Pharmacovigilance: Ensuring Drug Safety for All

FDA Approval is Just “Step 1” in the Life of Drug or Treatment

Pharmacovigilance is a term that refers to all the steps that go into detecting, assessing, understanding, and preventing adverse effects from drugs.

Raptiva was FDA approved in 2003 only to be removed from the market 6 years later.

I’ve saved this pen with the logo of the drug Efalizumab (Raptiva) for more than a decade. Efalizumab was approved for the skin disease psoriasis in 2003 - 6 years later it was removed from the market.

For me, the pen is a reminder of the importance of pharmacovigilance. It’s a reminder that FDA approval does not mean a drug is completely safe - it just means it is reasonably safe based on the data that companies submit after completing necessary clinical trials. If a company studies the benefits of a certain drug in 2000 patients and submits data on outcomes of those 2000 patients to the FDA, the FDA might approve the drug. Whether the drug is going to have any unusual side effects or even cause death might not be completely known until treatments start happening out in offices, clinics and hospitals in the “real world.”

The FDA approval of Raptiva was based on initial studies in approximately 2,700 patients - most received the drug for only a few months. 

Fast forward 6 years to 2009, after over 46,000 patients had received efalizumab. The world came to learn that 3-4 patients developed a rare and serious disease known as progressive multifocal leukoencephalopathy (PML) after using Efalizumab. 3 died. The only way that these side effects came to be realized was through pharmacovigilance after the drug was released: doctors saw the side effect and reported it regardless of whether they felt it was truly linked or not. Over time, it became clear it was linked.

FDA approval is only step 1 for a drug. When a drug/treatment is released into the world after FDA approval, we do not know all of the drug’s side effects. Ongoing monitoring of safety is needed for all drugs. If a drug causes problems 10 years later but studies that were done lasted only 4 months, we are not going to learn about these side effects for many years. If a drug causes severe harm or death in 1 in 100,000 patients, these concerning side effects might not be uncovered in clinical trials that involve only a few thousand patients.

My pen is a precious reminder of the importance of pharmacovigilance. Every single year the FDA receives 350,000 to 400,000 reports about some side effect in some drug. Companies are now required to conduct good follow up studies and perform careful monitoring after a drug is released onto the market and can face penalties if such studies are not done.

Spironolactone for Hair Loss: Can it be prescribed for patients with prior breast cancer?

Is Spironolactone Safe to Use in Patients with a Prior Diagnosis of Breast Cancer? Does it affect the chance of Cancer Recurrence ?

A new study examined whether the anti androgen pill spironolactone is safe to use if someone had a previous diagnosis of breast cancer.

About three studies to date have suggested that spironolactone does not increase the risk of breast cancer. However studies to date have not examined if using spironolactone once a patient is diagnosed with breast cancer confers any increased risk.

Estrogen levels are slightly increased in about one quarter of breast cancer patients using spironolactone which raised the question whether use of this medication might have other effects - such as increase the risk of breast cancer coming back in a patient who was previously diagnosed and treated for breast cancer. Breast cancer coming back is known as a recurrence and can be local recurrence (breast cancer coming back in the breast), regional recurrence (breast cancer coming back in the lymph nodes) or distant recurrence (breast cancer coming back in another part of the body such as the bone).

Preliminary Study Suggests Good Safety in First 2 Years

A new study by Wei and colleagues examined whether spironolactone increases the risk of recurrence within 2 years after a diagnosis of breast cancer. 746 breast cancer patients who had been prescribed spironolactone were matched to 746 breast cancer patients in a large database who had never used spironolactone

Breast cancer recurrence occurred in 16.5% of those who received spironolactone compared with 15.8% of those who did not receive spironolactone; the difference was deemed not statistically significant. The authors concluded that spironolactone was an option for treating hair loss in patients with breast cancer.

This study is valuable as it provides a start to understanding the use of these medications in women with breast cancer. I was surprised to see such a high rate of recurrence in this study (15 % at year 2). Most studies in the breast cancer literature do not have such high rates of recurrence by year 2. For example, stage 1 breast cancer is the most common type of breast cancer and only a very small proportion of women have recurrences by year 2 (well under 5 %).

More Studies Needed To Evaluate Safety in Years 2-20

More studies are needed especially longer studies that take us to five years (and beyond). Although recurrence risk is highest at 2 years (which was the cut off the authors of this study chose) well over 50 % of patients who are going to actually have a recurrence will have their recurrence beyond year two. For example, in some studies the median time is about 3 years meaning that one half of patients who are going to have a recurrence will have a recurrence after year 3 and one half will have a recurrence before year 3. We know the risk of recurrence is greatest in the first two years but most women are carefully followed for five years to evaluate for early recurrence. Five years is traditionally used in oncology as the benchmark not two years. 

The chance of recurrence between years 2 and 5 is not insignificant and 20 % of recurrences occur between year 5 and 20. So longer term studies are absolutely needed. In addition, factors such as size of the tumor, pathology of the cancer, and the presence or absence of lymph node involvement all affect recurrence risk. Therefore detailed studies of high risk vs low risk patients is needed. We know that women with younger age, advanced stages, negative hormone receptor status, and poorly differentiated tumor cells experienced the greatest hazard for recurrence. Hopefully, larger and longer term studies will build on the important initial observations by these authors.

Reference

Wei C, et al. Published online May 21, 2020. J Am Acad Dermatol.

Finasteride vs Spironolactone for Female Androgenetic Alopecia: How do side effects compare?

Comparison of Side Effects of Finasteride and Spironolactone For Women

Androgenetic alopecia (AGA), also called female pattern hair loss, is common among women. By age 50, about 40 % of women will have AGA. Treatments include minoxidil, anti androgens, oral contraceptives, laser, PRP, hair transplantation, as well as others. Minoxidil remains the only formally FDA approved treatment.

There are no FDA approved anti androgens for treating female AGA although many are used off label in treating this type of hair loss.  The evidence would suggest that anti-androgens are potentially the most consistently effective treatments. The antiandrogens finasteride and spironolactone are among the most commonly prescribed antiandrogens for treating female AGA. Dutasteride, bicalutamide, flutamide and cyproterone acetate are less commonly prescribed.

Finasteride vs Spironolactone: What are the side effects and how to they compare?

This article will focus on the side effects of spironolactone and finasteride. It is important for both prescribers as well as users of these medications to understand the risks and benefits of these medications before committing to use. The use of antiandrogens is lifelong when treating AGA. These medications can be helpful for treating AGA but are not appropriate for every female patent with AGA. The risks and benefits must be carefully reviewed. All anti androgens are contraindicated during pregnancy and also by any female patient who may become pregnant or is trying to conceive. Antiandrogens have the potential to cause serious harm to a developing fetus.

There have been studies of both finasteride in treating AGA and spironolactone in treating AGA. For Spironolactone, the vast majority of our understanding of side effects comes from understanding the side effects that this medication causes in women who use the medication for acne and hirsutism. There have been no good side by side comparative studies of finasteride and spironolactone in treating AGA.

Overall, studies would suggest that finasteride probably has fewer overall side effects which contributes to its discontinuation rate being lower. However, there are many reasons that physicians may choose spironolactone over finasteride, especially in premenopausal women.

1. Overall side effect rates, Discontinuation Rates and Effectiveness

2. Non specific Effects Spironolactone vs Finasteride among Female Users

3. Specific side Effects Spironolactone vs Finasteride among Female Users

4. Side Effects Related to Breast Health

5. Laboratory Changes among Female Finasteride and Spironolactone Users.

6. Dermatological Side Effects among Female Spironolactone and Finasteride Users.

Summary and Conclusion

One must understand the risks and benefits of finasteride and spironolactone if use of these medications is being considered. These medications remain options for female patients with androgenetic alopecia. A careful review of side effects with one’s physician is essential in all individuals considering these medications. There are clearly certain situations where one medication might be preferred over the other. For example, given the effects on blood pressure, the use of finasteride is often preferred in patients with issues with problematic low blood pressure.

Many of the side effects listed above improve over time. Trueb and colleagues showed showed that finateride side effects decrease over time. This incluces side effects such as libido reduction, breast tenderness, or hypertrichosis/hirsutism decrease over time. Probably, there are some adaptative hormonal changes in brain-hormonal axis or in brain perception that lead to these side effects being less and less noticed.

References

Donovan J. Spironolactone in Female AGA

Donovan J. Bicalutamide for Female AGA

Donovan J. Finasteride Use in Women: Yes or No?

Donovan J. Flutamide in Women who Don’t Respond to Spironolactone

Goodfellow A. Oral Spironolactone Improves Acne Vulgaris and Reduces Sebum Excretion.Br J Dermatol 1984 Aug;111(2):209-14.

Helfer EL et al. Side-effects of spironolactone therapy in the hirsute woman.J Clin Endocrinol Metab. 1988 Jan;66(1):208-11. doi: 10.1210/jcem-66-1-208.PMID: 3335604

Hu et al. The Efficacy and Use of Finasteride in Women: A Systematic Review. Int J Dermatol. 2019 Jul;58(7):759-776.

Hughes BR, Cunliffe W. Tolerance of spironolactone. Br J Dermatol. 1988 May;118(5):687-91. doi: 10.1111/j.1365-2133.1988.tb02571.x.PMID: 2969259

Kohler C, Tschumi K, Bodmer C, et al. Effect of finasteride 5mg (Proscar) on acne and alopecia in female patients with 72. normal serum levels of free testosterone. Gynecol Endocrinol. 2007;23:142–145.

Oliveira-Soares R, et al.  5 mg/day for Patterned Hair Loss in Premenopausal Women.Int J Trichology. 2018 Jan-Feb;10(1):48-50. doi: 10.4103/ijt.ijt_73_15. 

Plovanich M et al.. Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatol. 2015 Sep;151(9):941-4. doi: 10.1001/jamadermatol.2015.34.

Seale LR, Eglini AN, McMichael AJ. Side Effects Related to 5 α-Reductase Inhibitor Treatment of Hair Loss in Women: A Review. J Drugs Dermatol  2016 Apr;15(4):414-9.

Shaw JC, White LE.  Long-term safety of spironolactone in acne: results of an 8-year followup study. J Cutan Med Surg. 2002 Nov-Dec;6(6):541-5. doi: 10.1007/s10227-001-0152-4. Epub 2002 Sep 12.PMID: 12219252

Townsend KA, Marlowe KF. Relative safety and efficacy of finasteride for treatment of hirsutism. Ann Pharmacother. 2004 Jun;38(6):1070-3.

Trüeb RM, Swiss Trichology Study Group. Finasteride treatment of patterned hair loss in normoandrogenic postmenopausal women. Dermatology 2004;209:202-7.  

Yemisci A et al. Effects and side-effects of spironolactone therapy in women with acne. J Eur Acad Dermatol Venereol. 2005 Mar;19(2):163-6. doi: 10.1111/j.1468-3083.2005.01072.x.PMID: 15752283

Manuka Honey for Treating Folliculitis Decalvans

Antibacterial Properties of Manuka Honey May Provide Benefits in Treating Folliculitis Decalvans

Folliculitis decalvans (FD) is a scarring alopecia that affects both men and women. FD is less common than some of the other  scarring alopecias like lichen  planopilaris and central centrifugal cicatricial  alopecia. The cause of FD is not completely know although a  role for bacteria has been postulated.   Bacteria such as Staphylococcus aureus frequently are found in the scalp of patients with folliculitis decalvans. Eradication  of bacteria with antibiotics, isotretinoin and other treatments frequently is associated with improvement of the disease.

A preliminary report proposes that Manuka honey may have benefits in the treatment of folliculitis decalvans

In 2019, a dermatology group in  Boston reported a patient with folliculitis decalvans whose disease improved with use of topical Manuka honey applied to the scalp. Manuka honeyis well known to wound care professionals. In fact, 17 clinical trial s involving  almost 2000 patients have suggested Manuka honey helps wounds heal.  Manuka honey has antibacterial properties – perhaps  due to its low pH, and other  plant  based and hydrogen peroxide based ingredients. A 1999 paper by Cooper and  colleagues showed that  Manuka honey killed  Staph aureus bacteria in wounds. 

The patient in the 2019 paper was a 20 year old male who had used a considerable number of  treatment before he started applying manuka honey to his scalp. These treatments included steroid injections,  clobetasol lotion, prednisone, minocycline, doxycycline and isotretinoin. Some of these treatments were actually  quite helpful for the young man – however he had to  stop because of some side effects of these treatment.  

The  patient decided to start applying Manuka honey  to his scalp after about 1 month into a course of the oral antibiotic cephalexin. As he continued on both cephalexin and topical honey and found that after an additional 4 weeks of both treatments the scalp had improved considerably. 6 months later he stopped cephalexin. His disease eventually flared again and the man used honey alone to settle down his disease. 

Summary/Conclusion

This is an interesting paper. It doesn’t definitively prove Manuka honey helps FD but it hints that it might have a role. We also can’t rule out that the patients long term use of antibiotics and other treatments (like steroids) and isotretinoin have reduced disease activity that makes Manuka honey more likely to help. Nevertheless, this is an interesting paper that hopefully fuel more research in manuka honey.

Reference

Yeh et al. Resolution of folliculitis decalvans with medical honey. Dermatology Online Journal 2019;. 25(8); 

Bicalutamide for Female Pattern Hair Loss: Should we add it to the list of anti androgens ?

Bicalutamide (Casodex) is pure anti-androgen with Potential Benefit in Treating Female Androgenetic Alopecia

Bicalutamide is a non-steroidal pure anti androgen that was FDA approved for treating prostate cancer at a dose of 50 mg daily back in 1995. Recent studies have investigated its use in treating female androgenetic alopecia.

STUDY 1: Ismail and colleagues, 2020

Dr. Rodney Sinclair’s group from Australia (Ismail and colleagues, 2020) performed a retrospective review of 316 women treated with bicalutamide. The standard starting dose was 10 mg daily although starting doses ranged from 5 mg to 50 mg in the study. The average age of patients was 49 years with a range of 15-85 years. In the study bicalutamide was usually prescribed together with some other medication including oral minoxidil in 308 patients and spironolactone in 172 patients. Six patients received bicalutamide alone (i.e. monotherapy). The most common adverse effect was mild elevation of liver transaminases in 9 (2.85%) patients. This elevation was mild in all cases (less than twice the upper limit of normal) and asymptomatic in all cases as well.. Furthermore, the liver enzyme elevation resolved without needing to adjust the dose in 4 out of 9 patients. In 2 patients, the transaminitis resolved with further dose reduction. Other side effects bicalutamide in the study included peripheral edema in 2.5 % of patients and gastrointestinal complaints in 1.9 %. Use of bicalutamide provided benefit in the treatment of AGA in women.

STUDY 2: Fernandez-Nieto and colleagues, 2020

Dr. Sergio Vano Galvan’s group from Spain (Fernandez-Nieto et al. 2020) recently published their data of 44 women receiving bicalutamide at doses of 25-50 mg daily. The ages of patients in this study were 20-59 with an average age of 34.8 years. The authors chose higher doses than Sinclair’s group for the simple reason that higher doses of bicalutamide are already commonly used in treating hirsutism. Side effects in this particular study included transient elevation in liver enzymes with 5 of 44 (11.4%) patients having a mild increase liver enzymes - all of which self resolved without a need to stop the drug. In addition to elevated liver enzymes, other reported side effects including were shedding, amenorrhea, headaches and endometrial hyperplasia. None of the patients needed to stop treatment. Similar to the Ismail et al study mentioned above, use of bicalutamide in this study also provided benefit in the treatment of AGA in women.

COMMENTS

These are interesting studies and I suspect we’ll be hearing a lot more about bicalutamide in the years to come. I’ve been using it for a few years now and was encouraged to see some good data here with regard to side effect profile and generally good safety. Bicalutamide has fewer side effects than flutamide, another non stereoidal anti androgen (NSAA) and in general the side effects profile is acceptable when compared to the 2 other commonly used antiandrogens we use for treating androgenetic alopecia - spironolactone and finasteride. Further studies are needed to understand how bicalutamide compares to finasteride and spironolactone and what of side effects we might need to counsel our female patients.

Reference

Ismail et al. Safety of oral bicalutamide in female pattern hair loss: a retrospective review of 316 patients. Journal of the American Academy of Dermatology. Available online 19 April 2020

Fernadez-Nieto Et al. BICALUTAMIDE: A POTENTIAL NEW ORAL ANTIANDROGENIC DRUG FOR FEMALE PATTERN HAIR LOSS.J Am Acad Dermatol. 2020 Apr 19:S0190-9622(20)30667-8. doi: 10.1016/j.jaad.2020.04.054. Online ahead of print.

Topical tretnoin for Alopecia Areata: Is it still on the list?

Topical Tretinoin 0.05 % Cream May Help Some with Limited Alopecia Areata

Alopecia areata is an autoimmune disease that affects 2 % of patients. There are well over 2 dozen treatments available

More than Shots: The 30 Treatment Options for Alopecia Areata

Topical options are often viewed as safer than systemic options (pills) because the body gets exposed to less medication. Topical treatment options include: Topical steroids, Topical bimatoprost, Essential oils, Anthralin, Squaric acid, Diphencyprone, Minoxidil, Topical tofacitinib, Topical ruxolitinib, Onion juice, Garlic gels, Topical capsaicin and Topical retinoids

Treatments for alopecia are generally of three main types

1) those treatments that reduce inflammation around the hairs so the hairs can grow. Examples include topical steroids and topical tofacitinib.

2) those treatments that simply stimulate hair growth so that hairs can push through the skin and keep growing despite their inflammation. These options may also reduce inflammation as well. Examples include minoxidil and low level laser.

3) those treatments that cause inflammation somewhere else such as the surface of the skin layer so that inflammation gets slowly reduced from around the follicles. A variety of treatments fall into the third category include anthralin, Diphencyprone, squaric acid and tretinoin.

Use of Tretinoin in Treating AA

Today we’ll focus on the use of tretinoin in treating alopecia areata.

Tretinoin is a type of vitamin A. It is used as an acne treatment and as an anti-aging treatment and has been available to patients since the early 1970s. Several studies to date have suggested that tretinoin may have some benefit in the treatment of alopecia areata. It is not effective for everyone and is likely less effective than standard treatments like topical steroids, steroid injections and the oral immunosuppressants. But a small handful of studies suggest that it’s an option to be considered.

STUDY 1: Das and colleagues, 2010

In 2010, Das and colleagues published a study of 80 patients that sought to compare the benefits of 3 treatments, namely a strong topical steroid known as betamethasone diproprionate, tretinoin 0.05 % and anthralin paste 0.25% in the treatment of limited alopecia areata. A placebo group was also included in the study bringing the total number of study groups to four. Treatments were applied twice daily. Patients with alopecia areata in this study had more limited disease and could only be included in the study in their patches were less than 5 cm in diameter and if they had less than 5 patches in total. Results of the study showed that 70 % of patients received topical steroids had an improvement compared to 55 % with tretinoin, 35 % with anthralin and 20 % with placebo.

STUDY 2: Hussein 2020

In 2020, Hussein performed a study comparing the benefits of betamethsone diproprionate topical steroid to tretinoin 0.05% in 50 patients with limited alopecia areata. Treatments were applied twice daily. Similar to the 2010 Das study, patients could only be included in the study if they had less than 5 patches and if they had less than 25 % scalp involvement. After 12 weeks, 72 % of patients receiving the topical steroid had statistically significant clinical improvement compared to 36 % receiving tretinoin 0.05%.

STUDY 3: Kubeyinje and Mathur, 1997

A 1997 study showed that use of tretinoin in patients receiving steroid injections could have added benefit. The authors of the study evaluated the efficacy and safety of 0.05% tretinoin cream as an adjunctive therapy or ‘add on’ treatment with intralesional triamcinolone acetonide in aiopecia areata, by comparing the result of treatment with monthly intralesional triamcinolone acetone and daily application of 0.05% tretinoin cream in 28 patients with alopecia areata with 30 similar patients treated with only monthly intralesional triamcinolone acetonide as controls. Results at 4 months showed more than 90% regrowth in 85.7% of patients on triamcinolone acetonide and tretinoin cream, as compared with 66.7% of patients receiving only triamcinoione acetonide.

STUDY 4: Much, 1976

A 1976 study was among the first published studies to show benefits of tretinoin in treating alopecia areata.

Conclusion and Summary Points

With specific treatments like JAK inhibitors and others, the future of alopecia areata is bright. However, it is critically essential that we not forget our past and where we have come from over many decades of study. Physicians treating alopecia areata must appreciate that role of very simple and relatively inexpensive treatments and the large number of patients with limited alopecia areata they may potentially help. Tretinoin is on that list of simple treatments. Tretinoin is a topical treatment that certainly does not help everyone but may have a role in patients with more limited disease. In patients of mine with a few patches who can not tolerate minoxidil or who can not tolerate steroids, tretinoin remains an option.

We use tretinoin with several treatment including 1) tretinoin with topical minoxidil, 2) tretinoin with topical steroids, 3) tretinoin with steroid injections and 4) tretinoin with diphenyprone or squaric acid. 

Side effects including redness and irritation and that is in fact the reason that typically use it in alopecia areata. In other words, it is a side effect but not a concerning one as that is in fact that desired effect. We ask patients to keep close follow up with our office so that we can assist them in finding the right dose that works for them. Some need use daily, some twice weekly and some just 2-3 times per week. Tretinoin must not be used during pregnancy. 

When used alone, I may prescribe tretinoin daily to start  and then increase to twice daily. When used in conjunction with other treatments, we often start tretinoin 2-3 times weekly for a few weeks and then increase to 4 times weekly and then five times weekly and then six times weekly and finally using it daily. 

REFERENCE

Baird KA. Alopecia areata. Arch Dermatol. 1971;104:562-3.

Das et al. COMPARATIVE ASSESSMENT OF TOPICAL STEROIDS, TOPICAL TRETENOIN (0.05%) AND DITHRANOL PASTE IN ALOPECIA AREATA. Indian J Dermatol. 2010 Apr-Jun; 55(2): 148–149. 

Hussein AA. A comparative study of the outcomes of potent topical steroids versus topical tretinoin in patchy alopecia areata of scalp. Int J Res Dermatol. 2020 Jan;6(1):111-114

Kubeyinje EP, C'Mathur M. Topical Tretinoin as an Adjunctive Therapy With Intralesional Triamcinolone Acetonide for Alopecia Areata. Clinical Experience in Northern Saudi Arabia. Int J DermatolJ Dermatol. 1997 Apr;36(4):320

Much T. Treatment of alopecia areata with vitamin A acid. Z Hautkr, 51 (1976), pp. 993-998

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Alopecia Totalis and Alopecia Universalis: How long will I be on treatment?

How long is the treatment for alopecia totalis and universalis?

Alopecia areata is an autoimmune disease that affects nearly 2 % of the world. I’m often asked by patients, as well as doctors, exactly how long patients with alopecia areata will need treatment. This question is especially relevant for patents with more advanced forms of alopecia such as alopecia totalis and alopecia universalis. How long will they need treatment? We’ll take a look together why this answer is different for different types of alopecia areata. The key point of this article is that the potential length of expected treatment must be clearly discussed with patients. Patients with advanced forms often need long term treatment for many years and many will require lifelong treatment. This is of course, until better treatments arrive.

Alopecia Totalis and Universalis: Severe Forms of AA

First, what is alopecia totalis and universalis? These are both advanced forms of alopecia areata. Alopecia totalis refers to a situation whereby the patient does not have any scalp hair, although eyebrows, eyelashes and body hair may be present to various degrees. Alopecia universalis refers to the form of alopecia areata whereby the affected individual does not have any scalp hair and does not have eyebrow, eyelash and body hair either.

The important thing to understand as we talk about alopecia totalis and universalis is that these are more severe forms of these conditions. They are very different than so called ‘patchy’ alopecia areata whereby a patient experiences several patches of hair loss. Patchy alopecia can regrow on its own and often regrows with treatment. Once hair fully regrows in patchy alopecia areeata, treatments can generally be stopped without worry that there will be an immediate loss of hair. Now of course there can be hair loss at any time in the future for any patient with alopecia areata. But chances of hair loss with the next short period is rare in alopecia areata that has grown back.

Treatment for mild AA is usually short term; Treatment for severe AA is usually long term

Treatment duration for patents with mild forms of alopecia areata is generally short term. A patient with a single patch of alopecia might use a cream or lotion for a few months or get steroid injections … but hair is likely to regrow. Once the hair regrows, treatment can be stopped without a high likelihood that the disease will come back in that area

There is no definitive answer or prediction about whether or not long term treatment will be needed, simply a scale of how likely it will be that long term treatment is needed. For patients with alopecia areata unilocularis it is highly likely that short term treatment is all that will be needed. For patents with severe alopecia areata (alopecia totalis and alopecia universalis) it is highly likely that long term treatment will be needed.

Counselling Patients with Alopecia Areata: What should they be told?

Regardless of what analogy or chart or graph or statistic one wants to use, the basic message is always the same. Alopecia areata in mild forms is more likely to only require short term treatments and alopecia areata in severe forms is more likely to require long term treatments. It must always be kept in mind that many patients with alopecia totalis and universalis will require lifelong treatment. Attempts to stop medications or reduce doses can sometimes be associated with hair loss. Delphine Anuset et al studied 26 patients with advanced alopecia areata who were treatment with methotrexate and oral steroids. About 60 % of patients had total regrowth. After stopping treatments, 73 % of these patients experienced loss of hair (relapse).

References

Delphine Anuset et al. Efficacy and Safety of Methotrexate Combined With Low- To Moderate-Dose Corticosteroids for Severe Alopecia Areata. Dermatology. 2016.

S C Gordon et al. Rebound Effect Associated With JAK Inhibitor Use in the Treatment of Alopecia Areata. J Eur Acad Dermatol Venereol. 2019 Apr.

What are the types of alopecia areata?

Many Different Forms of Alopecia Areata

Alopecia areata is an autoimmune disease that causes hair loss. There are many different forms of the condition although most affected people experience ‘patchy’ alopecia areata whereby 1 or more patches develop on the scalp. When just a single patch develops, the term alopecia areata uniloculiaris is used. When 2 or more patches develop, we use the term alopecia areata multilocularis.

Together, most patients with alopecia areata unilocularis and multilocularis are classifed as having mild disease which means that less than 25 % of hair has been lost from the scalp. Overall, about 30% of patients with alopecia area will experience moderate and severe forms and many will still experienced regrowth with treatment.

How common are mild moderate and severe forms of AA?

Out of every 100 patients who develop alopecia areata, about 2/3 will regrow hair back spontaneously by 1 year. About 40 % of these are individuals with alopecia areata unilocularis and 27 % are multilocularis. About 33 % of patients with alopecia areata will not experience spontaneous regrowth by the end of the first year. These include patients with alopecai totals (AT), alopecia universals (AU) and patients with relapsing alopecia areata (RR).

Can I Use Minoxidil When My Lichen Planopilaris (LPP) is Active?

Using Minoxidil in Cases of Active Lichen Planopilaris (LPP)

I’m often asked if minoxidil can be used for patients who have active scarring alopecia. The answer really depends on the patient and other specific details. Before we tackle the question, we need to take a look at what constitutes ‘active’ scarring alopecia.

What is active scarring alopecia?

Active scarring alopecia refers to hair loss caused by an overactive immune system process. The patient may have scalp itching, have increased scalp burning and may be shedding more and more hair. All of these things point to active scarring alopecia. What do we do when scarring alopecia is deemed active? Well, we increased the amount of immunosuppressive and immunomodulatory treatments we are using.

Here are just come examples of how we change treatment is we feel LPP is active

Example 1: instead of using steroid injections, we might use steroid injections AND topical steroids.

Example 2: Instead of using topical steroids, we might ADD oral doxycycline.

Example 3: Instead of using oral doxycycline, and topical steroids, a patient might be started on oral doxycycline PLUS oral hydroxychoroquine

In other words, once the LPP is determined to be active (or still active) we are going to make some pretty important decisions about increasing treatment. These are indeed big decisions because treatments have potential side effects, cost money

What is are the potential side effects of minoxidil?

Now , let’s focus on minoxidil and the potential side effects. In addition to side effects like headaches, dizziness and heart palpitations and hair growth on the face, minoxidil can cause two important side effects for patients with scarring alopecia: 1) Minoxidil can cause increased hair shedding and 2) Minoxidil can cause scalp itching for some people. These two side effects can make it difficult to figure out if the itching and shedding are coming from the active LPP or coming from the minoxidil.

So can I use minoxidil if I have LPP or not?

I always advise that patients review use of any medication with their dermatologist. In general, if a patient was using minoxidil for a very long time (without any problem) before the LPP even started, it’s usually fine to continue. In these situations, it’s unlikely any increased shedding or scalp symptoms the patient experiences is going to be attributable to the minoxidil. But starting up or initiating the use of minoxidil when one has active LPP is active is not usually a good idea. If the patient gets more shedding or more scalp symptoms, it will impossible to tell if they are coming from active LPP or coming from the minoxidil. In the worse case scenario, one can imagine a situation where the doctor increases the dose of medications thinking that the change in clinical symptoms or signs was due to increased activity of the LPP when really it was just the minoxidil. Imagine if the patient developed a side effect of the new mediation - and it never needed to be started in the first place.

Delivering More Minoxidil to Hair Follicles: What's possible and what possibly helps?

How can I deliver more minoxidil to my hair follicles?

Topical 2 and 5 % Minoxidil are FDA approved and Health Canada approved for treating androgenetic alopecia. The drug does not help everyone but certainly helps a proportion of users. Given the benefits of minoxidil, there is a tremendous interest in understanding how best to delivery the minoxidil down into the scalp so that hair follicles can use it to stimulate their growth.

In this article, we’ll take a look at 5 methods to deliver more minoxidil to follicles as well as the challenges and limitations associated with these methods.

1. Use the same amount and same concentration of minoxidil and use it with the same frequency…. but apply it properly. 

There’s a bit of a learning curve to applying minoxidil and some people just don’t apply it correctly. Minoxidil probably absorbs better when applied after the scalp is washed and is still a bit warm. But clearly this is impractical for everyone as many do not shampoo daily and many who do like to apply minoxidil at night and shampoo the hair clean in the morning.  Despite this, it’s probably more important to remember to apply the minoxidil every day that fuss about when to apply it and how clean the hair is.

Regardless of how it’s applied, the minoxidil needs to get on the skin of the scalp so it can begin its journey into the scalp. Getting minoxidil on the hair shafts does not help. Similarly, if there is a great deal of gunk blocking the scalp surface, it becomes more difficult for minoxidil to penetrate the scalp. Gunk includes excessive amounts of gel, oils and hair fibers.

2. Use the same concentration of minoxidil, but use more of it... or use it more often.

For some patients, using more minoxidil allows more to get into the scalp. This is especially true for males using minoxidil and may be true for some women as well. It’s clear that using 5 % minoxidil twice daily is better when treating male pattern balding than using 5 % minoxidil once daily. For some women - but not all - this may be true too. The downside of using more minoxidil is a greater chance of side effects. The chance of headaches, dizziness, and hair on the face all increase as the amount of minoxidil increases.

3. Expose the hairs to higher concentrations of topical minoxidil

Theoretically, using higher concentrations of minoxidil may help more get into the scalp. Studies that support the ideal minoxidil concentration are few and far between. In fact, one study suggested surprisingly that 5 % minoxidil was more effective than 10 %. Researchers from Egypt set out to compare the efficacy and safety of 5% topical minoxidil with 10% topical minoxidil and placebo in 90 males with balding. Surprisingly, after the 9 months, partipcants in the 5 % minoxidil group had higher vertex and frontal hair counts compared to study participants in the 10 % minoxidil group and the placebo group. Clearly, we still have a lot to learn and a long way to go. Higher concentrations of minoxidil are not necessarily better.

4. Compound the minoxidil with different topical agents or via other drug delivery strategies to allow minoxidil to penetrate the scalp better.

There is a major interest in the hair research community to figure out how best to get minoxidil into the scalp. Different vehicles, use of so called nanoparticles as well as other techniques are the focus of many studies. 

It’s also clear that use of adjuvants like retinoids can help make minoxidil more effective. Before we look at this concept further, it’s important to understand a few concepts. In order for minoxidil to do it’s job, it needs to be converted to minoxidil sulphate. Hair follicles have the machinery to help with this but some people’s hair follicles are not really that good at it. Scientifically, we say that some people’s hair follicles lack high levels of an enzyme known as “sulfotransferase” and so they cannot convert minoxidil into the active form that actually does all the work.  (The public does not yet have minoxidil sulfotransferase testing kits available to them but this technology may be coming at some point in the near future.) For year now, it has been known that mixing retinoids with minoxidil makes minoxidil work better. It has long been thought that retinoids irritate the scalp and somehow by doing so allow minoxidil to get into the scalp. Now, based on interesting work published by Sharma and colleagues in 2019 it’s realized that retinoids upregulate the minoxidil sulfotransferase enzyme and by doing so help generate greater amounts of active minoxidil sulphate in the scalp.

The use of derma rolling may be yet another strategy to get more minoxidil into the scalp. Scalp Micro-needling" (dermrolling) is a technique whereby a controlled injury is created in the scalp. Skin injury (at least in some situations) can stimulate the production of growth factors and inflammatory cytokines that promote skin healing and possibly hair growth. A "dermaroller" is one such device to cause controlled injury. A dermaroller consists of teeth of different lengths that are attached to a wheel. Dermarollers of 0.5 mm, 1 mm, 1.5 mm are common. These are "rolled" back and forth across the skin to create redness. A 2013 study of 100 patients supports benefit of dermarolling. The study set out to determine in patients who use topical minoxidil (Rogaine, etc) could achieve even further benefit by dermarolling. In the study, half the patients received daily minoxidil and the other half of the patients received weekly dermarolling sessions (using a 1.5 mm dermaroller) in addition to minoxidil treatment. Results showed that patients using a dermaroller achieved greater benefits than those using minoxidil alone. Specifically, 82 % of patients receiving dermarolling felt they achieved greater than a 50 % benefit in their hair compared to just 4.5 % receiving minoxidil alone. Physicians rated the improvements similarly. Hair counts (at an up close level) were increased in the dermarolling group compared to the minoxidil alone group (91.4 vs 22.2 respectively). These studies support the potential benefit of dermarolling - especially to increase the efficacy of minoxidil. More studies need to be done to verify or refute these results as well as to determine the optimal parameters for dermarolling. These include comparisons of daily vs weekly vs monthly treatment and comparisons of 0.5 mm needles, 1 mm or 1.5 mm needles. Studies are also needed to determine if any proportion of patient actually worsen with dermarolling.

5. Eat the minoxidil (or eat more).

If someone has androgenetic alopecia but is not able to achieve high enough concentrations of minoxidil deep under the scalp with use of topical minoxidil, switching from topical minoxidil to oral minoxidil could make sense.  As reviewed above, in order for minoxidil to do it’s job, it needs to be converted to minoxidil sulphate. Hair follicles have the machinery to help with this but some people’s hair follicles are not really that good at it. Scientifically, we say that some people’s hair follicles lack high levels of an enzyme known as “sulfotransferase” and so they cannot convert minoxidil into the active form that actually does all the work. When oral minoxidil is ingested, the liver does the job of converting the minoxidil to minoxidil sulphate - bypassing the need for the hair follicle to do this job.

Patients who don’t respond to topical minoxidil may respond to oral minoxdil. Similarly, patients who don’t respond to very low doses (like 0.25 mg to 0.5 mg) may respond to moderate doses (like 1-2-5 mg). Of course, increasing the dose may increase side effects like headaches, swelling, fluid retention, hives and excessive hair growth on the body.

References

Dhurat R, et al. A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: a pilot study. Int J Trichology. 2013.

Ghonemy S et al. Efficacy and safety of a new 10% topical minoxidil versus 5% topicalminoxidil and placebo in the treatment of male androgenetic alopecia: a trichoscopic evaluation. J Dermatolog Treat. 2019 Oct 21:1-6. doi: 10.1080/09546634.2019.1654070. [Epub ahead of print]

Jeong WY et al. Transdermal delivery of Minoxidil using HA-PLGA nanoparticles for the treatment in alopecia. Biomater Res. 2019 Oct 31;23:16. doi: 10.1186/s40824-019-0164-z. eCollection 2019.

Sharma A et al. Tretinoin enhances minoxidil response in androgenetic alopecia patients by upregulating follicular sulfotransferase enzymes. Dermatol Ther. 2019 May;32(3):e12915. doi: 10.1111/dth.12915. Epub 2019 Apr 23.

Higher Minoxidil Concentrations: Is More Always Better?

10 % Topical Minoxidil vs 5 % Topical Minoxidil: Which is better?

Minoxidil is FDA approved for treating androgenetic alopecia (male pattern balding and female pattern hair loss). It would seem logical to propose that if the drug minoxidil helps in the treatment of males and females with androgenetic alopecia that more minoxidil should help even more.

Researchers from Egypt set out to compare the efficacy and safety of 5% topical minoxidil with 10% topical minoxidil and placebo in 90 males with balding.  The study was a double-blind placebo controlled randomized trial over 36 weeks. The study comprised three treatment groups: 1) study participants receiving 5 % minoxidil 2) study participants receiving 10 % minoxidil and 3) study participants receiving placebo.

Surprisingly, after the 9 months, partipcants in the 5 % minoxidil group had higher vertex and frontal hair counts compared to study participants in the 10 % minoxidil group and the placebo group.

Conclusion

This was a nice study showing us that even after 40 years of studying minoxidil, we still have a lot to learn and a long way to go. Higher concentrations of minoxidil are not necessarily better - although more studies are clearly needed.

Reference

Ghonemy S et al. Efficacy and safety of a new 10% topical minoxidil versus 5% topicalminoxidil and placebo in the treatment of male androgenetic alopecia: a trichoscopic evaluation. J Dermatolog Treat. 2019 Oct 21:1-6. doi: 10.1080/09546634.2019.1654070. [Epub ahead of print]

Managing Hair Loss During and After Pregnancy: Facts vs False Reassurance

Hair Loss During and After Pregnancy

Individuals with hair loss often ask what steps they should be taking to best help their hair during pregnancy and what steps they should take after delivery.

I have written on certain aspects of this topic before. Please consider reviewing my past articles on Hair Loss, Pregnancy & Breastfeeding:

July 23, 2019 - Stopping Medications in Pregnancy

May 6, 2018 - Pregnancy and Female Pattern Hair Loss

Mar 1, 2017 The Safety of Hair Loss medications in Pregnancy

May 19, 2012 - Which medications are safe during breastfeeding?

For many women who ask this question and are currently pregnant, I often say that there are two ways to help the hair while pregnant. The first is make sure that the individuals does not truly have any deficiencies by getting some basic blood tests if the individual or her doctor are worried about some type of deficiency. The second way to potentially help the hair is to consider reviewing the benefits of low level laser therapy (LLLT). Besides correcting a vitamin deficiency, administration of low level laser treatments is really the only treatment that can be safely used during pregnancy.

For women who were using minoxidil before pregnancy but needed to stop during the pregnancy, I strongly encourage them to see an expert to determine when minoxidil might best be restarted after delivery. Both the American Academy of Pediatrics and the American Academy of Dermatology have stated that Rogaine is reasonably safe for breastfeeding women (yes, despite the fact that all warning labels say otherwise). I can’t emphasize enough the importance of speaking to the dermatologist about this. in my opinion, we need to let years and years of medical research and years of observation help guide how we make tough decisions not simply outdated warning labels that protect companies from legal ramifications. These decisions are of course taken on a case by case basis.

False resurgence has no place in the management of any type of hair loss - and this is particularly true in managing hair loss around the time of pregnancy. It would be wonderful if I could reassure women that hair always grows back “fully” after delivery (i.e. to the same density as before pregnancy) - but this is not accurate. For most women who shed hair post partum, the shedding eventually slows down around month 6-9 post partum and shedding returns to normal and hair regrowth happens. However, hair density does not always grow back as full as it was before pregnancy if a woman has the genes for genetic hair loss instructing the hairs what to do.  For many women it does - but not all. This is far more than my professional medical opinion - it’s fact. For this reason, I encourage patients to have a solid treatment plan in place.

False reassurance that hair “always” grows back and not to worry leaves many women confused and disappointed. I sometimes advise a conservative approach and sometimes an aggressive approach to treatment after delivery. It all depends on the stage of the patient’s androgenetic alopecia, her current age and health and her family history of hair loss and other conditions. We don’t yet have tests available to set the known genes for genetic hair loss - so this is not part of the evaluation. The decision on what to use during pregnancy is easy as only laser is safe (and supplementing any deficiencies that are uncovered in the blood tests).  

Is Androgenetic Alopecia (AGA) Caused Only by the Effects of DHT ?

Despite the Myth, Androgenetic Alopecia is Not Simply a Story of DHT

Androgenetic alopecia is a type of hair loss that affects men and women. In males, this condition is also referred to as male balding or male pattern hair loss and eventually affects some 80 to 90 % of males. In females, the condition is referred to as female pattern hair loss or simply hair thinning and affects 40% of women by age 50. The purpose of this article is to deal with some misconceptions, wrong information, errors and myths that many people have about the role of DHT in the balding process. DHT is certainly important - but other factors must be considered too.

The Evolution of the DHT Theory of Male Balding

Some of the earliest observations about the role of hormones in male balding happened in the time of Aristotle back in 300 BC. Aristotle showed that castrated males (eunuchs) did not develop balding. JB Hamilton in 1942 did additional pioneering work to understand male balding. He showed that male hormones are relevant to the balding process. Specifically, he confirmed observations by Aristotle and others that males that were castrated before puberty did not go on to develop balding. Hamilton took this further and showed that if testosterone was given back to castrated males, the males proceeded to develop male balding. This showed that male balding was an “androgen-dependent” process.

Further key work in understanding male balding was done in the 1970s and ultimately published in the New England Journal of Medicine. These were studies that showed that male pseudohermaphrodite living in the Dominican Republic with a genetic deficiency known as 5 alpha reductase deficiency did not produce dihydrotestosterone (DHT) and did not develop male balding. These findings lead ultimately to the rational development of drugs such as finasteride and dutasteride which block 5 alpha reductase and lower DHT levels.

The Story of Male Pattern Balding has a DHT Chapter but Don't Forget to Read the Others

From 300 BC to the 1990’s, the story of male balding seemed pretty clear. Male hormones, particularly the infamous DHT, seemed to be what male balding was all about. Blocking DHT was what treatments were all about.

Many people incorrectly assume that male balding is just a DHT story. Many people incorrectly assume that this DHT chapter is the only chapter they need to read when trying to understand male balding. While it’s true that DHT has a whole lot to do with male balding - the correct way to state it is “male balding is due in part to the effects DHT on hair follicles that are genetically sensitive to this hormone.”

DHT not the only chapter in the balding story

DHT not the only chapter in the balding story. One only need to consider a few other treatments that are used for balding to very quickly realize that male balding must be much more complex than just a DHT story. Minoxidil (Rogaine), for example, has nothing to do with DHT - and yet it helps some people with male balding. Granted I agree that finasteride and dutasteride are much much better treatments than minoxidil - but if DHT was the only thing we need to think about when it comes to treating male balding then minoxidil would not be expected to have any sort of benefit. Well, it does. Low level laser therapy also has nothing to do with DHT hormone levels - and yet it helps some males with their male balding. Platelet rich plasma (PRP) also has very little to do with DHT- and yet it helps some males with their male balding.

Drug Companies are Investing Large Sums with the Knowledge that Male Balding is Far Far More than A Simply DHT Story.

At least 12 pharmaceutical companies are investing millions upon millions of dollars with the clear understanding that DHT is not the only chapter in the balding storybook. These companies are hoping to the first to market with brand new types of drugs - again drugs that have nothing really to do with DHT. A brief summary of the drugs is below.

If Male AGA is Far More than A Simply DHT Story, Female AGA is Far Far Far More than A DHT Story

If you have now come to realize that male balding is a bit more complex than simply a story about DHT, I’d like to point out that female androgenetic alopecia (i.e. female pattern hair loss) is even more complex. If you think for even a moment that you’re going to apply the same DHT story that you used in males to explain balding to the mechanisms operating in females with androgenetic alopecia, you’re going to come up short in terms of your ability to explain hair thinning in women.

Androgenetic alopecia in females is a far more complex story - and we still don’t know all of the mechanisms that govern how hairs thin in women. Of course, there is some aspects of the DHT story that relevant to female thinning. But finasteride and spironolactone and anti-androgens are far less consistently helpful in females than in males. Other treatments such as minoxidil and laser may be far more helpful in some women than in males. In other words, there are likely several different mechanisms that are contributory to androgenetic alopecia in females besides simply a DHT story. As further information for reflection to readers who still doubt this information, one must consider that some women with a genetic condition that completely makes them insensitive to the effects of androgens (called androgen insensitivity syndrome) can still develop androgenetic alopecia. Even women with low testosterone and low DHT levels can develop androgenetic alopecia. There are even some androgen deficient women who do not develop any balding whatsoever when you give them back supplemental androgens through various means of testosterone replacement therapy.

Conclusion

Is androgenetic alopecia simply due to the sensitivity of hair follicles to DHT? Well, it’s a good story, but it’s only part of the story. The DHT chapter is an important chapter to read in the story of male balding and female thinning, but be sure to read the remaining chapters of the story book. The DHT story is not the only story - and many pharmaceutical companies are banking on this concept.

The Course of Treating Lichen Planopilaris: What do we hope for?

A Closer Look at the Typical Course of Treating Lichen Planopilaris

Lichen planopilaris is a scarring alopecia. Treatments are largely focused on reducing inflammation in hopes that by doing so the disease can be stopped. 

In the present day, there are many aspects of LPP that are difficult to predict. We know to some degree which treatments are better than others. We know the proportion of patients that are expected to benefit from a certain type of treatment and the proportion of patients who are not expected to benefit. However, we do not know if a given patient will require several trials of medications before finding one that ‘works’ to suppress the disease and whether a given patient will need 1, 2 3 or more treatments to suppress the disease completely (and therefore stop it). In addition, we do not know how long the patient will need to use their treatments before the disease completely stops. It ranges from a year or two to many decades.

When all goes well, LPP disease activity eventually settles down with use of one or more medications. Disease flares and micro flares can still happen even when patents are on the right treatment plan. Some patients, but not all, finally enter a state where their disease is completely quiet. When the disease stays quiet and mediations can be stopped, we call the condition “burnt out.”

Flares and MIcroflares in LPP

Even when a patient’s disease achieves a fairly inactive state, flares and microflares may still happen from time to time.  These refer to sudden increases in the activity of the disease. Patients who are experiencing flares may become more itchy, or notice more daily hair shedding. Stress, heat, can humidity can cause such microflares and sometimes these sorts of flares occur for no apparent reason at all.Some patients, but not all, finally enter a state where their disease is completely quiet. When the disease stays quiet and mediations can be stopped, we call the condition “burnt out.” 

 Although no patient is really ‘typical’ when it comes to LPP, a standard treatment protocol is summarized in this graph above.

Hydroxychloroquine (Plaquenil) and Hair Loss: Is my Plaquenil causing me to lose hair?

Losing Hair on Plaquenil: The 5 Possibilities

Hydroxychloroquine (also known by its popular brand name Plaquenil) is an oral medication that is commonly used to treat a variety of autoimmune diseases including systemic lupus, dermatomyositis, rheumatoid arthritis, Sjogren’s and many other conditions as well. In the field of hair loss, conditions such as lichen planopilaris, frontal fibrosing alopecia and discoid lupus are frequently treated with hydroxychloroquine.

Can hydroxychloroquine cause hair loss?

It’s possible for any medication to cause hair loss, but for some medications it’s quite rare and for others it’s much more common. Whenever a patient using hydroxychloroquine reports hair loss there are 5 possibilities to consider.

1. The Plaquenil is Causing Hair Loss

One needs to always consider the possibility that Plaquenil is causing the hair loss. Usually Plaquenil related hair loss starts 2-6 months after the Plaquenil was started. We call this a drug induced telogen effluvium. If the Plaquenil was started 10 years ago and a patient reports hair loss last month, it’s not very likely that the Plaquenil is the culprit. That is often forgotten.

2. The Autoimmune Disease the Plaquenil is Used for is Causing Hair loss

Autoimmune disease can cause inflammation in the body and this type of inflammation itself can trigger hair loss in the form of a hair shedding or ‘telogen effluvium.’ When rheumatoid arthritis flares patients can shed hair. When lupus flares, patients can lose hair. If it’s not clear if the disease itself is contributing to hair loss, the specialist (ie rheumatologist) can help chart the activity of the patient’s disease over the past 1-2 years. It this correlates with hair shedding episodes experienced by the patient, then disease activity is likely involved in the patient’s hair loss.

3. A New Autoimmune Disease is Causing Hair Loss

It's well known that once a patient develops one autoimmune disease that he or she is more likely to develop a second autoimmune disease. One must always keep this in mind. Autoimmune scarring alopecias and autoimmune alopecia areata must always be considered when a patient with one autoimmune disease reports hair loss.

4. A New and Unrelated Hair Loss Condition has Developed

Hair loss is common and other conditions can develop. A 37 year old female with systemic lupus who uses Plaquenil for many years and now reports hair loss may have a number of possible hair loss conditions including telogen effluvium, female pattern (androgenetic alopecia), traction alopecia, or scarring alopecia. 40 % of women by age 50 will develop female pattern hair loss. This means that 40 % of female patients who use Plaquenil will develop female genetic hair loss - not from the drug itself but because that is the expected frequency in the population.

5. A New Treatment that was Introduced is Causing the Hair loss

For any patient who is currently using Plaquenil and develops new hair loss one must keep a very open mind as to the possibilities for the hair loss. In addition to the discussion points above, one must review whether new medication have been started. Was another medication introduced to treat the autoimmune disease? Was another mediation introduced to treat some other health condition. I recently saw patient with lupus who developed hair loss from an antacid type medication. We reviewed the precise course of the hair loss, pinpointed that it must have been the antacid medication and changed the medication. 2 months later the shedding had slowly considerably and 8 months later the patient’s hair has returned.

Conclusion

There are many reasons for hair loss in patients who use Plaquenil. One must always consider the possibility that the drug itself is triggering the hair loss but at the same time keep an open mind to other possibilities.

Steroid Injections for Hair Loss - A Look at Triamcinolone Acetonide

Steroid Injections with Triamcinolone Acetonide

Steroid injections are extremely helpful for many hair loss conditions - particularly some forms of localized alopecia areata (AA) some patients with lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA) and folliculitis decalvans. I sometimes even use in the early stages of traction alopecia when I feel the condition is in its earliest stages.

Triacminolone acetonide is a common medication used for steroid injections for inflammatory related causes of hair loss. Kenalog is a popular brand name and available in 10 mg and 40 mg bottles. The final dose the physician uses is typically 2.5 to 5 mg per mL.

There are two common doses of triamcinolone acetonide that one orders from the manufacturer - 10 mg per mL and 40 mg per mL. Either is fine to order provided one keeps in mind that when using the 40 mg per mL dose one is going to need to use 4 times less than if using the 10 mg per mL dose. Every few months I get calls from physicians who call me in a panic because they have prepared their injections using a 40 mg per mL bottle but they thought it was a 10 mg per mL bottle. (the correct way to deal with this is to 1) admit one’s error to the patient, and then 2) flood the scalp generously with saline injections to dilute out the steroid and see the patient back in 4 weeks and 8 weeks to see if any atrophy developed). There are many brands of triamcinolone acetonide one can order. Kenalog is one brand (shown here) but there are others. I have used many over the years and find some do get clogged up when using tiny 30 gauge needles. I don’t find this happens with Kenalog.

As reviewed in other posts, I believe in starting steroid injections at 2.5 mg per mL and only going to 5 mg per mL if needed. The low dose can be helpful and allows more injections to be performed as the maximum dose is 4 mL if one uses a 5 mg/mL concentration or 8 mL if one uses a 2.5 mg per mL concentration.

Cetirizine (Zyrtec) in Lichen Planopilaris: Best Viewed as an Adjunct not Main Treatment

Cetirizine (Zyrtec) for Treating Lichen Planopilaris: Where does it fit in?

Antihistamines are increasingly being studied for the treatment for various types of hair loss. For the autoimmune disease known as alopecia areata for example, use of antihistamines like fexofenadine (Allegra) as well as others (i.e. ebastine) may have some treatment related benefits. In scarring alopecia. the use of antihistamines has only received a limited amount of study. Today, we will discuss the use of the antihistamine cetirizine for treating lichen planopilaris.

Lichen planopilaris is an immune medicated disease. There are a number of proposed mechanisms that lead ultimately to the disease. Cetirizine is an antihistamine medication and widely used for various types of allergy related symptoms. However, the medication may have a number of general and wide reaching effects on the immune system.

How does cetirizine work and how does it affect the immune response ?

Cetirizine is an H1 receptor antagonist. The drug minimally crosses the so called ‘blood brain barrier’ and so limited amounts actually get into the brain. This results in less sedation with cetirizine compared to any other traditional antihistamines. The 5 mg and 10 mg doses are unlikely to give sedation for most people. However, the 20 mg and 30 mg doses are much more likely to give sedation. There has been concern in recent years among long term chronic use of high doses of antihistamines on cognitive decline in patients so this needs to be taken into account when discussing high dose cetirizine as chronic therapy with patients with any medical condition.

Cetirizine has a number of potential effects to modify the immune response. These include

1. Inhibit DNA binding activity of NF-kappa B,

2. Inhibit the expression of adhesion molecules on immunocytes and endothelial cells

3. Inhibit the production of IL-8 and LTB4, two potent chemoattractants, by immune cells.

4. Induce the release of PGE2, a suppressor of antigen presentation and MHC class II expression, from monocyte/macrophages

5. Reduces the number of tryptase positive mast cells in inflammation sites.

The 2010 d’Ovidio Lichen Planopilaris Study

In 2010, d’Ovidio and colleagues studied the use of cetirizine at high doses. Rather than using 5 mg to 10 mg daily that is commonly use over the counter, the authors studied the benefits of 30 mg/daily. Twenty-one patients with lichen planopilaris (LPP) were treated with cetirizine as well as their topical steroids. in 18 or 21 patients (85.7 %) there was a reduction in redness, scaling and a reduction in extractable anagen hairs by the pull test. The authors reported that one patient developed cardiac arrhythmia after 3 months of successful treatment and dropped out of the study.

Cetirizine is an antihistamine and functions as an H1 receptor antagonist. In 2010, d’Ovidio showed that cetirizine at high doses (30 mg) could benefit some patients with lichen planopilaris. Over the counter antihistamine dosing like shown in the phone is 10 mg.

What are the side effects of cetirizine?

Side effects of cetirizine and other information can be found in our Handout.

Cetirizine Handout for LPP

Rare side effects including heart failure, angioedema and tachycardia. These side effects are rare at low doses such as the 5 mg and 10 mg (over the counter doses). Side effects increase as one increased the dose. The 30 mg dose used in the d’OIividio study would be expected to have a greater degree of side effects than the lower doses.

Conclusion

Cetirizine may have some benefit in treating lichen planopilaris. I sometimes prescribe cetirizine as an adjective treatment in patients with persistent itching and burning who are not fully responding to mainstay topical, intralesional and oral treatments. Generally I use 5 mg or 10 mg and only rarely do I prescribe 15-20 mg. I do not typically prescribe 30 mg doses as I find side effects increase greatly. One must respect the drug interactions and contraindications for the drug (as outlined in the handout). In many ways, I view cetirizine as a helpful add on - much the same way as I view the use of low level laser therapy in this disease. I do not think in the present day that cetirizine should find itself at the top of the therapeutic ladder but certainly has a place.

Reference

d’Ovidio R et al Therapeutic hotline. Effectiveness of the association of cetirizine and topical steroids in lichen planus pilaris--an open-label clinical trial. Dermatol Ther. 2010 Sep-Oct;23(5):547-52.

Namazi MR et al. Cetirizine and allopurinol as novel weapons against cellular autoimmune disorders.Int Immunopharmacol. 2004 Mar;4(3):349-53.

Is Immunotherapy (DPCP, SADBE) Effective for Lichen Planopilaris or Frontal Fibrosing Alopecia ?

Immunotherapy (DPCP, SADBE) Does NOT Help Scarring Alopecia

Diphencyprone (DPCP) and Squaric Acid Dibutyl Ester (SADBE) are long standing treatments for the autoimmune hair loss condition alopecia areata. The cause itching and burning in the scalp and essentially trigger an allergic contact dermatitis. The inflammation that these chemicals create can trigger hair growth in some patients with alopecia areata. It’s quite remarkable.

FIGURE 1. Diphenycyprone (DPCP) is a liquid that is applied to the scalp to treat alopecia areata. It causes an allergic reaction but can stimulate hair growth in some users.

FIGURE 2: Hair Regrowth in a patient with ‘ophiasis” type of alopecia areata who was treated with diphenyprone.

Does DPCP and Squaric Acid Help Lichen Planopilaris or Frontal Fibrosing Alopecia (FFA)?

DPCP and Squaric acid are not effective in these scarring alopecias. It’s not that large studies have been done - it’s just that I’ve seen patients many patients over the years with scarring alopecias who have come to see my after having DPCP. These patients were all mistakenly diagnosed as having alopecia areata when really they had frontal fibrosing alopecia or lichen planopilaris. Hair regrowth did not occur and many experiencing a significant worsening.

FIGURE 3: Patient with frontal fibrosing alopecia who was first thought to have the ophiasis form of alopecia areata and was treated with DCPC for many months. The patient did not experience regrowth.

There is absolutely no reason to believe that DPCP or squaric acid are effective in LPP or FFA. The pathogenesis of these two conditions is very different than alopecia areata. While it’s true that some treatments overlap - many do not. The following table summarizes some of these important differences. DPCP is effective for some patients with alopecia areata but is not effective in LPP. Doxycycline is effective for some patients withLPP but not helpful in treating alopecia areata.

Table 1: Treatments in Alopecia Areata vs Lichen Planopilaris

Reference

[1] DPCP for Hair Loss: Can I Apply it at Home?

Prescribing Dutasteride in Males with Balding: Are there any criteria ? Should there be any criteria?

Prescribing Dutasteride in Males

The most effective medical treatments for male balding (at the time of this article being written) are oral finasteride and oral dutasteride. There is no debate about this particular comment. In the present day, as the world grapples with the meaning of “post finasteride syndrome”, dutasteride is increasingly a choice for many physicians where it never might have been a choice before. I see it - and I see more now than I did 2 years ago. I see dutasteride being used and 0.5 mg three times weekly. I see dutasteride used at 2.5 mg once weekly or twice weekly. I see dutasteride being used at 0.5 mg daily. I see dutasteride being used more often - and I too prescribe it more now than I did 10 years ago.

Dutasteride is not formally FDA approved for treating male balding but is still widely used. It’s used “off label” though and certainly has a large number of studies to back up its effectiveness. In some countries, dutasteride does have formal approval.

The public is also increasing asking about dutasteride - and increasingly requesting it. After all, we don’t have a great deal of data implicating dutasteride in the same set of issues that finasteride has. Furthermore, it’s more effective than finasteride. These two points lead many to turn to the drug. Some data suggests side effects like sexual dysfunction are greater with dutasteride than finasteride but certainly not all studies show this. Some in fact, show that side effects of dutasteride are similar to placebo.

We don’t yet fully understand everything behind post finasteride syndrome to even begin to dig into what might be called a post dutasteride syndrome or a general 5 alpha reductase syndrome. More studies are needed.

So, will you prescribe me dutasteride or not?

Many patients come in the clinic wanting to know if I’ll prescribe them dutasteride. Some have been on finasteride and haven’t found that it works - and they want dutasteride. Some don’t want to try finasteride at all - they want dutasteride. Some want both. Some know the dose they want.

it all comes down to understanding the medical evidence and the 20 years of science that comes before. There is not a “yes” or “no” answer to whether I will prescribe dutasteride. I don’t know when a patient walks in the door if these medications are right for them - but I do know before the patient walks out the door if these medications are right for them.

The following are the criteria I use in the clinic for determine if the patient is a candidate for dutasteride. These are my criteria and may not necessary be the guideline principles for everyone.

Top 10 Criteria for Prescribing Dutasteride (Donovan)

1. The patient understands the treatment is life-long if he wishes to maintain active medical treatment of his androgenetic alopecia.

2. The patient is aware of the array of possible side effects that have been reported with use of 5 alpha reductase inhibitors including mood changes, depression, anxiety, sexual dysfunction, enlargement of breast tissue (gynecomastia), penile shrinkage, loss of penile sensation, weight gain, muscle weakness and others. The potential effects of dutasteride on males wishing to father are not completely understood. The patient accepts the risk of these side effects if he chooses to use dutasteride.

3. The patient does not currently have severe depression or currently have severe anxiety that might otherwise present a contraindication to using dutasteride. The patient has not been suicidal in the past or been hospitalized for depression and mental illness within the past 5 years.

4. The patient is aware of reports that some patients have experienced persistent (long lasting) problems even when the drug has been stopped. These are mainly studied in the context of finasteride but should be assumed for now to be relevant to the use of dutasteride. The patient accepts the risk of these side effects if he chooses to use dutasteride.

5. The patient is aware that class action lawsuits have been launched regarding the persistent side effects related to finasteride use.

6. The patient is aware of alternatives for treatment including topical minoxidil, oral minoxidil, topical anti androgens (topical finasteride), low level laser, platelet rich plasma and hair transplantation.

7. The patient has no known issues currently related to male inferility or infertility in a female partner.

8. The patient understands the possibility of dutasteride causing a reduction in sperm count and the rare possibility that these reductions may be permanent or long lasting (even when the drug is stopped). The original dutasteride studies showed that after 6 months of stopping the drug, sperm counts had not returned to normal in all study participants and that the total sperm count in the dutasteride group remained 23% lower than baseline.

   Males who are concerned about the possibility of lower sperm count or fertility issues may consider having baseline semen analysis or baseline FSH, LH, Free T4 and testosterone measurements before starting. These lab tests may provide some guidance about baseline fertility. These issues in point 5 are relevant to males who may wish to father children in the future.

9. The patient does not wish to donate blood and understands that blood donation is not possible for at least 6 months after stopping the drug.

10. The patient understands that dutasteride may affect future prostate cancer screening by affecting the PSA value. These issues need to be discussed at the time of such screen and consideration might be given to baseline screening depending on the age of the patient when starting dutasteride.

Conclusion

I can’t say if a patient is a candidate for starting dutasteride when they walk in the office but after 20-30 minutes I can determine if they are likely to be a good candidate for the drug or not. The answers to the questions and issues above help guide the decision making that goes into figuring out if a patient is a candidate for dutasteride or not. It’s not something that can be ascertained in a matter of a few minutes.

References

Meeker JD, Godfrey-Bailey L, Hauser R. Relationships between serum hormone levels and semen quality among men from an infertility clinic. J Androl 2007;28:397–406.

The Use Metformin in Lupus: How does this apply to our Discoid LE (DLE) Patients?

Metformin for Lupus: Will it help discoid lupus?

Metformin is a well known diabetes drug. Recent evidence has suggested that metformin may have a positive impact on the treatment of some autoimmune diseases.

Metformin is well understood to reduce glucose production by the liver and to reduce absorption of glucose in the gastrointestinal tract and to increase insulin sensitivity. However, metformin may also reduce production of reactive oxygen species (ROS) which help create inflammation in lupus. The possible benefits of metformin in lupus was demonstrated in 2015 where Wang and colleagues in the journal Arthritis and Rheumatolgy showed that metformin reduce the risk of disease flares by 51 % compared to conventional treatment.

In a 2018 poster by McLeod and colleagues presented at the 2018 meeting of the American College of Rheumatology, authors showed that metformin helps patients with lupus improve control of their disease. The researchers studied 15 patients with lupus using metformin and compared to 1331 patients not using metformin. The authors found there ws a difference in disease activity in patients using metformin.

Metformin for Discoid Lupus: Will it help?

These studies are interesting as they suggest that metformin has the potential to help patients with lupus. What we don’t know yet is whether metformin will help the various types of ‘cutaneous’ lupus including discoid lupus.

Metformin may have an impact not only on autoimmune diseases (including effects on monocytes, macrophages and neutrophils), but improve gut microbiota and have an antifibrotic effect as well. These effects together make them ideal to consider in the study of scarring alopecia. We already know that drugs as pioglitazone may be helpful in lichen planopilaris.

REFERENCES

Wang et al. Neutrophil Extracellular Trap Mitochondrial DNA and Its Autoantibody in Systemic Lupus Erythematosus and a Proof-of-Concept Trial of Metformin.Arthritis Rheumatol. 2015 Dec;67(12):3190-200. doi: 10.1002/art.39296.

McLeod C, Olayemi G, Bhatia N, Migliore F, Quinet R. The Impact of Metformin on Disease Activity in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/the-impact-of-metformin-on-disease-activity-in-systemic-lupus-erythematosus/. ABSTRACT NUMBER: 2645