Best Way To Get Collagen And Biotin For Skin, Hair, And Nails Is Through A Well-Rounded Diet, Researchers Say
CNBC (7/22, Onque) reported, "Skin, hair and nail supplements often contain much more biotin than the human body needs," according to findings published in a research letter in the Journal of the American Academy of Dermatology. This could become problematic, because "high doses of biotin 'can alter test results that healthcare providers may order, like thyroid testing, cardiac testing [and] potentially even vitamin D testing.'" As for collagen "supplements, which are often touted as a skin health aid," they "can often be taken without undue concern – but when tested, many popular brands contained toxic heavy metals like lead and mercury...dermatologists note." The best way to get collagen and biotin is through "a well-rounded diet...researchers agree."
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CYCLING BACK TO DOXYCYCLINE’S ROOTS AS THERAPY FOR BULLOUS PEMPHIGOID
By Warren R. Heymann, MD, FAAD July 26, 2023 Vol. 5, No. 30
Patients with moderate to severe bullous pemphigoid are usually treated with systemic corticosteroids. Four patients were treated with tetracycline hydrochloride and niacinamide because of the steroid-sparing anti-inflammatory properties of these agents. An excellent clinical response free of side effects was observed in all patients. The lesions recurred whenever treatment was discontinued. It is believed that these drugs suppress the complement-mediated inflammatory response at the basement membrane zone by suppressing neutrophil chemotaxis and mediators of the inflammatory response in this bullous disease.
This 1986 abstract from the seminal article by Berk and Lorincz crystallized the use of tetracyclines as anti-inflammatory agents, rather than antimicrobial drugs, as steroid-sparing agents for treating bullous pemphigoid (BP) in concert with niacinamide. (1) The concept of antibiotics (usually doxycycline or minocycline) as anti-inflammatory agents was novel in the 1980s and has become a standard first-line treatment for BP, aside from corticosteroids (ultrapotent topical or systemic). Treating BP requires a thorough medical knowledge of the patient and their comorbidities — tailoring therapy to include second-line agents (azathioprine, mycophenolate mofetil, dapsone, or methotrexate) or third-line therapies (IVIG, rituximab, omalizumab, dupilumab, and others) must be individualized to the patient's overall health. (2)
This commentary will focus on the use of doxycycline for BP. Can its efficacy be solely due to its anti-inflammatory effect?
Doxycycline was FDA-approved as an antibiotic in 1967. It is a broad-spectrum bacteriostatic agent that inhibits bacterial protein synthesis by targeting the 30S ribosomal subunit of gram-positive and gram-negative bacteria. The anti-inflammatory effects of doxycycline have been reviewed by Henehan et al and include inhibition of multiple matrix metalloproteinases, diminishing protease-activated receptor 2 (PAR2), reducing both random migration and guided chemotaxis of neutrophils, decreasing pathogenic nitrous oxide synthase levels, reducing IgE production, scavenging radicals thereby reducing oxidative stress, hindering granuloma formation, and inducing apoptosis via caspase pathways. (3)
Eosinophils are potent pro-inflammatory cells; the tetracyclines (tetracycline, doxycycline, minocycline) have been used to advantage in disorders such as asthma or BP where eosinophils play a pathogenic role. Gehring et al have demonstrated that the tetracyclines significantly induce eosinophil apoptosis and strongly overcome the strong survival-enhancing effects of pro-eosinophilic cytokines and Staphylococcus aureus (SA) enterotoxins. (4)
(Niacinamide, also known as nicotinamide, was initially observed to be beneficial for dermatitis herpetiformis, hence its use in BP. Niacinamide is the pyridine-3-carboxamide form of niacin, a component of the vitamin B complex. It is the precursor for nicotinamide adenine dinucleotide and acts as an inhibitor of poly- [adenosine diphosphate–ribose] polymerase, which plays an essential role in the expression of cytokines, chemokines, and adhesion molecules via enhanced transcription of nuclear factor kB. It also blocks IgE-induced histamine release.) (1,5)
The anti-inflammatory effects of doxycycline, which seemed revolutionary decades ago, are now accepted as routine. For years, I have been telling patients that we are administering the drug as an anti-inflammatory agent, not for its role as an antibiotic. That statement is correct when using doxycycline in subantimicrobial doses — in typical doses, however, perhaps doxycycline is exerting its antibiotic effect.
Any seasoned dermatologist will be on the prowl for secondary infection in patients with BP. In a retrospective review of 110 hospitalized patients with BP, infections were present in 40% (44/110) of the patients. Staphylococcus aureus (72.7%, 32/44) was the most common bacterium, and it was highly resistant to penicillin (81.3%, 26/32), erythromycin (62.5%, 20/32), and clindamycin (56.3%, 18/32), but 100.0% sensitive to vancomycin and tigecycline. (6) BP may be complicated by methicillin-resistant SA (MRSA) and sepsis. (7)
Image from DermNetNZ.
The complex interplay of SA with skin disease is well-known in atopic dermatitis when SA is isolated from patients during flares; as the normal microbiota is reduced, many species that produce inhibitors of SA are also decreased. (8) Scaglione et al studied microbiota of patients with pemphigus vulgaris (PV) and BP using high-throughput sequencing of the V1-V3 hyper-variable regions of 16S rRNA to compare the bacterial community composition of stool, skin, and oral mucosae swabs in a cohort of PV and BP patients. They determined that the Firmicutes phylum and Staphylococcus genus were the most represented bacteria in oral cavity and cutaneous swabs of PV and BP microbial populations. (9)
Last week, we discussed the "intimate dance" of SA and cutaneous T-cell lymphoma. Could SA be a trigger of BP aside from being a potential infectious complication? Is doxycycline working as an antibiotic AND an anti-inflammatory agent?
Messingham et al propose that the antimicrobial effects of tetracyclines play an important therapeutic role in BP by the clearance of SA. Their abstract follows: "A potential role of S. aureus in bullous pemphigoid was explored by examining the colonization rate in patients with new-onset disease compared with that in age- and sex-matched controls. S. aureus colonization was observed in 85% of bullous pemphigoid lesions, 3-6-fold higher than the nares or unaffected skin from the same patients (P ≤ 0.003) and 6-fold higher than the nares or skin of controls (P ≤ 0.0015). Furthermore, 96% of the lesional isolates produced the toxic shock syndrome toxin-1 superantigen, and most of these additionally exhibited homogeneous expression of the enterotoxin gene cluster toxins. Toxic shock syndrome toxin-1‒neutralizing antibodies were not protective against colonization. However, S. aureus colonization was not observed in patients who had recently received antibiotics, and the addition of antibiotics with staphylococcal coverage eliminated S. aureus and resulted in clinical improvement. This study shows that toxic shock syndrome toxin-1‒positive S. aureus is prevalent in bullous pemphigoid lesions and suggests that early implementation of antibiotics may be of benefit. Furthermore, our results suggest that S. aureuscolonization could provide a source of infection in patients with bullous pemphigoid, particularly in the setting of high-dose immunosuppression." (10)
I reread Berk and Lorincz's article. (1) None of the four cases had any wound cultures performed.
The latest data about doxycycline's anti-inflammatory capabilities, especially in eosinophil-rich disorders, and the purported role SA plays in triggering (or complicating) them, solidifies its position as a first-line therapeutic agent for BP. Despite its potential benefit, clinicians must use antibiotics judiciously in this age of increasing antimicrobial resistance to SA and other bacteria. (11)
Point to Remember: Staphylococcus aureus has the potential to trigger or complicate bullous pemphigoid by infection. Tetracyclines may exert their efficacy via their anti-inflammatory and antimicrobial properties.
Our expert's viewpoint
Janet Fairley, MD, FAAD Chair, John S. Strauss Professor and Head of Dermatology University of Iowa Carver College of Medicine
Tetracycline antibiotics have been used in bullous pemphigoid (BP) for almost 30 years. Multiple mechanisms have been proposed for their beneficial effects in BP, including antioxidant effects, inhibition of matrix metalloproteinases, and through their antimicrobial activity (12,13,14). These possibilities are not exclusive, and it is likely the beneficial effect of tetracyclines in BP is multifactorial.
BP patients are typically elderly with multiple co-morbidities, and most will receive therapeutic immunosuppression. In addition, BP patients suffer increased hospitalizations and mortality within the first year of diagnosis, with the most common causes being infectious complications, including sepsis and pneumonia (15, 16). Thus, clinicians should be aware of the widespread S. aureus colonization of BP lesions (10) and consider that early implementation of antimicrobial therapy may be of benefit, particularly in patients receiving immunosuppressants.
In practice, doxycycline is usually included in the initial therapy for our BP patients. Based on our detection of S. aureus toxins in BP blister fluid, we have used short-term clindamycin in patients with severe disease since it inhibits toxin production in a manner independent of its antimicrobial activity (17). Rapid elimination of S. aureus toxins may be important in BP patients due to the direct effect of these toxins on immune cell dysregulation, keratinocyte inflammatory responses, and upregulation of damaging matrix metalloproteinases, all of which are of concern for potential worsening of BP (18, 19, 20).
Our understanding of role of S. aureus in BP is evolving but this topic story is of interest to those of us who treat this disease. Stay tuned.
Berk MA, Lorincz AL. The treatment of bullous pemphigoid with tetracycline and niacinamide. A preliminary report. Arch Dermatol. 1986 Jun;122(6):670-4. PMID: 2940979.
Bilgiç A, Murrell DF. Bullous pemphigoid. In Lebwohl MG, Heymann WR, Coulson IH, Murrell DF (eds) Treatment of Skin Disease, Sixth Edition. Elsevier, 2022, pp 115-118.
Henehan M, Montuno M, De Benedetto A. Doxycycline as an anti-inflammatory agent: updates in dermatology. J Eur Acad Dermatol Venereol. 2017 Nov;31(11):1800-1808. doi: 10.1111/jdv.14345. Epub 2017 Jun 7. PMID: 28516469
Gehring M, Wieczorek D, Kapp A, Wedi B. Potent Anti-Inflammatory Effects of Tetracyclines on Human Eosinophils. Front Allergy. 2021 Oct 4;2:754501. doi: 10.3389/falgy.2021.754501. PMID: 35386966; PMCID: PMC8974775.
Heymann WR. Nicotinamide and reflections on Alan Shalita and George Hambrick Jr. Cutis. 2014 Mar;93(3):151-2. PMID: 24738097.
Li F, Bian W, Wu Y, Zhu X, Chen X, Wang M. Bacterial Skin Infections in Hospitalized Patients with Bullous Pemphigoid. Adv Skin Wound Care. 2021 Jul 1;34(7):365-370. doi: 10.1097/01.ASW.0000752704.10152.30. PMID: 34125726.
Souaid R, Wang J, Landow SM, Noska A. Bullous Pemphigoid Complicated by MRSA Cellulitis and Bacteremia. R I Med J (2013). 2019 Jun 4;102(5):46-48. PMID: 31167529.
Geoghegan JA, Irvine AD, Foster TJ. Staphylococcus aureus and Atopic Dermatitis: A Complex and Evolving Relationship. Trends Microbiol. 2018 Jun;26(6):484-497. doi: 10.1016/j.tim.2017.11.008. Epub 2017 Dec 9. PMID: 29233606. Scaglione GL, Fania L, De
Paolis E, De Bonis M, Mazzanti C, Di Zenzo G, Lechiancole S, Messinese S, Capoluongo E. Evaluation of cutaneous, oral and intestinal microbiota in patients affected by pemphigus and bullous pemphigoid: A pilot study. Exp Mol Pathol. 2020 Feb;112:104331. doi: 10.1016/j.yexmp.2019.104331. Epub 2019 Nov 6. PMID: 31705881.
Messingham KN, Cahill MP, Kilgore SH, Munjal A, Schlievert PM, Fairley JA. TSST-1+Staphylococcus aureus in Bullous Pemphigoid. J Invest Dermatol. 2022 Apr;142(4):1032-1039.e6. doi: 10.1016/j.jid.2021.08.438. Epub 2021 Oct 1. PMID: 34606884.
George S, Muhaj FF, Nguyen CD, Tyring SK. Part I Antimicrobial resistance: Bacterial pathogens of dermatologic significance and implications of rising resistance. J Am Acad Dermatol. 2022 Feb 2;86(6):1189–204. doi: 10.1016/j.jaad.2021.11.066. Epub ahead of print. PMID: 35122894; PMCID: PMC8808428.
C. Feliciani, P. Joly, M.F. Jonkman, G. Zambruno, D. Zillikens, D. Ioannides, et al. Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Acad Dermatol and Venereol. 2015. Br J Dermatol, 172:867-877.
M. Schaller. Anti-inflammatory effects of tetracyclines. 2017. J Eur Acad Dermatol Venereol, 31 (2017), p. 1774.
H.C. Williams, F. Wojnarowska, G. Kirtschig, J. Mason, T.R. Godec, E. Schmidt, et al. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial [published correction appears in Lancet 2017;390:1948]. 2017. Lancet, 389:1630-1638
P. Joly, S. Baricault, A Sparsa, et al. Incidence and mortality of bullous pemphigoid in France. 2012. J Invest Dermatol 132:1998-2004.
Z. Ren, D.Y. Hsu, J. Brieva, N.B. Silverberg, S.M. Langan, J.I. Silverberg. Hospitalization, inpatient burden and comorbidities associated with bullous pemphigoid in the U.S.A. 2017. Br J Dermatol, 176: 87-99.
D. L.Stevens, Y. Ma, D. B. Salmi, E. McIndoo, R. J. Wallace, A. E. Bryant. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. 2007/ J Infectious diseases. 195:202-11.
P. M. Schlievert, F. A. Gourronc, D. Y. M. Leung, A. J. Klingelhutz. Human Keratinocyte Response to Superantigens. 2020. mSphere. 5(5):803-20.
L. M. Breshears, P. M. Schlievert, M. L. Peterson. A disintegrin and metalloproteinase 17 (ADAM17) and epidermal growth factor receptor (EGFR) signaling drive the epithelial response to Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1). J Biol Chem. 2012 Sep 21;287(39):32578-87.
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Characteristics and Management of Immune Checkpoint Inhibitor–Induced Pruritus
Abstract
BACKGROUND
Limited data on immune checkpoint inhibitor (ICI)-induced pruritus per se and efficacy of different therapeutic modalities in its management exist.
OBJECTIVE
To study the quantitative and qualitative characteristics of ICI-induced pruritus per se and to assess the efficacy of the therapeutic modalities usually applied.
METHODS
We retrospectively reviewed the records of 91 patients who were under treatment with ICIs for any kind of neoplasia and developed pruritus during treatment.
RESULTS
Twenty out of 91 individuals (22.0%) with ICI-induced pruritus had pruritus as the only symptom, while 71/91 (78.0%) presented with pruritus coexisting with an additional cutaneous toxicity. Pruritus was treated with antihistamines (18/20, 90.0%) and/or topical regimens, as first-line choice. In resistant cases, as a second therapeutic intervention, narrow-band UVB (NBUVB), oral steroids and GABA analogs were added (70.0%). Statistical analysis revealed a significant difference in mean pruritus Numerical Rating Scale (NRS) scores between baseline and sequential visits. Moreover, subgroup analysis revealed a significant reduction in mean NRS scores in those treated with phototherapy.
LIMITATIONS
Retrospective design, low number of patients and survivorship bias.
CONCLUSION
Pruritus per se was present in a substantial portion of our cohort (22.0%). Our study confirms the efficacy of current treatment strategies and suggests NBUVB as a potential steroid-sparing therapeutic alternative.
Photodermatology, Photoimmunology & Photomedicine
A retrospective multicentric cohort study of checkpoint inhibitors-induced pruritus with focus on management
Photodermatol Photoimmunol Photomed 2023 Jun 12;[EPub Ahead of Print], C Papageorgiou, E Lazaridou, K Lallas, K Papaioannou, V Nikolaou, V Mateeva, K Efthymiadis, C Koukoutzeli, K Loga, E Sogka, E Karamitrousis, G Lazaridis, D Dionysopoulos, A Lallas, C Kemanetzi, C Fotiadou, E Timotheadou, Z Apalla
This limited retrospective cohort study evaluated the effect of a few treatment modalities in the management of immune checkpoint inhibitor–induced pruritus (ICI-pruritus). A total of 20 patients with pruritus as their only symptom from ICI therapy were studied. Patients received first-line and second-line therapies to address their pruritus. First-line therapy included oral antihistamines for all 20 patients, in addition to topical therapy in 18 of 20 patients. Of the 20 patients, 14 required second-line therapy, which included phototherapy in 7 patients, oral steroids in 2, further oral antihistamines in 2, a GABA-analogue in 1, and combination therapy in 2.
The average pruritus Numerical Rating Score (NRS) for all patients decreased from 6.0 to 4.1 after first-line therapy and then further from 4.1 to 1.6 after all second-line therapies regardless of treatment modality. Subgroup analysis revealed that the average NRS for the 7 patients treated with phototherapy decreased from 6.6 to 4.8 after first-line therapy, and then from 4.8 to 0.8 after second-line therapy with phototherapy. These results were similar in magnitude to those seen with systemic steroids, although only 2 patients were treated with systemic steroids compared with 7 patients with phototherapy.
This study provides some data in support of the use of the current expert consensus guidelines for the treatment of ICI-pruritus (PMID: 32856211) and adds some data in support of the use of phototherapy as a steroid-sparing agent in the treatment of ICI-pruritus. All dermatologists should consider the use of phototherapy for ICI-pruritus, given its steroid-sparing nature and favorable side-effect profile, especially in the oncology patient population, which is already burdened with medication side-effects.
This study was underpowered to discern differences in treatment response among the various second-line therapies listed above. The overall sample sizes for second-line therapies are very small and limit the external validity of this study. The authors did not provide dosages of phototherapy used, nor did they comment on how long into the phototherapy treatment course patients experienced improvement with their pruritus; the latter is of particular concern, given the time-sensitive nature of treating ICI-pruritus so that patients can stay on schedule with their ICI therapy.
NB: In Table 4 line 1, the authors report an NRS after second-line therapy for 20 patients; it is unclear where this number is derived from, as only 14 patients in this study actually receive second-line therapy.
TAKE-HOME MESSAGE
This retrospective cohort study included 91 oncologic patients with immune checkpoint inhibitor (ICI)–induced pruritus, with 78% of them experiencing pruritus in association with a rash and 22% of them experiencing pruritus as the only symptom. Among patients with pruritus without rash, the most common first-line therapy was antihistamines (90%). Among patients with persistent pruritus (70%), the most common second-line therapy was phototherapy (35%). There was a statistically significant difference in mean pruritus Numerical Rating Scale (NRS) scores between baseline and after first-line and second-line interventions. Specifically, there was a significant decrease in mean NRS scores after phototherapy treatment.
This study showed that a substantial proportion of patients (22%) can have ICI-induced pruritus without a rash. Dermatologic treatment using a variety of topical and systemic agents is effective in managing ICI-induced pruritus. In particular, phototherapy has been shown to be effective and can serve as an alternative to steroids and other immunomodulating agents.
A Liver Disease Gets a New Name, Diagnostic Criteria
Nonalcoholic fatty liver disease will now be called metabolic dysfunction–associated steatotic liver disease, or MASLD, according to new nomenclature adopted by a global consensus panel composed mostly of hepatology researchers and clinicians.
The new nomenclature, published in the journal Hepatology, includes the umbrella term steatotic liver disease, or SLD, which will cover MASLD and MetALD, a term describing people with MASLD who consume more than 140 grams of alcohol per week for women and 210 grams per week for men.
Metabolic dysfunction–associated steatohepatitis, or MASH, will replace the term nonalcoholic steatohepatitis, or NASH.
Mary E. Rinella, MD, of University of Chicago Medicine led the consensus group. The changes were needed, Dr. Rinella and her colleagues argued, because the terms "fatty liver disease" "and nonalcoholic" could be considered to confer stigma, and to better reflect the metabolic dysfunction occurring in the disease. Under the new nomenclature, people with MASLD must have a cardiometabolic risk factor, such as type 2 diabetes. People without metabolic parameters and no known cause will be classed as having cryptogenic SLD.
While the new nomenclature largely conserves existing disease definitions, it allows for alcohol consumption beyond current parameters for nonalcoholic forms of the disease. "There are individuals with risk factors for NAFLD, such as type 2 diabetes, who consume more alcohol than the relatively strict thresholds used to define the nonalcoholic nature of the disease [and] are excluded from trials and consideration for treatments," the authors wrote.
Moreover, they wrote, "within MetALD there is a continuum where conceptually the condition can be seen to be MASLD or ALD predominant. This may vary over time within a given individual."
Respondents overwhelmingly agreed, however, that even moderate alcohol use alters the natural history of the disease and that patients with more than minimal alcohol consumption should be analyzed separately in clinical trials.
The new nomenclature reflects a 3-year effort involving some 236 panelists from 56 countries who participated in several rounds of online surveys using a Delphi process. Pediatricians, gastroenterologists, and endocrinologists also participated as well as some patient advocates. Changes were based on a super-majority of opinion (67% or higher), though the consensus on whether the term "fatty" was stigmatizing never reached that threshold. In early rounds of surveys only 44% of respondents considered the word "fatty" to be stigmatizing, while more considered "nonalcoholic" to be problematic.
"Substantial proportions of the respondents deemed terms such as 'fatty' stigmatizing, hence its exclusion as part of any new name," Dr. Rinella and her colleagues wrote. "Although health care professionals may contend that patients have not reported this previously, this likely reflects in part a failure to ask the question in the first place and the power imbalance in the doctor-patient relationship." The authors noted that the new terminology may help raise awareness at a time when new therapeutics are in sight and it becomes more important to identify at-risk individuals.
Of concern was whether the new definitions would alter the utility of earlier data from registries and trials. However, the authors determined that some 98% of people registered in a European NAFLD cohort would meet the new criteria for MASLD. "Maintenance of the term, and clinical definition, of steatohepatitis ensures retention and validity of prior data from clinical trials and biomarker discovery studies of patients with NASH to be generalizable to individuals classified as MASLD or MASH under the new nomenclature, without impeding the efficiency of research," they stated.
The effort was spearheaded by three international liver societies: La Asociación Latinoamericana para el Estudio del Hígado, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver, as well as the cochairs of the NAFLD Nomenclature Initiative.
Each of the authors disclosed a number of potential conflicts of interest.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Efficacy and Safety of Slow Mohs Micrographic Surgery for Treating Nail Apparatus Melanoma in Situ
TAKE-HOME MESSAGE
A total of 10 patients were included in this retrospective study from China to evaluate the safety and efficacy of slow Mohs micrographic surgery (MMS) for the treatment of nail apparatus melanoma in situ (NAMIS). The procedure was well-tolerated, with no local recurrence during a median follow-up time of 46 months. A median number of two stages and a median margin of 8 mm were required.
This case series demonstrates the successful use of slow MMS in achieving optimal outcomes and preserving nail function in patients with NAMIS.
The two articles by Le and Zhang provide real-world evidence that Mohs surgery is an effective treatment for melanoma in situ (MIS) of the nail unit. Is this evidence-based practice changing? The preponderance of evidence to date, including these articles, confirms that Mohs is at least non-inferior. There are no randomized controlled trials, nor will there likely be one. But, as pointed out in a recent JAMA article, real-world evidence has a meaningful role in health care decision-making, and this evidence supports the value of Mohs surgery in nail unit MIS.1,2 Although the number of patients is small, comparison of raw recurrence rates may be misleading; the pooling of data helps to strengthen the evidence.
These reports have weaknesses repeated in many case studies and reviews. First, they do not define local recurrence. All studies should define local persistence and separate persistent disease recurrence from satellite metastatic disease. This might be a moot point because these reports were for MIS, and any local recurrence was likely due to persistent disease; nonetheless, the distinction is important. Second, follow-up time is extremely important. Most local recurrences from persistent disease occur later than metastatic disease (5 years vs 2 years). All studies should specify how long patients were followed, and Kaplan–Meier statistics should help extrapolate the data to provide a projected 5-year recurrence rate.
My opinion based on my treatment of dozens of nail unit MIS is that Mohs is extremely valuable when performed properly. Mohs surgery with frozen sections and Mart 1 immunostaining is the most accurate way to assess the margin. The use of blue Mart 1 improves detection of melanocytes.3 Fellowship training is valuable due to the increased difficulty of removing layers from the nail bed, periosteum, nail horns, and even bone when necessary. In the end it all comes down to – should 100% of the margin be examined by Mohs, or is it good enough to sample less than 1% of the margin with traditional pathology exam? The controversies about the value of Mohs surgery for melanoma are melting away.
Fazio J, Heras A, Stein E, et al. Melanoma Antigen Recognized by T Cells With Blue Chromogen Improves Identification of Melanocytes From Background Melanized Keratinocytes on Frozen Sections. Dermatol Surg 2023;49:709-711.
Abstract
BACKGROUND
Nail apparatus melanoma is a malignant tumor with a high incidence in Chinese melanoma patients. Slow Mohs micrographic surgery is an emerging technique for treating nail apparatus melanoma in situ (NAMIS).
OBJECTIVE
This study evaluated the efficacy and safety of slow Mohs micrographic surgery for treating NAMIS.
METHODS
Patients were enrolled in this retrospective study and treated in a single center from October 1, 2016, to June 30, 2022. Each patient underwent standard slow Mohs micrographic surgery, and follow-up was regularly conducted at clinics.
RESULTS
Ten patients were enrolled in the study. Two patients underwent one Mohs stage, seven underwent two Mohs stages, and one underwent seven Mohs stages. The resection margin ranged from 5 to 25 mm. No severe complications were reported in the treatment, and recurrence of NAMIS was not observed during the follow-up period.
CONCLUSION
Slow Mohs micrographic surgery is a valuable surgical method to treat NAMIS that preserves digit function and can be well tolerated by patients.
International Journal of Dermatology
Slow Mohs micrographic surgery for nail apparatus melanoma in situ
Int. J. Dermatol 2023 Jun 23;[EPub Ahead of Print], S Zhang, Y Wang, K Fang, Q Jia, H Zhang, T Qu
Treatment-Free Survival After Nivolumab vs Pembrolizumab vs Nivolumab–Ipilimumab Therapy in Patients With Advanced Melanoma
TAKE-HOME MESSAGE
A total of 316 patients with advanced melanoma were included in this cohort study investigating treatment-free survival (TFS) outcomes of various first-line immune checkpoint inhibitor therapies between 2013 and 2020. The results showed that patients treated with nivolumab–ipilimumab combination therapy had longer mean TFS (12.4 months) compared with those receiving pembrolizumab (11.1 months) or nivolumab (8.9 months) monotherapy.
This study provides real-world data to support the use of nivolumab–ipilimumab combination therapy in patients with advanced melanoma and underscores the significance of incorporating TFS as a measure to potentially capture the impact on the quality of life of patients.
This paper by Gupta et al describes a cohort of patients from the Alberta Immunotherapy Database (AID), a multicenter observational database. They report on a somewhat novel surrogate endpoint: treatment-free survival (TFS).
Why is this an interesting surrogate endpoint to look at?
Well, first of all, we know that immunotherapy can have durable responses, even if they are not complete responses. Secondly, combination immunotherapy with ipilimumab and nivolumab (IPI/NIVO) is associated with a higher response rate than single-agent anti–PD-1 (either nivolumab or pembrolizumab). Thirdly, we also know that combination immunotherapy has significantly more toxicity and therefore a higher rate of discontinuation by patients due to toxicity.
The question therefore is: Do patients benefit more from combination immunotherapy — compared with a single-agent anti–PD-1 — if they more often must discontinue therapy prematurely due to toxicity?
Gupta et al report on 316 patients from the AID with stage IV melanoma receiving first-line immunotherapy, either single-agent nivolumab (n = 51) or pembrolizumab (n = 158) or IPI/NIVO (n = 107). They found that TFS was best with the combination immunotherapy and concluded that this is valuable as a patient-centric outcome.
Although I do strongly agree with their conclusions, the study did have a few weaknesses. For example, the retrospective nature of the study, the small sample size, and some imbalances in baseline characteristics among the groups, likely pointing towards a bias regarding why certain patients received combination immunotherapy while others received only single-agent anti–PD-1.
In this case, the added toxicity of combination immunotherapy not only leads to higher response rates and an improved progression-free survival compared with single-agent anti–PD-1, but the duration of treatment is shorter too, leading to an improved TFS. In other words: patients "suffer" the higher rate of toxicity in order to benefit more and be undergoing treatment for a shorter amount of time.
Finally, TFS is an interesting emerging patient-centric outcome measure, which will be used more frequently in future oncology trials.
Abstract
IMPORTANCE
Treatment-free survival (TFS) represents an alternative time-to-event end point, accurately characterizing time spent free of systemic therapy, providing a more patient-centric view of immune checkpoint inhibitor (ICI) therapy regimens. There remains a lack of studies evaluating TFS outcomes among patients with advanced melanoma who are receiving immunotherapy, especially outside of the clinical trial setting.
OBJECTIVE
To evaluate TFS outcomes for patients with advanced melanoma receiving first-line ICI therapy outside of a clinical trial setting.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter cohort study of patients with advanced melanoma receiving first-line ICI therapy between August 1, 2013, and May 31, 2020, was conducted in Alberta, Canada. Data analysis was performed in August 2022.
EXPOSURES
Patients received standard-of-care, first-line ICI therapy treatment regimens including single-agent nivolumab, single-agent pembrolizumab, or ipilimumab-nivolumab.
MAIN OUTCOMES AND MEASURES
Treatment-free survival was defined as the difference in the 36-month restricted mean survival time between 2 conventional survival end points: (1) time from treatment initiation to ICI cessation, death, or censoring at last follow-up and (2) time from treatment initiation to subsequent systemic anticancer therapy, death, or censoring at last follow-up.
RESULTS
A total of 316 patients with advanced melanoma receiving first-line nivolumab (n = 51; median age, 66 years [IQR, 56-78 years]; 31 men [60.8%]), pembrolizumab (n = 158; median age, 69 years [IQR, 60-78 years]; 112 men [70.9%]), or combination nivolumab-ipilimumab (n = 107; median age, 53 years [IQR, 42-60 years]; 72 men [67.3%]) were included. Treatment groups were similar with regard to sex, primary tumor location, and presence of metastasis, although patients receiving combination nivolumab-ipilimumab had a lower Eastern Cooperative Oncology Group status, were younger, and were more likely to be BRAF V600E positive than those receiving anti-programmed cell death protein 1 (anti-PD-1) monotherapy. The restricted mean TFS was longer for nivolumab-ipilimumab (12.4 months [95% CI, 8.8-16.0 months]) compared with nivolumab (8.9 months [95% CI, 4.4-13.5 months]) and pembrolizumab (11.1 months [95% CI, 8.5-13.8 months]). During the 36-month follow-up interval, patients treated with nivolumab-ipilimumab spent 34.4% of their time (12.4 of 36 months) not receiving systemic anticancer treatments compared with 30.8% (11.1 of 36 months) and 24.7% (8.9 of 36 months) of the time for the pembrolizumab and nivolumab treatment groups, respectively.
CONCLUSIONS AND RELEVANCE
This cohort study of patients with advanced melanoma receiving first-line ICI therapy suggests that TFS represents a patient-centric, informative end point. Patients treated with combination nivolumab-ipilimumab spent more time alive and free from systemic anticancer therapy than those treated with anti-PD-1 monotherapy alone.
JAMA Network Open
Treatment-Free Survival After Nivolumab vs Pembrolizumab vs Nivolumab-Ipilimumab for Advanced Melanoma
JAMA Netw Open 2023 Jun 01;6(6)e2319607, M Gupta, I Stukalin, D Meyers, S Goutam, DYC Heng, T Cheng, J Monzon, V Navani
This limited retrospective cohort study evaluated the effect of a few treatment modalities in the management of immune checkpoint inhibitor–induced pruritus (ICI-pruritus). A total of 20 patients with pruritus as their only symptom from ICI therapy were studied. Patients received first-line and second-line therapies to address their pruritus. First-line therapy included oral antihistamines for all 20 patients, in addition to topical therapy in 18 of 20 patients. Of the 20 patients, 14 required second-line therapy, which included phototherapy in 7 patients, oral steroids in 2, further oral antihistamines in 2, a GABA-analogue in 1, and combination therapy in 2.
The average pruritus Numerical Rating Score (NRS) for all patients decreased from 6.0 to 4.1 after first-line therapy and then further from 4.1 to 1.6 after all second-line therapies regardless of treatment modality. Subgroup analysis revealed that the average NRS for the 7 patients treated with phototherapy decreased from 6.6 to 4.8 after first-line therapy, and then from 4.8 to 0.8 after second-line therapy with phototherapy. These results were similar in magnitude to those seen with systemic steroids, although only 2 patients were treated with systemic steroids compared with 7 patients with phototherapy.
This study provides some data in support of the use of the current expert consensus guidelines for the treatment of ICI-pruritus (PMID: 32856211) and adds some data in support of the use of phototherapy as a steroid-sparing agent in the treatment of ICI-pruritus. All dermatologists should consider the use of phototherapy for ICI-pruritus, given its steroid-sparing nature and favorable side-effect profile, especially in the oncology patient population, which is already burdened with medication side-effects.
This study was underpowered to discern differences in treatment response among the various second-line therapies listed above. The overall sample sizes for second-line therapies are very small and limit the external validity of this study. The authors did not provide dosages of phototherapy used, nor did they comment on how long into the phototherapy treatment course patients experienced improvement with their pruritus; the latter is of particular concern, given the time-sensitive nature of treating ICI-pruritus so that patients can stay on schedule with their ICI therapy.
NB: In Table 4 line 1, the authors report an NRS after second-line therapy for 20 patients; it is unclear where this number is derived from, as only 14 patients in this study actually receive second-line therapy.