Does methotrexate increase the risk of melanoma? The latest research gives the answer

*For medical professionals only

Influenced, and it seems to have no impact?

Methotrexate is believed to be familiar to
every rheumatologist.

Low-dose methotrexate has been widely used to treat immunomediated inflammatory diseases and is recommended as the mainstay of treatment for inflammatory arthritis, and can also be used to treat a variety of inflammatory skin diseases
.
Methotrexate exerts immunomodulatory effects
by inhibiting dihydrofolate reductase and thymidylate synthase, increasing extracellular adenosine, and inhibiting intracellular signaling pathways, including nuclear factor-kB and JAK-STAT pathways.

Figure 1 The article was published in JAMA Dermatology, however, a recent article published in JAMA Dermatology
revealed the link between methotrexate and the pathogenesis of melanoma[1].

The study found that individuals exposed to low-dose methotrexate had a 15%
increased risk of melanoma compared to individuals who were not exposed to low-dose methotrexate.
However, this risk may be negligible at the population level
.

Can methotrexate be associated with an increased risk of melanoma?

       

Melanoma is an aggressive skin cancer that spreads easily and is the most fatal of all skin cancers
.
In recent years, the incidence of melanoma has also increased
globally.
With the advancement of biologics and small molecule research and development, the cost of treatment for melanoma is also rising rapidly, and the huge public health and economic burden of melanoma highlights the need to identify high-risk individuals for surveillance
.

Despite decades of clinical use, some studies suggest that low-dose methotrexate may be associated
with an increased risk of skin cancer.
Observational studies have reported an association between melanoma and low-dose methotrexate, however, there is still a lack of high-quality evidence-based medical evidence
for this problem due to a number of unadjusted melanoma risk factors (UV exposure and personal and family history of melanoma).

It can be seen that a comprehensive determination of the melanoma risk associated with low-dose methotrexate is critical
for clinicians, especially rheumatologists who regularly use methotrexate.
To determine whether exposure to low-dose methotrexate is associated with a high risk of malignant melanoma, Professor E.
Wluka et al.
from Australia conducted a systematic review and meta-analysis
.

Compared to the unexposed group,

The exposure group was associated with a small increase in the risk of melanoma

       

After searching, screening, and deduplication, 17 studies were included, including 8 randomized controlled trials (RCTs), 5 cohort studies, 2 nested case-control studies, and 2 case-control studies, including 889799 participants, including 17513 melanoma patients
.

All but two RCTs included participants with active immune-mediated inflammatory disease and multiple intervention groups (i.
e.
, methotrexate vs methotrexate versus other immunomodulators used separately from other immunomodulators
).

Most RCTs have a short follow-up time, typically 1 to 2 years, of which melanoma events have a low rate but remain an adverse event
.
Most observational studies had longer follow-up and used the general population as a comparator
.

Professor E.
Wluka conducted a meta-analysis of 12 of these studies to examine the association between methotrexate and melanoma risk, and a total of 16,642 melanoma patients
were included.
The study found that exposure was associated with a small increase in the risk of melanoma (RR 1.
15, 95% CI 1.
08 to 1.
22) compared with no methotrexate use, with minimal
heterogeneity.
Figure 2 Forest map of the relative risk of melanoma in patients exposed to methotrexate versus those not exposed to methotrexate

Although it increases the risk of morbidity, the effect is minimal

       

To further determine the associated effects of other immunosuppressants with disease, Professor E.
Wluka next performed a subgroup analysis
.
The study found that although the combination of methotrexate and immunomodulators showed an increased risk of melanoma compared with immunomodulators alone, the relative risk was low (RR 1.
23, 95% CI 0.
56 to 2.
68).


Next, by comparing the effects of methotrexate monotherapy on another immunomodulator (azathioprine, JAK inhibitor, tumor necrosis factor-α inhibitor), they found an increased risk of melanoma treated with methotrexate, but also a lower relative risk (RR 1.
38, 95% CI 0.
48 to 3.
97
).

Figure 3 Effects of methotrexate and immunomodulators on
melanoma risk So how much does methotrexate use affect morbidity? The study calculated the number of melanoma need-to-harm (NNH) melanoma using melanoma incidence rates globally, North America, and Australia, respectively, with a corresponding absolute risk increase of 0.
0005%, 0.
002%, and 0.
005%,
respectively.
NNH: Refers to the average number of
patients who need to be exposed to some risk factor to cause harm.
The higher the NNH of a given drug or treatment, the lower
the risk factor for that drug or treatment.

summary

     

This systematic review and meta-analysis, which brought together 16,642 melanoma cases, found a 15%
increased risk of melanoma in individuals exposed to low-dose methotrexate compared with individuals who were not exposed to low-dose methotrexate.

However, the melanoma risk associated with methotrexate exposure does not appear to have a significant effect, and this risk may be negligible at the population level, even for people with a high incidence of melanoma
.

For example, NNH is greater than 18,000 in high-incidence areas such as Australia, and NNH is greater than 195,000
in global melanoma incidence.
Thus, although low-dose methotrexate may be associated with a higher risk of malignant melanoma, the true effects are negligible
.

Determining the carcinogenic potential of low-dose methotrexate is critical
for long-term care in patients with immune-mediated disease.
Large prospective studies of long-term follow-up of disease populations remain cutting-edge issues that rheumatologists need to focus on
.

References:

[1] Yan M K,Wang C,Wolfe R,et al.
Association Between Low-Dose Methotrexate Exposure and Melanoma:A Systematic Review and Meta-analysis[J].
JAMA Dermatol,2022.
DOI:10.
1001/jamadermatol.
2022.
3337.

Where to see more rheumatic medication knowledge? Come to the "doctor's station" to take a look at the source of this articleMedical Rheumatic Immunization Channel 👇
Fan Zhihua This article reviewChen Xinpeng Deputy Chief Physician Responsible Editor Tangerine
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