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Derm

Primary Care Corner with Geoffrey Modest MD: Cimetidine for Warts?

4 Apr, 16 | by EBM

By Dr. Geoffrey Modest

I was going through piles of old medical articles, intent on throwing them out in this electronic age, but then found one from 2005 looking at the use of cimetidine for warts (see J Am Podiatr Med Assoc 95(3):229). I have had several very impressive cases where using cimetidine, an H2-blocker but also used in the past as an immunoenhancer for some chemotherapy regimes, really worked. The first case was a 5yo male I saw about 25 years ago with very extensive longstanding perianal warts (condyloma acuminata). The dermatologist was planning rather extensive surgery, but commented to me that there were often responses to cimetidine. The patient took the med and the warts completely vanished within 1-2 weeks. The second case was me, complaining of a rather painful plantar wart. I saw our podiatrist, who tried liquid nitrogen therapy (which exceeded my pain threshold, though I had thought that was very high). So, I tried imiquimod for 6 weeks, to no avail. Given my experience with cimetidine with condyloma, I asked the podiatrist if cimetidine might help, and he produced this paper. So, several weeks after stopping the imiquimod, I began cimetidine 800mg bid and the wart was completely gone, literally within days!! I have recommended cimetidine to several people since then, with variable results (though a few also being quite dramatic. Including a young woman with really bad genital warts, where the warts recurred after extensive cryotherapy, and the dermatologists were at a loss on what to do next. I suggested cimetidine and the warts resolved within days and did not recur). In this light, here is the study I found:

  • 8-year retrospective analysis of cimetidine as first-line therapy for pedal verruca (plantar warts). 216 patients treated, 169 (78%) completed questionnaires a minimum of 15 months post-therapy
  • 90 males, 126 females; 180 were <18 yo, 18 were >25 yo
  • Cimetidine dose: kids –25-40 mg/kg/d in divided doses, adults 800 bid
  • Results:
    • Overall treatment success rate for all age groups: 84.3%
    • ​12 recurrences were after the completion of the study (7.2%): 7 in kids (5%) and 5 in adults (20%); in 2 of the recurrences, retreatment with cimetidine worked without further recurrences
    • Mean duration of treatment was 6.1 weeks in kids and 7.9 weeks in adults
    • In looking at the specific patients involved, 27 patients had personal or family history of autoimmune diseases (treatment success in 81.5%), 13 patients had prior failed surgical excision/curettage (cimetidine worked in 84.6%), 9 patients had successful response despite stopping the cimetidine early because of adverse effects, 5 patients had had symptomatic warts for >100 weeks with 80% success on cimetidine
    • ​Of the 47 patients who did not complete the questionnaires, 40 had documented outcomes by their clinician and 80% were treated successfully
    • Adverse effects: 15.7% (7.4% were GI, rather interestingly for cimetidine).

So, a few points

  • On review of what exists in the literature, there was another open-label study of 47 patients with multiple, nongenital warts treated with oral cimetidine for 3 months (at 30-40 mg/kg and a higher dose of 800mg tid for adults) finding improvement in 87% of children and 68% of adults, and complete clearance in 56% of kids and 44% of adults. followup data showed no recurrences in the 65% of patients they could reach who had complete clearance by the end of the study, though warts recurred if treatment stopped before all warts had cleared (see Clin Exper Dermalol 2000; 25: 183).
  • There were 2 RCTs looking at cimetidine, but the only RCT I could find was of 54 patients with nongenital warts of at least 6 months duration, putting 36 patients on cimetidine 400mg tid vs placebo, finding positive responses in 37% on cimetidine and 25% on placebo, a nonsignificant difference (i.e., though the cimetidine group did better, this was too small a study to draw conclusions (see Arch Dermatol 1997: 133: 533)). Of note, another report (Eur J Dermatol 2003; 13(5): 445) found that only high-dose cimetidine worked clinically (30-40 mg/kg/d vs <20 mg/kg/d), and that those who responded had increased levels of IL-2 and IFN-gamma mRNA levels (as produced by Th1 cells) and decreased IL-16 mRNA levels in tissues of effectively treated warts. And the inconclusive RCT used a lower dose.
  • Overall, cimetidine does seem to work somewhat better in kids (who do have higher likelihood of spontaneous resolution, though the success rate above is impressive). I could not find much data regarding condyloma acuminata, other than occasional anecdotal reports (J Urol 2000; 164:1074, which found 4 of 4 kids with extensive genital warts had resolution with 3 months of cimetidine; though there are also some small reports of failure)​. And bigger, better RCTs are pretty unlikely to happen, given this is a cheap generic drug, hence unlikely to get a drug company to sponsor.
  • How should it be given??? Unclear. I have used the higher doses above (adults: 800mg bid; kids 30-40 mg/kg) until the warts resolve. Of note, in the above studies, most people got the drug for 2-3 months. And some not responding by that time did so by extending the course several months more.
  • I should also add that in my experience, I have had better response to condyloma acuminata with cimetidine than with repeated cryotherapy, or use of caustics such as podophyllin. I have prescribed imiquimod cream with some success, though it is also irritating and very expensive (and only approved for those >12yo)
  • So, it is with some trepidation that I present this study, since the RCTs were not so good, cimetidine is not even listed as an option by the CDC in their sexually-transmitted disease compendium, and Up-To-Date mentions it dismissively. But given the above anecdotes (one quite close to my heart), and given that this is such a benign treatment, it might be worth considering.

Primary Care Corner with Geoffrey Modest MD: Melanoma increasing (a lot)

23 Jun, 15 | by EBM

By: Dr. Geoffrey Modest

MMWR just released an analysis of melanoma incidence, mortality trends, and projections in the US from 1982-2030 (see here). Melanoma is common (5th most common cancer in men and 7th in women) and is associated with the most skin cancer deaths, with deaths occurring most frequently in younger people (average of 20.4 years of potential life lost). Costs of treatment are high ($3.3 billion/yr in the US). And melanoma is largely preventable — 90% are attributable to skin damage from UV light exposure, with sunburns being a significant risk factor and 40% of US people reporting sunburn every year. There is clear efficacy of sun-protective behaviors in decreasing UV skin exposure, such as sunscreen, protective clothing. In addition there are suggestive data that cumulative UV radiation exposure over time may also be a culprit. results from MMWR:

–in 2011: 65,647 invasive melanomas in the US, with age-adjusted incidence rate of 19.7/100K, increasing with age and highest in non-Hispanic whites, in women 15-49yo, and in men >50.

–in 2011: 9,128 melanoma deaths, with age-adjusted death rate of 2.7/100K, higher in non-Hispanic whites, increasing with age, and higher in men (4.0) than women (1.7)

–from 1982-2011: melanoma incidence rates increased (doubling), though mortality remained the same.

–without intervention, there are projected to be 112,000 new cases in 2030 with annual cost for treatment projected to increase 252.4% from 2011-2030 (from $454 million to $1.6 billion)

–a comprehensive skin care prevention program (modeled after the one in Australia, which raised community awareness through mass media campaigns, programs in schools and workplaces, provider education, etc, had projected savings of $2.30 for every $1 spent) is estimated to prevent 20% of US melanoma cases from 2011-2030, averting 21,000 cases/yr, and reducing spending $250 million/yr (saving $2.7 billion from 2020-2030).

So, this seems like a largely preventable problem. There are pretty easy individual strategies available, including not using indoor tanning salons and using appropriate sunscreen protection — correct amount, reapplication rates, etc.  But, as in Australia, the major potential impact would be from concerted, community-oriented and community-based public health initiatives. Some of the above gender differences may be attributable to the increased female use of indoor tanning salons (a 2013 report found that approx 1/3 of non-Hispanic white women aged 16-25 use indoor tanning salons each year) and decreased male use of sunscreen protection. It is also important to remember that there still is a melanoma risk in darker skinned individuals. Overall black incidence in 2011 was 1.0/100K, vs 24.6/100K in non-Hispanic whites; but the mortality in black americans was 0.4/100K vs 3.1/100K reflecting a 3-fold increased mortality-to-incidence ratio vs non-Hispanic whites. This higher mortality is perhaps related to data suggesting that darker-skinned people report more frequent sunburns, are less likely to use sun-protection strategies, have a higher incidence of poorer-survival melanomas perhaps related to later diagnosis, a lower perceived risk by patients and providers, and more melanomas in non-sun-exposed areas.

Primary Care Corner with Geoffrey Modest MD: Vitamin D and atopic dermatitis in kids

12 May, 15 | by EBM

By: Dr. Geoffrey Modest

Atopic dermatitis (AD) is pretty common in kids (up to 25%), typically occurring early on (45% of cases begin within first 6 months of life, 60% within first year), and 70% remit spontaneously by adolescence. In those with AD there are significant immunologic changes (increase in Th2 cells and decrease in Th1 cells in their skin, though there are differences in these T-cell subsets in the acute AD phase, with Th2 cells and their associated cytokines of IL-4, IL-5, IL-13 predominating, but in the chronic phase the Th1 cells and their associated IFN-g, IL-5,IL-12 predominate. Vitamin D receptors are all over the body, including in the skin and in the immune system, and a small RCT in AD patients randomized to vitamin D 1,600 IU/d found clinical improvement after 60 days. The current study looked further into the immunologic changes and clinical effects of vitamin D supplementation in AD patients (see Arch Allergy Immunol 2015;166:91–96​).

Atopic_dermatitis_child

Details:

–39 children with chronic AD (mean age 4, 38% with family history of asthma, 87% family history of allergies, 33% of the kids had asthma and 33% had rhinitis; 8% had mild AD/46% moderate and 46% severe; 90% with total IgE increased and 23% had documented food allergy, 21% for inhalants only; 38% tested positive for dust mite allergen and 44% for eggs. overall skin test positivity was present in 79%). These AD patients were compared with 20 nonallergic healthy controls.​

— baseline cytokine (IL-2, IL-4, IL-6, IFN-g, TNF-a) and vitamin D levels were assessed, along with SCORAD (an AD clinical scoring system) index.

–then the patients were treated with vitamin D (1,000 IU/day) for 3 months.

–Families of AD patients were asked not to use topical steroids (6 did use them sporadically) or oral steroids (none used)

Results:

–all cytokines except TNF-a were elevated in the AD kids
–baseline vitamin D levels in the AD and control patients were similar (23 ng/ml in AD group and 20 ng/ml in controls)

–after vitamin D supplementation, the vit D levels increased from 23 ng/ml to 29 ng/ml

–the altered cytokines  (IL-2, IL-4, IL-6, IFN-g) were all statistically significantly and dramatically reduced after the vitamin D supplementation, and were within the range of the normal kids

–the SCORAD index decreased from 46.13 +/- 15.68 to 22.57 +/- 15.28, p<0.001) — a SCORAD index of 25-50 reflects moderate AD

In terms of the role of helper T cell subsets, in brief Th1 cells are moere involved in immunity to intracellular pathogens and in autoimmunity; Th2 more with defense against parasites and with atopic diseases. the balance of Th1/Th2 may be important in terms of disease progression. People with higher ratios and HIV infection have slower disease progression. The most significant initial cytokine associated with Th1 is IL-12, and also IFN-g. Th2 is most strongly associated with IL-4.

Although there was no formal control in this study, they did find that those kids who did not adhere to the vitamin D supplementation or did not have much of a bump in their vitamin D levels did not have a significant change in their SCORAD index or cytokine levels. So, given the data that vitamin D may well be important in immune function in general and the results in this and the other study cited above, it certainly seems reasonable to me to check vitamin D levels and supplement in kids with atopic dermatitis.

Primary Care Corner with Geoffrey Modest MD: Choosing wisely — infectious disease society recommendations

3 Mar, 15 | by EBM

By: Dr. Geoffrey Modest

Will pass along the infectious disease society “choosing-wisely” recommendations for decreasing antibiotic use. Although none of these are new or surprising, data suggest that antibiotics are still being prescribed for these conditions unwisely….  (see here)

  1. Don’t treat asymptomatic bacteruria with antibiotics. (except pregnant patients, those undergoing invasive urological surgery including prostate surgery, or those within 1 year of kidney or kidney pancreas transplant)
  2. Avoid antibiotics for upper respiratory infections. most are viral. But one should treat group A strep and pertussis
  3. Don’t use antibiotics for stasis dermatitis of lower extremities. Use leg elevation and compression. [in my experience, this can be a difficult call: stasis dermatitis can really look like cellulitis with bright red, well-demarcated erythema, though with less induration than cellulitis. And i would add that topical steroids do work quickly with stasis dermatitis]
  4. Don’t test for clostridium difficile infection in the absence of diarrhea. Except if ileus from c. difficile is suspected. In general​, c. diff carriage should not be treated so shouldn’t be looked for
  5. Don’t use prophylactic antibiotics for treatment of mitral valve prolapse as a means to prevent endocarditis.

So, just a reminder.

Primary Care Corner with Geoffrey Modest MD: Hydroxyzine and prolonged QTc

18 Feb, 15 | by EBM

By: Dr. Geoffrey Modest

The Pharmacovigilence Risk Assessment Committee (PRAC) of the  European Medicines Agency just issues a warning about hydroxyzine being associated with increased QTc intervals and torsade de pointes (see here). Hydroxyzine is a first-generation antihistamine, commonly used for pruritus, anxiety disorders, sleep disorders and as a premedication before surgery, as well as off-label as an anti-emetic.  They felt it was okay to continue using hydoxyzine since the cardiac arrhythmias were most likely to occur in those with risk factors, but they do suggest:

–maximum dose of 100mg/d or 2 mg/kg for kids up to 40 kg. Use lowest effective dose and for shortest time possible

–avoid using in those “at risk of heart rhythm problems” or in those taking other medications that prolong the QTc

–try to avoid using in those taking medications that lower the potassium or slow the heart rate, since these may predispose to arrhythmias.

–try to avoid use in the elderly, but if necessary, only up to 50mg/d

–there was no comment in the warning about the frequency of prolonged QTc, the length of the prolongation, or the frequency of torsades or ventricular tachycardia/fibrillation

So, quite unfortunate. hydroxyzine has been my go-to med for persistent pruritus.​ However, I will now try to avoid it especially in those on other meds which prolong the QTc, especially azithro/clarithromycin, tricyclics, citalopram, as well as in patients predisposed to arrhythmias. And decreasing the maximum dose in elderly seems appropriate.

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