Some approaches have tried to quantitatively assess the severity of AK across an affected area, namely the AK Area and Severity Index (AKASI) developed in 2017 and focused on the head.24 This approach is based on other severity scoring systems in dermatology, the Psoriasis Area and Severity Index (PASI).
To calculate AKASI, 4 regions are first delimited, each assigned a weighting based on their relative size: scalp (40%), forehead (20%), left face (20%), and right face (20%). Within each region, the investigator calculates the percentage of the area affected by AK lesions, in a range from 1 (1%-9% affected area) to 6 (90%-100%). In parallel, the severity of 3 clinical signs of AK (distribution, erythema, and thickness) is assessed on a scale from 0 (none) to 4 (maximum). The area score and the sign scores are summed and multiplied by the area weight factor (eg, 20% = 0.2) to obtain an area total score. The 4 area scores are summed to obtain a total head score ranging from 0 (no AK) to 18 (most severe degree possible).
In our opinion, the AKASI fulfils the condition of taking a global look over the affected area because both the extent of AK and the severity of 3 clinical signs of AK are assessed within each area. This adds value to the classification as these aspects may also guide therapeutic decisions. It also attempts to quantify the characteristics of sun-damaged regions and it is not timeconsuming, making it is easy to use in routine clinical practice. In addition, the affected area is already perceived as FC through sight and palpation.
Still, the decision to treat an area with FC will rely not only on AKASI, but also on medical assessment and patient characteristics such as medical history (ie, previous iSCCs, presence of immunosuppression). Other limitations are the restriction to head lesions only, and the determination of the percent extent of AK within each area in a subjective way.
Also in 2017, and shortly after AKASI, the Actinic Keratosis Field Assessment Scale (AK-FAS) was developed to assess the severity of AK.27 This scale is outlined considering that most previous tools were established on counting AK lesions and were poorly reproducible. AK-FAS is based on 3 criteria: AK area, hyperkeratosis, and sun damage. AK area is the most important criterion in the scale and the key differentiator from previous tools.
Initially, the scale was validated on photographs of 12 patients and was based on a combination of the Olsen criteria and an assessment scale developed by the principal investigator. However, the proposed definitions were difficult to interpret consistently as many clinical presentations fell between grades. Therefore, the AK area was added, defined as the total skin surface affected by AK lesions (including non-visible, subclinical lesions) and expressed as a percentage of the total skin surface assessed. Depending on this percentage, a score from 0 (0% area affected) to IV (>50%) is assigned.
Originally, hyperkeratosis and sun damage in the area were labeled as either present or absent; but, again, preliminary testing showed that this label was subject to interpretation, leading to discrepancies during clinical assessment. In addition, sun damage was of little interest as it was invariably marked as "present". Therefore, in the current version of the scale, the AK area has been retained, and pre-defined criteria for presence/ absence of hyperkeratosis and sun damage have been added.27 The development path of this scale highlights the difficulty and inconsistency of AK-affected areas, especially regarding the presence or absence of hyperkeratosis.
Key endpoints for the management of AK: are the clinical trials endpoints consistent with those used in routine practice? Whether available classifications help to adequately define AK lesions, both in routine clinical practice and in clinical trials when assessing treatment outcomes, is still unclear. Reynolds and colleagues28 highlight in a recent consensus (including a final sample of 29 physician and patient stakeholders) the heterogeneity of safety and efficacy outcomes reported in clinical trials of AK treatments, which makes comparisons difficult. Accordingly, endpoints do not generally include the clinical classification systems, nor do they take into account aspects that defined some of their earlier versions (ie, presence/ absence of hyperkeratosis).
Outcomes for lesion improvement newly defined in Reynolds work that were 'more similar' to those established in previous clinical classifications were the: clearance of AK lesions (without further specification), progression to SCC, and number of clinically apparent AK lesions. However, of these, only complete clearance of AK lesions and percentage of AK lesions removed were voted among the key outcomes. This is a major problem as the classification systems are not being used to assess the efficacy of AK treatments in clinical trials.
The lack of consistency between clinical trials and standard practice endpoints in AK has a clear recent example with tirbanibulin. This drug was approved by the U.S. Food and Drug Administration (FDA) in December 2020, and in July 2021 the European Medicines Agency (EMA) approved marketing authorization for Klisyri® (Almirall), intended as a 5-day medicinal product for the treatment of AK on the face or scalp.
It is interesting to note that while the FDA specifies that tirbanibulin 1% ointment is "indicated for the topical treatment of actinic keratosis of the face or scalp",29 the EMA, on the other hand, opts for a different indication: "indicated for the field treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) of the face or scalp in adults".30,31 In
To calculate AKASI, 4 regions are first delimited, each assigned a weighting based on their relative size: scalp (40%), forehead (20%), left face (20%), and right face (20%). Within each region, the investigator calculates the percentage of the area affected by AK lesions, in a range from 1 (1%-9% affected area) to 6 (90%-100%). In parallel, the severity of 3 clinical signs of AK (distribution, erythema, and thickness) is assessed on a scale from 0 (none) to 4 (maximum). The area score and the sign scores are summed and multiplied by the area weight factor (eg, 20% = 0.2) to obtain an area total score. The 4 area scores are summed to obtain a total head score ranging from 0 (no AK) to 18 (most severe degree possible).
In our opinion, the AKASI fulfils the condition of taking a global look over the affected area because both the extent of AK and the severity of 3 clinical signs of AK are assessed within each area. This adds value to the classification as these aspects may also guide therapeutic decisions. It also attempts to quantify the characteristics of sun-damaged regions and it is not timeconsuming, making it is easy to use in routine clinical practice. In addition, the affected area is already perceived as FC through sight and palpation.
Still, the decision to treat an area with FC will rely not only on AKASI, but also on medical assessment and patient characteristics such as medical history (ie, previous iSCCs, presence of immunosuppression). Other limitations are the restriction to head lesions only, and the determination of the percent extent of AK within each area in a subjective way.
Also in 2017, and shortly after AKASI, the Actinic Keratosis Field Assessment Scale (AK-FAS) was developed to assess the severity of AK.27 This scale is outlined considering that most previous tools were established on counting AK lesions and were poorly reproducible. AK-FAS is based on 3 criteria: AK area, hyperkeratosis, and sun damage. AK area is the most important criterion in the scale and the key differentiator from previous tools.
Initially, the scale was validated on photographs of 12 patients and was based on a combination of the Olsen criteria and an assessment scale developed by the principal investigator. However, the proposed definitions were difficult to interpret consistently as many clinical presentations fell between grades. Therefore, the AK area was added, defined as the total skin surface affected by AK lesions (including non-visible, subclinical lesions) and expressed as a percentage of the total skin surface assessed. Depending on this percentage, a score from 0 (0% area affected) to IV (>50%) is assigned.
Originally, hyperkeratosis and sun damage in the area were labeled as either present or absent; but, again, preliminary testing showed that this label was subject to interpretation, leading to discrepancies during clinical assessment. In addition, sun damage was of little interest as it was invariably marked as "present". Therefore, in the current version of the scale, the AK area has been retained, and pre-defined criteria for presence/ absence of hyperkeratosis and sun damage have been added.27 The development path of this scale highlights the difficulty and inconsistency of AK-affected areas, especially regarding the presence or absence of hyperkeratosis.
Key endpoints for the management of AK: are the clinical trials endpoints consistent with those used in routine practice? Whether available classifications help to adequately define AK lesions, both in routine clinical practice and in clinical trials when assessing treatment outcomes, is still unclear. Reynolds and colleagues28 highlight in a recent consensus (including a final sample of 29 physician and patient stakeholders) the heterogeneity of safety and efficacy outcomes reported in clinical trials of AK treatments, which makes comparisons difficult. Accordingly, endpoints do not generally include the clinical classification systems, nor do they take into account aspects that defined some of their earlier versions (ie, presence/ absence of hyperkeratosis).
Outcomes for lesion improvement newly defined in Reynolds work that were 'more similar' to those established in previous clinical classifications were the: clearance of AK lesions (without further specification), progression to SCC, and number of clinically apparent AK lesions. However, of these, only complete clearance of AK lesions and percentage of AK lesions removed were voted among the key outcomes. This is a major problem as the classification systems are not being used to assess the efficacy of AK treatments in clinical trials.
The lack of consistency between clinical trials and standard practice endpoints in AK has a clear recent example with tirbanibulin. This drug was approved by the U.S. Food and Drug Administration (FDA) in December 2020, and in July 2021 the European Medicines Agency (EMA) approved marketing authorization for Klisyri® (Almirall), intended as a 5-day medicinal product for the treatment of AK on the face or scalp.
It is interesting to note that while the FDA specifies that tirbanibulin 1% ointment is "indicated for the topical treatment of actinic keratosis of the face or scalp",29 the EMA, on the other hand, opts for a different indication: "indicated for the field treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis (Olsen grade 1) of the face or scalp in adults".30,31 In
