importance of a multifaceted approach to optimize medical weight management as first-line therapy for obesity and associated comorbidities.

In summary, although endobariatric procedures are an important tool for gastroenterologists to incorporate into their weight management plans, they must be implemented with care and only after lifestyle and medical interventions have failed to produce desired results. Shared decision making among providers and patients enhances weight loss efforts and augments sustainability of outcomes. Considering the rapidly evolving landscape of obesity medicine, gastroenterologists need to continue to stay up to date on best practices to improve patient care, reduce associated morbidity, and enhance outcomes of novel endobariatric procedures.
 

Dr. Newberry is with the Innovative Center for Health and Nutrition in Gastroenterology (ICHANGE), division of gastroenterology, Weill Cornell Medical Center, New York. She disclosed receiving speaker honorariums from Baxter International and InBody USA.

References

1. Acosta et al. Clin Gastroenterol Hepatol. 2017 May;15(5):631-49.

2. Jensen et al. Circulation. 2014;129:S102-38.

3. Grunvald et al. Gastroenterology. 2022;163(5):1198-225.

4. Athansiadis et al. Surg Endosc. 2021 Aug;35(8):4069-84.

Dear colleagues,

Treating obesity easily falls under our purview as gastroenterologists. But like the mouse who would bell the cat, our direct involvement has been limited. However, over the past decade, advances in endobariatrics and medical management have given us many options. But how do we choose from this growing armamentarium of minimally invasive procedures and weight loss medicines? What combination is best? And what about the standard “diet and exercise”?

In this issue of perspectives, Carolyn Newberry, MD, director of GI nutrition at Innovation Center for Health and Nutrition in Gastroenterology, Weill Cornell Medicine, New York, will emphasize the benefits of medical and lifestyle management. Pichamol Jirapinyo, MD, MPH, ABOM, director of bariatric endoscopy fellowship at Brigham and Women’s Hospital/Harvard Medical School, Boston, responds with robust data for endoscopic therapies. We hope that their expert perspectives will help guide you in your own approach to obesity management – certainly no one size fits all. I welcome your thoughts on this growing field in gastroenterology – share with us on Twitter @AGA_GIHN.

Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, Conn., and chief of endoscopy at West Haven (Conn.) VA Medical Center. He is an associate editor for GI & Hepatology News.

Exciting time for endoscopic bariatric and metabolic therapies (EBMTs)

BY PICHAMOL JIRAPINYO, MD, MPH, ABOM

2022 was an exciting year for our field of endoscopic bariatric and metabolic therapy (EBMT). Not only did it mark the 10th year anniversary since the very first-in-human endoscopic sleeve gastroplasty (ESG) performed by Christopher Thompson and Robert Hawes in India, but also the MERIT trial (a randomized-controlled trial on ESG) was published.¹ This decade of work led to the OverStitch Endoscopic Suturing System (Apollo Endosurgery, Austin, Tex.) being granted de novo authorization from the Food and Drug Administration for the treatment of obesity and weight regain following bariatric surgery.

Currently, at our institution, we offer four primary EBMTs for patients who are seeking endoscopic weight loss therapy and have not yet undergone prior bariatric surgery. These include the Orbera intragastric balloon (IGB) (Apollo Endosurgery), ESG (Apollo Endosurgery), primary obesity surgery endoluminal (POSE: USGI Medical, San Clemente, Calif.), and a gastric plication procedure using Endomina (Endo Tools Therapeutics, Gosselies, Belgium). While the former two have FDA approval, the latter two devices have FDA clearance for tissue approximation. The indication for primary EBMTs includes having a body mass index of at least 30 kg/m².

From our experience, patients who present to our bariatric endoscopy clinic consist of three groups. First are those who have tried several anti-obesity medications (AOMs), but are unable to tolerate the side effects or their BMI remains greater than 30 kg/m². Second are those who have heard about EBMTs and are interested in the procedures. Usually, these patients are either too light to qualify for bariatric surgery (BMI 30-35 kg/m² or 35-40 kg/m² without an obesity-related comorbidity) or are not interested in bariatric surgery for a variety of reasons, including its perceived invasiveness. The last group are those whose BMI falls within the “super obese” category, defined as a BMI ≥ 50 kg/m², who are deemed too high risk to undergo medically necessary procedures, such as an orthopedic, colorectal, or transplant surgery.

During the initial consultation, I always discuss pros and cons of all treatment modalities for obesity with the patients, ranging from lifestyle modification to AOMs, EBMTs, and bariatric surgeries. While the data on AOMs are promising, especially with the most recent FDA-approved semaglutide (Wegovy: Novo Nordisk, Bagsvaerd, Denmark) yielding 14.9% total weight loss (TWL) at 1 year, in reality, the starting doses of this medication have been out of stock for over a year.² Other AOMs, on the other hand, are associated with 6%-8% TWL and are frequently associated with intolerance due to side effects. In comparison, meta-analyses demonstrate that an IGB is associated with 11.3% TWL and ESG with 16.5% TWL at 1 year. Our recent publication describing a new technique for POSE, also known as a distal POSE procedure with a double-helix technique, demonstrates a 20.3% TWL at 1 year.³ The rate of serious adverse events for EBMTs is low with 0.1% for IGB and 1%-2% for ESG/POSE.

The question regarding a comparison between AOMs and EBMTs comes up quite frequently in clinical practice. In reality, I often encourage my patients to consider combination therapy where I prescribe an AOM at 3-6 months following EBMTs to augment the amount of weight loss. However, since this is a debate, I will highlight a few advantages of EBMTs. First, the amount of weight loss following EBMTs, especially with ESG/POSE (which is currently the most commonly-requested procedure in our practice), tends to be higher than that of most AOMs. Second, while we are eagerly awaiting the long-term safety and efficacy data for semaglutide, ESG has been shown to be durable with the patients maintaining 15.9% TWL at 5 years.⁴ Third, an EBMT is a one-time procedure. In contrast, AOMs rely on patients’ compliance with taking the medication(s) reliably and indefinitely. A study based on HMO pharmacy data of over a million patients who were prescribed AOMs showed that fewer than 2% completed 12 months of weight loss medication therapy.⁵ The long-term use of AOMs also has cost implications. Specifically, a month supply of semaglutide costs about $1,400, which translates to $16,800 in 1 year and $84,000 in 5 years, which clearly outweighs the cost of ESG/POSE that has been demonstrated to be durable up to at least 5 years. IGBs have limitations similar to those of AOMs upon removal. Nevertheless, with the average cost of an IGB being $8,000, placing one every year would still be less costly, although this would likely be unnecessary considering the weight loss trend after IGB.

There are a few hurdles that need to be overcome before EBMTs are widely adopted. Reimbursement remains a major issue at most centers in the United States. Currently, most EBMTs are offered as a self-pay procedure, making the majority of patients who are otherwise eligible and interested not able to afford the procedure. With the recently published MERIT trial, long-term data on ESG as well as several upcoming society guidelines on EBMTs, we are hopeful that insurance coverage for EBMTs is nearing. Another important aspect is training. While IGB placement and removal are simple procedures, performing a high-quality ESG/POSE requires rigorous training to ensure safety and optimal outcomes. Several professional societies are working hard to develop curriculums on EBMTs with a focus on hands-on training to ensure endoscopists are properly trained prior to starting their bariatric endoscopy program. At our institution, we have a dedicated training program focusing on bariatric endoscopy (i.e. separate from the traditional advanced endoscopy fellowship), where fellows learn advanced bariatric suturing and plication as well as multidisciplinary care for this patient population. I am hopeful that this kind of training will become more prevalent in the near future.

With mounting evidence supporting the benefits of EBMTs, bariatric endoscopy has revolutionized the care of patients suffering from obesity and its related comorbidities. Moving forward, the field will continue to evolve, and EBMT procedures will only become simpler, safer, and more effective. It is an exciting time for gastroenterologists to get involved.
 

Dr. Jirapinyo is the director of bariatric endoscopy fellowship at Brigham and Women’s Hospital/Harvard Medical School, Boston. She is board certified in internal medicine, gastroenterology, and obesity medicine and completed her bariatric endoscopy and advanced endoscopy fellowships at Brigham and Women’s Hospital. She serves as a consultant for Apollo Endosurgery, Spatz Medical, and ERBE, and she receives research support from USGI Medical, GI Dynamics, and Fractyl.

References

1. Abu Dayyeh BK et al. Lancet. 2022;400(10350):441-51.

2. Wilding JPH et al. N Engl J Med. 2021;384:989-1002.

3. Jirapinyo P and Thompson CC. Gastrointest Endosc. 2022;96(3):479-86.

4. Sharaiha RZ et al. Clin Gastroenterol Hepatol. 2021;19(5):1051-57.

5. Hemo B et al. Diabetes Res Clin Pract. 2011;94(2):269-75.

A new frontier for weight management: Assess your options carefully

BY CAROLYN NEWBERRY, MD

Considering the continued rise in obesity rates in this country coupled with an increase in associated digestive disease burden from conditions such as nonalcoholic fatty liver disease (NAFLD), gastroesophageal reflux disease (GERD), and select gastrointestinal malignancies, I believe it is now more important than ever for gastroenterologists to familiarize themselves with weight management principles and incorporation into clinical practice. A growing arsenal of tools is available for addressing excess weight, including medications and novel endobariatric techniques. Although the latter is an important consideration in patients with obesity, lifestyle counseling with or without weight loss medications sets the stage for sustainable weight loss success and may eliminate the need for procedural intervention. As such, current guidelines set forth by multiple societies, including the American Gastroenterological Association (AGA), emphasize the importance of lifestyle counseling targeting caloric restriction and increased physical activity along with medical augmentation via pharmacological agents in eligible patients.^1,2 These guidelines underline the importance of medical weight management prior to consideration of procedural options, including both endobariatrics and more classic bariatric surgeries. This ensures patients understand approaches to weight loss via noninvasive means, reduces risk of weight regain by building foundational habits, and enhances overall success of procedures long term if they are pursued. In addition, newer pharmacological agents are now approaching total body weight loss percentages of currently available endobariatric techniques while still showing high tolerance rates and long-term efficacy, indicating some patients who previously would require procedures to meet weight loss goals may no longer need them.³ Alternatively, these medications may augment efforts prior to procedures, enhancing overall total body weight loss achieved. If patients are not introduced to such options initially and as a part of comprehensive care management planning, they may not achieve the same degree of weight loss success and metabolic optimization.

As a gastroenterologist co-leading a multidisciplinary weight management and lifestyle clinic, I have witnessed firsthand the enhanced outcomes in patients who pursue endobariatric procedures after establishing care with a clinical team and attempting (and succeeding) in weight loss via changes in diet, physical activity, and medication use. Patients should be encouraged to gain understanding of one’s own “personal relationship” with food and/or address medical and social barriers to weight loss maintenance prior to procedural intervention, which requires some lead time and ideally professional expertise from multiple team members, including a dietitian. Weight regain after anti-obesity surgery is common, with significant gain occurring in up to half of patients. Several factors have been associated with weight regain, including lack of consistent follow-up, excess calorie and simple carbohydrate intake, and inconsistent physical activity.⁴ As such, most insurance companies mandate a trial of at least 6 months of lifestyle and/or medical weight management prior to considering procedural reimbursement. Although robust longitudinal data for endobariatric outcomes is not yet available, it is reasonable to believe similar concepts may be in play. In fact, since endobariatric procedures are less invasive but also therefore more temporal (as in the case of endoscopic balloon placement, which is only approved for 6 months of continuous use), behavioral modification and medical management to reduce risk of significant weight regain is even more imperative. Even in the case of more durable procedures, such as endoscopic gastroplasty, lack of compliance with recommended dietary protocols can reduce efficacy by loosening and even ripping sutures prior to establishment of bridging fibrotic mucosal changes, which enhance longevity of the procedure and support continued gastric restriction and reduction in motility. Some patients who undergo endoscopic gastroplasty end up seeking out revision and repeat procedure later due to lack of results, which may be avoided with alternative dietary and lifestyle decisions in the postprocedural state.

The landscape of non-procedural weight management tools has changed in the last 1-2 years with the approval of newer injectable medications that disrupt insulin and hormonal pathways and produce sustainable weight loss similar to reported outcomes achieved with endobariatric procedures. These medications are becoming increasingly accessible and of interest to patients, with continued destigmatization of the use of weight loss drugs in practice, which had previous negative connotations and concerns regarding safety. New guidelines put forth by the AGA recommend adding pharmacological agents to lifestyle interventions over continuing lifestyle interventions alone if adequate weight loss has not been achieved with the latter.³ This further exemplifies the importance of a multifaceted approach to optimize medical weight management as first-line therapy for obesity and associated comorbidities.

In summary, although endobariatric procedures are an important tool for gastroenterologists to incorporate into their weight management plans, they must be implemented with care and only after lifestyle and medical interventions have failed to produce desired results. Shared decision making among providers and patients enhances weight loss efforts and augments sustainability of outcomes. Considering the rapidly evolving landscape of obesity medicine, gastroenterologists need to continue to stay up to date on best practices to improve patient care, reduce associated morbidity, and enhance outcomes of novel endobariatric procedures.
 

Dr. Newberry is with the Innovative Center for Health and Nutrition in Gastroenterology (ICHANGE), division of gastroenterology, Weill Cornell Medical Center, New York. She disclosed receiving speaker honorariums from Baxter International and InBody USA.

References

1. Acosta et al. Clin Gastroenterol Hepatol. 2017 May;15(5):631-49.

2. Jensen et al. Circulation. 2014;129:S102-38.

3. Grunvald et al. Gastroenterology. 2022;163(5):1198-225.

4. Athansiadis et al. Surg Endosc. 2021 Aug;35(8):4069-84.

Happy New Year, everyone! In early December, I attended the 2022 AGA Women’s Leadership Collaboration Conference to discuss strategies to promote gender equity in our profession. It was an inspiring weekend and reminded me how many talented individuals we have in the field of gastroenterology, all with fascinating personal and professional stories and much to contribute. I think I speak for all attendees in saying that it was a privilege to have the opportunity to interact with this amazing group of women leaders, reflect on our shared experiences and visions for the future of GI, and expand our networks.

This month we are excited to launch a new recurring feature in the newspaper and online – the Member Spotlight column. AGA has more than16,000 members from varied backgrounds. Yet the reality is that each of our individual networks is much smaller, and we would all benefit from learning more about one other and building a greater sense of community. To that end, starting with this issue, we will feature a different AGA member each month in our Member Spotlight column. The goal of this new feature is to recognize AGA members’ accomplishments across all career stages and practice settings, to highlight the diversity of our membership, and to help AGA members feel more connected by learning more about each other. Our inaugural Member Spotlight column highlights Patricia Jones, MD, associate professor at the University of Miami and an accomplished hepatologist. We thank Dr. Jones for sharing her story with us.

This will be a recurring monthly feature, so please consider nominating your colleagues (including trainees, practicing GIs in academics and community practice, those with non-traditional careers or unique pursuits outside of medicine, and others) to be featured in future Member Spotlight columns! It’s a great way for the nominee’s accomplishments to be recognized and to build a sense of community among the broader AGA membership. To submit a nomination, please send the nominee’s name, email, and a brief description of why you are nominating them to: [email protected]. We look forward to reviewing your submissions and hope you will use these Member Spotlights as an opportunity to strike up a conversation with someone new and expand your networks.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

Happy New Year, everyone! In early December, I attended the 2022 AGA Women’s Leadership Collaboration Conference to discuss strategies to promote gender equity in our profession. It was an inspiring weekend and reminded me how many talented individuals we have in the field of gastroenterology, all with fascinating personal and professional stories and much to contribute. I think I speak for all attendees in saying that it was a privilege to have the opportunity to interact with this amazing group of women leaders, reflect on our shared experiences and visions for the future of GI, and expand our networks.

This month we are excited to launch a new recurring feature in the newspaper and online – the Member Spotlight column. AGA has more than16,000 members from varied backgrounds. Yet the reality is that each of our individual networks is much smaller, and we would all benefit from learning more about one other and building a greater sense of community. To that end, starting with this issue, we will feature a different AGA member each month in our Member Spotlight column. The goal of this new feature is to recognize AGA members’ accomplishments across all career stages and practice settings, to highlight the diversity of our membership, and to help AGA members feel more connected by learning more about each other. Our inaugural Member Spotlight column highlights Patricia Jones, MD, associate professor at the University of Miami and an accomplished hepatologist. We thank Dr. Jones for sharing her story with us.

This will be a recurring monthly feature, so please consider nominating your colleagues (including trainees, practicing GIs in academics and community practice, those with non-traditional careers or unique pursuits outside of medicine, and others) to be featured in future Member Spotlight columns! It’s a great way for the nominee’s accomplishments to be recognized and to build a sense of community among the broader AGA membership. To submit a nomination, please send the nominee’s name, email, and a brief description of why you are nominating them to: [email protected]. We look forward to reviewing your submissions and hope you will use these Member Spotlights as an opportunity to strike up a conversation with someone new and expand your networks.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

Happy New Year, everyone! In early December, I attended the 2022 AGA Women’s Leadership Collaboration Conference to discuss strategies to promote gender equity in our profession. It was an inspiring weekend and reminded me how many talented individuals we have in the field of gastroenterology, all with fascinating personal and professional stories and much to contribute. I think I speak for all attendees in saying that it was a privilege to have the opportunity to interact with this amazing group of women leaders, reflect on our shared experiences and visions for the future of GI, and expand our networks.

This month we are excited to launch a new recurring feature in the newspaper and online – the Member Spotlight column. AGA has more than16,000 members from varied backgrounds. Yet the reality is that each of our individual networks is much smaller, and we would all benefit from learning more about one other and building a greater sense of community. To that end, starting with this issue, we will feature a different AGA member each month in our Member Spotlight column. The goal of this new feature is to recognize AGA members’ accomplishments across all career stages and practice settings, to highlight the diversity of our membership, and to help AGA members feel more connected by learning more about each other. Our inaugural Member Spotlight column highlights Patricia Jones, MD, associate professor at the University of Miami and an accomplished hepatologist. We thank Dr. Jones for sharing her story with us.

This will be a recurring monthly feature, so please consider nominating your colleagues (including trainees, practicing GIs in academics and community practice, those with non-traditional careers or unique pursuits outside of medicine, and others) to be featured in future Member Spotlight columns! It’s a great way for the nominee’s accomplishments to be recognized and to build a sense of community among the broader AGA membership. To submit a nomination, please send the nominee’s name, email, and a brief description of why you are nominating them to: [email protected]. We look forward to reviewing your submissions and hope you will use these Member Spotlights as an opportunity to strike up a conversation with someone new and expand your networks.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief