This month's news from across the specialty

March 1, 2022

In this monthly column, members of the DermWorld Editorial Advisory Workgroup identify exciting news from across the specialty.  

If we can get ahead of the variants through testing and new treatment regimens, we should be able to put this all behind us — meaning the melanoma. Selective targeting of the mutant BRAF function in melanoma with BRAFV600 mutations has delivered marginal results and commonly leads to tumor relapse after a year. Early data in mice and case reports supported a regimen of intermittent BRAF-targeted therapy to decrease the development of resistant variant tumor lineages. Unfortunately, this hypothesis was not supported in randomized trials and the recent RCT by Gonzalez-Cao et al in Nature Communications adds a second phase 2 trial with worse outcomes with intermittent relative to continuous BRAF targeted therapy.

This study provides interesting data in a secondary analysis of the DNA fragments circulating in the blood away from the tumor. While all the patients in the study had BRAF mutations identified in their tumors, only half of the patients had evidence of DNA with BRAF mutations in their blood. The authors collected blood samples at multiple time points through both treatment arms. The worst clinical outcomes were found in the patients with evidence of the BRAFV600 circulating in their blood before the initiation of treatment. Subsequent testing for BRAFV600 only demonstrated a confirmation of tumor progression in a portion of patients with new mutations of non-BRAF genes identified in a small portion of the patients with progression but no evidence of BRAFV600 in their blood.

In conclusion, skin cancer is a frustrating foe. The super-high mutational burden of melanoma challenges targeted therapy with most of our efforts to date only removing fractions of tumor and selecting for cells that are immune to the targeted therapy. Unfortunately, our current testing for circulating fragments of tumor DNA only reliably identifies our treatment failures of the known variant. The absence of that signal of the known variant does not provide solace for our clinicians nor our patients. Still, there is promise that our surveillance for new variant tumor lineages may eventually be found circulating in the blood. That data may eventually guide the changes to individual treatment regimens. If we can get ahead of the variants through testing and new treatment regimens, we should be able to put this all behind us.

Digital ulcers (DUs) occurring secondary to systemic sclerosis (SSc) associated Raynaud’s and other connective tissue disease pose a high risk of tissue loss, infection, and digital auto-amputation. As such, DUs should be considered a medical emergency in dermatology, prompting rapid recognition and management to prevent permanent tissue loss in this patient population. A recent paper in Clinical Rheumatology compared the outcomes and cost effectiveness of two approaches to managing DUs in 26 patients with SSc: botulinum toxin-A (BTX-A) injections (received by 16 patients) and prostaglandin analog infusions (received by 10 patients) (2022. 41:95-104).

This paper found that both treatments were incredibly effective for the management of DUs with resolution of DUs in 95.5% and 90.5% of patients treated with BTX-A and prostaglandin analogues, respectively. Additionally, DU-associated pain was significantly decreased in both treatment groups (p<0.0001). However, the cost of prostaglandin analogue infusions was 15 times higher and more time consuming for patients and providers. BTX-A is readily available and commonly used in dermatology practices across the United States. A number of studies have now demonstrated the efficacy of BTX-A in helping to treat and manage severe Raynaud’s, and BTX-A is being used to treat Raynaud’s with increased frequency in autoimmune skin disease clinics across the United States. Although insurance approval continues to be a challenge, approval can be achieved on a majority of commercial plans following prior authorization. Dermatologists should consider the use of BTX-A in the treatment of severe Raynaud’s, particularly for high-risk patients with underlying connective tissue disease.

A quote from Confucius, “To know that we know that we know, and that we do not know what we do not know, that is true knowledge,” came to my mind after reading a retrospective study regarding clinical mimickers of calciphylaxis (J Am Acad Dermatol. 2021. 85(6):1520-7). I commonly tell my trainees that we have a biased view of our practices. Our patients have what we say they have. We celebrate our successes but lose track of our failures who oftentimes seek care elsewhere.

In this review of 119 calciphylaxis patients diagnosed between 2006 and 2018, 87 patients (73.1%) were initially misdiagnosed, leading to an increased median time from initial presentation to correct diagnosis of 33 versus 4.5 days. The most common misdiagnoses were cellulitis (31.0%), infection (8.0%), peripheral vascular disease (6.9%), hematoma (5.7%), and venous stasis (5.7%). Specialties rendering most of the misdiagnoses were emergency medicine (28.7%), primary care (18.4%), inpatient medicine (10.3%), and dermatology (8.0%). To be fair, early-stage disease may be as difficult to diagnose as it is to find clear answers with initial skin biopsies. Out of 103 patients with biopsies, only 39.5% demonstrated medial calcification within blood vessels.

Initial correct diagnosis was associated with end-stage renal disease (ESRD) and distal lesions. Patients with distal disease more commonly had ESRD (24/25 patients) versus those with proximal disease (67/94 patients).

Early diagnosis can decrease morbidity and avoid unnecessary treatments and procedures. Read this article — the clinical pearls to help distinguish the misdiagnoses from calciphylaxis will certainly come in handy!

Ideally, patch testing is conducted when the patient is not on immunosuppressants, not using topical immunosuppressives at the site of patch testing, and has not had a recent sunburn to the area of patch test application. These situations are felt to potentially suppress positive reactions and reduce patch-test accuracy; however, studies looking at the effects of immunosuppressive therapy are limited. An expert opinion by the North American Contact Dermatitis Group in 2012 suggested the following: topical corticosteroids should be avoided at the patch test site for 3-7 days; prednisone 10 mg or lower is acceptable but should be avoided if possible; intramuscular steroids 40 mg should be avoided for 4 weeks prior to patch testing; tumor necrosis factor alpha inhibitors, methotrexate, and ustekinumab likely have little to no effect on patch testing; there is a dose-dependent effect for azathioprine, cyclosporine, mycophenolate mofetil, and tacrolimus (Dermatitis. 2012. 23(6): 301-3).

A recent study looked at 16 studies comprising 195 patients who were patch tested while on immunosuppressants. Seven studies involved 85 patients who had patch testing done both before and during immunosuppression. Many immunosuppressant drugs, such as dupilumab, cyclosporine, and prednisone <10 mg/day, as well as TNF inhibitors, ustekinumab, and methotrexate, were associated with positive patch test results for numerous allergens. Dupilumab resulted in 10.4% of patch test allergens being lost after immunosuppression. No specific class of allergen was blocked in this review (Dermatitis. 2021. 32(6): 365-74).

This systematic review supports that strongly positive reactions are less likely to be lost when patch testing is conducted on immunosuppressive drugs. Patch testing is likely to still have some benefit to patients on immunosuppressive drugs especially dupilumab, cyclosporine, low-dose prednisone (<10 mg/day), TNF alpha inhibitors, ustekinumab, and methotrexate. Given the limited data regarding testing on and off immunosuppressives, the relevance of patch test results, and the strength of results, it is still ideal to patch test off immunosuppressants when able and at the lowest possible dose when immunosuppression is unavoidable. But this study shows that testing on immunosuppressant drugs can still provide useful information. The clinician must decide and discuss with the patient the risks and benefits of patch testing while on immunosuppressants and consider the possibility of incomplete or suppressed results.

Additional DermWorld Resources