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Moving in to first place: Antimalarials for treating generalized granuloma annulare

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By Warren R. Heymann, MD
March 26, 2017

Granuloma Annulare
Localized granuloma annulare. Erythematous annular plaques may be singular (A) or multiple (B). Localized granuloma annulare may also present as papules coalescing into circular plaques (C).
Credit: JAAD
At a University of Pennsylvania Duhring Conference years ago, an inquiring dermatologist asked Jim Leyden how he knew the patient had generalized granuloma annulare (GGA). “It’s easy” Jim replied. “It just looks like somebody poured a box of Cheerios on them, and they stuck.” I have never seen a patient with GGA since without conjuring that mental image!

Treating patients with GGA is often frustrating for patients and dermatologists alike. As a resident, I was taught that dapsone was the treatment choice; only every so often would a patient respond, necessitating other approaches. First-line therapies listed in the latest edition of Treatment of Skin Disease also include UVA 1, isotretinoin, tacrolimus, and photodynamic therapy. Hydroxychloroquine was listed as a second-line option (amongst many others) with only limited evidence for its use (1).

In my experience, antimalarials have benefitted some patients with GGA, but reasonable data to substantiate this impression was lacking. In their retrospective study of 35 histologically confirmed cases of granuloma annulare, Misha Rosenbach’s group identified 27 diagnosed as GGA (although 3 of these 27 had histologic features of annular elastolytic giant cell granuloma). Of the GGA group, 9 responded to hydroxychloroquine and 4 to chloroquine. Comorbidities in the GGA patients included diabetes (28.6%), dyslipidemia (80%), thyroid disease (38.1) and evidence of hepatitis C infection (20%). The authors concluded dermatologists should consider antimalarials as first-line treatment for GGA (2). I’m delighted that my suspicions have been confirmed (at least in this study – a prospective randomized trial would be ideal).

The mechanism of action of antimalarials is incompletely understood and is under active scrutiny. They act on many different cellular targets, including ion channels, nucleic acids, and cellular organelles. Recent research has implicated their role in modifying innate immunity pathways including Toll-like receptors and the recently described cGAS-STING pathway, which ordinarily induces interferon-1 production (3).

It is crucial that antimalarials be used appropriately. Recommendations for drug monitoring have been modified recently, and I encourage you to read the following carefully. This is a slightly modified table from the outstanding, soon to be released, article by Ferndandez (4).

*Optimal patient dosing for is ≤5.0 mg/kg of actual (real) body weight or 400 mg daily, whichever is lower, for most patients*.

*Whole blood HCQ levels should be checked in patients not adequately responding, with goals for efficacy being >750 ng/ml and for compliance being >500 ng/ml.

*Smokers should be educated about benefits of cessation, but effects of smoking on HCQ therapy are unclear and HCQ treatment should still be attempted in lieu of other, more potent immunosuppressive medications.

*Expert opinion suggests HCQ can be continued during both pregnancy and lactation in patients felt to be benefiting from it.

*The biggest risk factor for HCQ ocular toxicity is daily dose, with safe dosing believed to be 4-5 mg/kg.

*Caution should be exercised when considering HCQ use in patients with pre-existing maculopathy or renal disease (50% reduction in renal function correlates with 2x retinopathy risk), long-term HCQ users, and women concurrently taking tamoxifen (increases retinopathy risk about fivefold). Hepatic disease and older age were thought to be retinopathy risk factors, but this was recently disputed.

Baseline screening for HCQ-induced ocular toxicity should be performed within the 1st year of treatment (implying HCQ can be started prior to baseline screening).
Annual ocular toxicity screening is recommended to begin only after 5 years of use unless patients are considered high-risk or develop ophthalmologic symptoms.
Amsler grids are no longer appropriate for screening.
Appropriate ocular toxicity testing should include 10–2 visual field testing and spectral domain ocular coherence tomography.
Bruising may be a risk factor for the development of HCQ-induced hyperpigmentation.
Periodic CBC and chemistry profiles (including liver and renal function) should be obtained
ABW, Actual body weight; HCQ, hydroxychloroquine; IBW, ideal body weight.

*Similar studies for chloroquine have not been performed, but 5.0 mg/kg HCQ would be equivalent to 2.3 mg/kg chloroquine. Ideal dosing is unclear for obese patients. For example, maximum daily dosing for a woman 5′2″ and 164 lbs (a body mass index of 30 implying obesity per National Institutes of Health guidelines) would be 372 mg based on <5.0 mg/kg ABW and 325 mg based on <6.5 mg/kg IBW (∼50.1 kg). This is a significant difference and may have implications concerning ocular toxicity risk over time.

In Monopoly (which just revised their board pieces — the boot got the boot, but I’m glad the Scottie remains!) you may go directly to jail, without passing go, or collecting $200. In GGA, if without contraindiciations, consider going directly to antimalarials to potentially retrieve your patients from the GGA prison.

1. Recica HF, Ilchyshyn A. Granuloma annulare. In Treatment of Skin Disease, fourth edition. Elsevier 2014; pp 280-3.
2. Grewal SK, et al. Antimalarial therapy for granuloma annulare: Results of a retrospective analysis. J Am Acad Dermatol 2017; 76: 765-7.
3. An J, et al. Antimalarial drugs as immune modulators: New mechanisms for old drugs. Annu Rev Med 2017; 68: 317-330.
4. Fernandez AP. Updated recommendations on the use of hydroxychloroquine in dermatologic practice. J Am Acad Dermatol (in press). DOI: http://dx.doi.org/10.1016/j.jaad.2017.01.012

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