Methotrexate and Isotretinoin: Can they be used together?
Methotrexate and Isotretinoin: What concerns exist when both are used together?
I’ve selected this question below for this week’s question of the week. It allows us to review some concepts related to the use of methotrexate and isotretinoin.
Question
I have been prescribed isotretinoin 10 mg three times weekly and methotrexate 15 mg once weekly for severe LPP that has not responded to most treatments. A few dermatologists were nervous about this treatment and even the pharmacist phoned my doctor about it. Is this something that you prescribe?
Answer
The answer is yes - but not routinely. These two medications have been used together to treat a variety of conditions but only when prescribed by an experienced practitioner and only when prescribed alongside appropriate counselling of the patient and appropriate monitoring.
But the short answer is yes - it is possible to use these.
The main concern here is that both drugs can irritate the liver and raise liver enzymes. Methotrexate is well known to be hepatotoxic.
Methotrexate and Isotretinoin can been used in combination for psoriasis, skin cancer (mycosis fungoides), and other skin issues such as keratosis lichenoides chronic and acne. So this is not a first.
On should take special note that in June of 1999, the US Food and Drug Administration (FDA) Advisory Panel decided to go ahead and slightly modify the package insert for methotrexate, issuing a precaution regarding the potential for increased hepatotoxicity (liver toxicity) when administered concurrently with retinoids (drugs like isotretinoin and acitretin). The FDA recommended “close monitoring of patients.”
One must not miss the fact that this change came more than 50 years after methotrexate was approved for the treatment of cancer. As some authors have pointed out this change from the FDA came without all that great of evidence, In fact, the FDA acknowledged that no formal study was performed, only that “hepatotoxicity was reported in such cases.” interestingly, the FDA did not provide references for these mentioned cases.
Searles et al 2011
In 2011, Searles and colleagues reviewed the published medical literature regarding whether methotrexate and retinoids (such as acitretin and etretinate) in combination were a problem in patients with psoriasis. They found that few cases were reported and in the case of a patient using etretinate - it was possible that the etretinate itself rather than the combination was the problem.
The authors state that “the contraindication in the acitretin package insert is not evidence-based and may discourage appropriate use of this combination therapy for patients who require it for severe psoriasis.
Conclusion
All in all, methotrexate and isotretinoin is not a treatment one should use without careful thought. But it certainly is possible to use provided the prescriber is experienced and proper monitoring is done. In other words, if the doctor knows what he or she is doing and is the doctor is willing to order lots of blood tests to keep close watch of liver enzymes - it can be a very helpful treatment for some patients.
Now, is is not a treatment that I might use in someone with risk factors for liver disease already including risk factors for what used to be called non alcoholic steataohepatitis. These include obesity, age, and diabetes. So patients with these risk factors and patients with alcohol use and not willing to do blood tests, this might not be a good combination.
I will require baseline blood tests for CBC, creatinine, cholesterol, triglycerides, hepatitis B, hepatitis C, and liver enzymes (AST, ALT, bilirubin), urinalysis (and possibly other tests) and then after starting I will perform close monitoring of AST, ALT, bilirubin, creatinine, urinalysis, cholesterol, triglycerides according to current guidelines.
REFERENCE
Woo YR, Lee HM, Lee JS, Koo DW. Long-term follow-up of refractory mycosis fungoides which achieved remission with the addision of isotretinoin to methotrexate and psoralen plus ultraviolat a therapy. Ann Dermatol. 2013 May;25(2):259-60. doi: 10.5021/ad.2013.25.2.259. Epub 2013 May 10.
Rodríguez-Lomba E, Molina-López I, Monteagudo-Sáez I, Suárez-Fernández R, Campos-Domínguez M. A case of acne fulminans with sacroiliitis successfully treated with methotrexate and isotretinoin. Dermatol Ther. 2016 Nov;29(6):476-478. doi: 10.1111/dth.12382. Epub 2016 Jun
Alvin W Li, William Damsky and Brett A King. Keratosis lichenoides chronica successfully treated with isotretinoin and methotrexate. JAAD Case Rep . 2017 Apr 14;3(3):205-207.
Alyssa D Searles, Andrew D Lee, Steven R Feldman. Is concomitant use of methotrexate and oral retinoids dangerous? A review of the data regarding this combination. J Am Acad Dermatol . 2011 Apr;64(4):791-3.