1. Velykoredko, Yuliya
  2. Cecchini, Michael
  3. Tsoulis, David J.

Article Content


Scott, F. I., Mamtani, R., Brensinger, C. M., Haynes, K., Chiesa-Fuxench, Z. C., Zhang, J., [horizontal ellipsis] Lewis, J. D. (2016). Risk of nonmelanoma skin cancer associated with the use of immunosuppressant and biologic agents in patients with a history of autoimmune disease and nonmelanoma skin cancer. JAMA Dermatology, 152(2), 164-172.


Nonmelanoma skin cancers (NMSCs) are the most commonly diagnosed malignancies in the United States. A number of well-defined risk factors are linked to these cancers. Chief among them are sun exposure and skin phototype. Commonly used photosensitizing immunosuppressive drugs such as methotrexate and thiopurines (i.e., 6-mercaptopurine and azathioprine) can increase this risk. These have been associated with NMSC in the treatment of various diseases. Newer biologic therapies such as antitumor necrosis factor (anti-TNF) inhibitors have mixed associations with NMSC. Despite these known risks, there have been little data on the risk of developing subsequent NMSC while undergoing immunosuppressive therapy.


Scott and colleagues designed a retrospective cohort study to examine the risk of developing a second NMSC in patients with autoimmune conditions. They examined Medicare data for adult patients with rheumatoid arthritis (RA) or inflammatory bowel disease (IBD), who had been followed for 6 months before their first NMSC. The primary outcome of interest was the diagnosis of a subsequent NMSC at least 12 months after the incipient NMSC. The 12-month separation was to help ensure that the second event was unlikely to be related to the first NMSC. Avariety of confounders including demographics, latitudes, comorbidities, presence of actinic keratoses, and so forth were considered. As patients with RA and IBD are commonly treated with multiple immunosuppressants, comparisons were made between treatment regimens and variousdurations of therapy.


The study population included 6,672 patients with RA, 2,619 patients with IBD, and 169 patients with both RA and IBD (total = 9,640 patients). The incidence rate of a second NMSC was 58.2 per 1,000 person-years (95% CI [54.5, 62.1]) and 58.9 (95% CI [53.2, 65.2]) in patients with RA and IBD, respectively. Among patients with RA, methotrexate increased the risk of a second NMSC (HR = 1.60, 95% CI [1.08, 2.37]) in a pooled group of methotrexate with sulfasalazine/hydroxychloroquine versus sulfasalazine/hydroxychloroquine alone and methotrexate with anti-TNF versus anti-TNF alone. Furthermore, longer duration of methotrexate therapy was associated with increased NMSC risk with 2-3 years of therapy (HR = 1.36, 95% CI [1.05, 1.77]) and >3 years (HR = 1.59, 95% CI [1.09, 2.32]) compared with <1 year. With regard to biologics, rituximab and abatacept had no increased risk of subsequent NMSC. Anti-TNFs were associated with the development of a second NMSC in patients with RA if they were started before the first NMSC (compared with methotrexate monotherapy: HR = 1.49, 95% CI [1.03, 2.16]). In patients with IBD, thiopurines and anti-TNFs were not associated with a statistically significant increased subsequent NMSC risk in various comparisons.


REMARKS: This study showed an increased risk of a second NMSC in patients with RA receiving methotrexate and in those receiving anti-TNF inhibitors. This research is important because it is the largest cohort to examine the risk of NMSC recurrence in the setting of immunosuppressive therapy for IBD and RA. It is important to note that the findings of this study are not generalizable to other cancers, as the study only collected data on NMSC.


Limitations on the analysis include retrospective study design, use of claims-based data, small sample size for some therapies (rituximab, tocilizumab, abatacept, and leflunomide), and surveillance bias. That being said, this study emphasizes that the risk of NMSC is an important consideration in patients with previous NMSC starting immunosuppressive therapies. Moreover, it highlights the need for follow-up and monitoring for NMSC in patients who are immunosuppressed, especially in the setting of RA. Future studies should examine this relationship prospectively.



Gunaratne, D. A., Howle, J. R., & Veness, M. J. (2016). Sentinel lymph node biopsy in Merkel cell carcinoma: A 15-year institutional experience and statistical analysis of 721 reported cases. The British Journal of Dermatology, 174(2), 273-281.


Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that is more common in older White men with a propensity for lymphatic spread. Although distal lymph node involvement is rare in MCC, microscopic metastases to the regional lymph nodes are seen in 20%-50% of cases. Similar to other cancers, such as melanoma, the staging and management of this cancer involve a sentinel lymph node biopsy (SLNB). The sentinel lymph node is the first node to receive lymphatic drainage from the tumor. The latest American Joint Committee on Cancer guidelines published in 2010 advocate for the use of SLNB in MCC management. Although there is variability in individual management practices, the SLNB result helps determine the need for further surgery and adjuvant treatment such as radiotherapy. An important issue with performing an SLNB is the significant false-negative rate in MCC. The gaps in the current understanding of the accuracy and prognostication of SLNB in patients with MCC need further investigation.


Gunaratne and colleagues designed a study to examine the use of SLNB in MCC. They performed an extensive literature review along with their own single-institution case series of 29 patients. After MEDLINE and EMBASE searches, the authors identified 375 relevant studies published between 1997 and 2015, with only 36 of these included in the review. The inclusion criteria consisted of biopsy-confirmed Stage I or II MCC, a minimum of three cases of SLNB reported, and availability of follow-up information specifically pertaining to regional recurrence. The mean follow-up time was 32.4 months (9.6-61.5 months) per patient. There were 736 SLNBs in 721 patients because 15 patients had dual sites examined.


The major findings of the study highlighted that 218 of 736 (29.6%) cases had a positive SLNB. There were 518 of 736 (70.4%) negative SLNBs. In this group, regional nodal relapse occurred in 45 cases, making the false negative rate 17.1%, which is higher than previously documented in the literature.


The treatment differed between groups as 92.9% of SLNB-positive patients received surgery and/or radiotherapy compared with only 8.4% of SLNB-negative patients. Rates of regional nodal relapse were similar between SLNB-positive and SLNB-negative groups with rates of 11.2% and 8.7%, respectively (p = .16). The mean time to regional nodal disease after a negative SLNB was 10.3 months (interquartile range = 3-11.5 months). However, distal relapse was noted far more frequently after a positive rather than negative SLNB (17.5% vs. 7.3%, p < .001). In the subset of patients with a negative SLNB who underwent radiotherapy, the rate of regional recurrence did not vary between groups (14.3% with radiotherapy vs. 4.6% without radiotherapy, p = .31)


REMARKS: According to the authors, this study is the largest compilation of SLNB evaluation in MCC to date, and the large sample size is one of its strengths. The research shows that an SLNB is positive in 29.6% of patients but the false negative rate of 17.1% is higher than previously reported. Moreover, it is observed that an SLNB and subsequent treatment do not change regional lymph node recurrence but appear to impact distant spread. However, conclusions regarding these outcomes should be interpreted with caution because the study was not powered to detect a statistically significant difference between groups.


We must keep in mind that 42% of the overall cohort was from two large single-institution studies and institution-specific practices could be driving the result. The retrospective design along with the lack of a control group presents another limitation to the study. Other limitations include the possible heterogeneity in the SLNB technique, pathological analysis, variations in adjuvant therapy, and follow-up duration.


The prognostic value of SLNB in MCC remains controversial. Given the low incidence of this disease, randomized controlled trials in MCC are likely not feasible, and we have to rely on observational data to help guide management. Nodal evaluation will likely continue to have a role in Stage I and II MCC. It is unclear whether adjuvant radiotherapy or surgery is required in SLNB-negative MCC, and further studies are needed.



Nagler, A. R., Milam, E. C., & Orlow, S. J. (2016). The use of oral antibiotics before isotretinoin therapy in patients with acne. Journal of the American Academy of Dermatology, 74(2), 273-279.


Acne is a common and multifactorial disorder affecting a disproportionately high number of teenagers. The goal of treatment is resolution of lesions without scarring, as cosmetic and psychosocial morbidities are well-documented negative outcomes. Mild acne is often managed topically, whereas more severe forms require oral agents. Antibiotics help reduce the burden of Propionibacterium acnes and inflammation, but long-term use is associated with altered natural flora, increased risk of infections, and resistance. Isotretinoin is an oral retinoid that is effective for severe acne and is often reserved for nonresponders to antibiotics. Unfortunately, it is associated with prescribing challenges. Few studies have evaluated the duration of antibiotic use before initiating isotretinoin in patients with inflammatory or nodulocystic acne.


The purpose of this study was to evaluate the duration of oral antibiotic use in patients with acne who eventually required isotretinoin. The authors performed a retrospective chart review of acne diagnostic codes at a single dermatology site in the United States between 2005 and 2015. Patients were included if they were at least 12 years old, had a chart description consistent with inflammatory or nodulocystic acne, had or presented for least two documented visits, had antibiotic use for at least 30 days, and had isotretinoin use during the study period. Patients with exclusively comedonal acne, prior isotretinoin use, endocrinopathy, medications known to cause or exacerbate acne, or ineligibility for isotretinoin because of pregnancy or refusal to comply with iPLEDGE and those requiring antibiotics for another diagnosis were excluded. Patients who had started their antibiotics at another site were included if they could provide a full prescription history. The primary outcome was antibiotic duration before isotretinoin, which was determined by a review of prescription records.


Only 137 of the 5,053 charts met the inclusion criteria, of which 69 patients received antibiotic prescriptions exclusively at the study site whereas the remaining 68 received a portion of their treatment elsewhere. Minocycline and doxycycline were the two most commonly prescribed antibiotics. Some patients received multiple antibiotics. Those who initially received minocycline most often (45%) received azithromycin as a second-line option. Furthermore, 80% of those who initially received doxycycline subsequently received minocycline. The mean duration of total antibiotic use was 331.3 days (37-1501 days). Only 15.3% of patients used antibiotics for 3 months or less, whereas 64.2% and 33.6% of patients used antibiotics for at least 6 months and at least 1 year, respectively. The mean time elapsed between the first chart note regarding the possibility of isotretinoin use and the actual initiation of therapy was 155.8 days (0-258 days).


REMARKS: Although research suggests that courses of antibiotics lasting more than 6 months are likely to induce resistance, the results of this study show that most patients with acne were treated for at least 6 months. This exceeds the recommended 3-month course advocated by multiple expert groups worldwide. The authors propose that the observed elapsed time before the prescription of isotretinoin may be related to the stringent iPLEDGE requirements, concerns about potential side effects, and a lack of continuity of care between dermatology providers.


This study highlights that many patients receive and fail extended courses of antibiotics in the treatment of inflammatory or nodulocystic acne. It also emphasizes that identifying the patients who may require isotretinoin and prescribing it earlier may help decrease antibiotic resistance and improve acne outcomes.


Limitations to this retrospective study include a small number of charts that met inclusion criteria at a single site. Larger multicenter studies assessing length of antibiotic use and the time lapse before starting isotretinoin may provide further insight for the updating of acne guidelines.