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Aha! The iodide paradox now makes sense!

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By Warren R. Heymann, MD
Oct. 1, 2018

Dermatitis herpetiformis
Dermatitis herpetiformis. Grouped papulovesicles with excoriations on the extensor surface of the shoulder.
Credit: JAAD

In the pre-direct immunofluorescence days of yore (before my time in dermatology), the exacerbation of dermatitis herpetiformis  (DH) by oral or topical iodides could be used as a diagnostic tool.  I have always been perplexed by the “iodide paradox” (my term), wondering why potassium iodide (KI ) is beneficial for neutrophilic disorders such as Sweet syndrome or pyoderma gangrenosum, but aggravating for DH, with its neutrophiic papillary microabscesses.

Aside from neutrophilic disorders, KI has many uses in dermatology including infections (especially sporotrichosis), panniculitides (erythema nodosum, nodular vasculitis), and miscellaneous diseases (erythema multiforme, Beçhet syndrome, Wegener’s granulomatosis). (1)

According to Costa: “Diseases whose pathogenesis involves the action of neutrophils respond well to iodide. It has been demonstrated that iodine, as well as dapsone, has the ability to suppress the production of toxic oxygen intermediates by polymorphonuclear cells and thus exert its anti-inflammatory effect. It also inhibits neutrophil chemotaxis, which is observed in vivo in peripheral blood when KI is taken by the oral route at a dose of 15 mg/kg/day for three days. It is speculated that iodine participates in halogenation reactions by myeloperoxidases, which are fundamental for the action of phagocytes. This mechanism also helps to understand, in part, the usefulness of this medicine against infectious diseases.” (2)

An example of the utility of KI (prescribed as SSKI) is the case of a 5-month-old boy with Sweet syndrome who would respond to systemic steroids, but would flare upon tapering. The addition of SSKI allowed for complete resolution of the disorder following discontinuation of prednisolone. (3)

The exacerbation of DH by iodides was demonstrated in a study of the KI patch test performed in 26 patients with DH. All 5 patients with active disease, but not on treatment, had a positive test, while only 2 of 6 patients on a gluten-free diet, and only 1 of 8 on dapsone, were positive. All 3 patients in remission, and 2 with linear IgA (but with active disease) were negative.  (4)

Mirza and Gharbi state: “The pathology in dermatitis herpetiformis and GSE [gluten-sensitive enteropathy] results from an IgA dominant autoimmune response to transglutaminase molecules. In GSE, the principal target is tissue transglutaminase, whereas in dermatitis herpetiformis there is increasing evidence that epidermal transglutaminase 3 (TG3) may be the dominant antigen. Both proteins have significant homologies in their enzymatic domains and are expressed in normal epidermis, where TG3 is important in cross-linking and maintenance of the cornified envelope.” (5)

KI is a chaotropic agent (a molecule in water solution that can disrupt the hydrogen bonding network between water molecules, which alters the stability of other molecules in solution by weakening the hydrophobic effect). Taylor and Zone hypothesized that conformational change in TG3 induced by high concentrations of KI would allow for increased enzymatic activity. They were able to confirm this hypothesis in a dose-dependent manner in vitro. Presumably the IgA-aggregated enzyme’s increased activity induced by KI enhanced DH in these patients. (6)

Louis Duhring described DH in 1884; the observation that iodides could aggravate the disorder was recognized 7 years later (when Benjamin Harrison was President). I can only imagine how thrilled Dr. Duhring would be to witness the deciphering of DH’s mysteries. I find the work by Taylor and Zone truly illuminating.

Point to remember: KI is useful in most neutrophilic disorders. DH is an exception because of KI’s conformational effect on TG3.

1. Sterling JB, Heymann WR. Potassium iodide in dermatology: A 19th century drug for the 21st century – Uses, pharmacology, adverse effects, and contraindications. J Am Acad Dermatol 2000; 43: 691-7.
2. Costa RO, et al. Use of potassium iodide in dermatology: Updates on an old drug. An Bras Dermatol 2013; 88: 396-02.
3. Tangtatco JAA, et al. Potassium iodide in refractory, recurrent pediatric Sweet syndrome: Guidance in dosing and monitoring. Pediatr Dermatol 2018; 35: 271-3.
4. Haffenden GP, et al. The potassium iodide patch test in dermatitis herpetiformis in relation to treatment with a gluten-free diet and dapsone. Br J Dermatol 1980; 102: 313-317.
5. Mirza HA, Gharbi A. Dermatitis herpetiformis. StatPears (Internet). Treasure Island (FL): StatPearls Publishing 2018-2018 Mar 30
6. Taylor TC, Zone JJ. Sensitivity of transglutaminase 3 in the IgA aggregates in dermatitis herpetiformis skin to potassium iodide. J Invest Dermatol 2018; 138: 2066-8.

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