Insight into the mechanisms of type III minocycline-induced pigmentation removal: A case of repeated immediate pigment clearing with the Q-switched 755-nm alexandrite laser over a 13-year period (2019)

A 68-year-old man with rheumatoid arthritis presented for laser treatment of facial pigmentation (Fig 1, A). He had taken oral minocycline 100 mg 3 times weekly for 8 years (cumulative dose, 124.8 g) because of severe arthritic discomfort. Physical examination showed patchy slate blue/grey hyperpigmentation of the face, gums, teeth, and nail beds, consistent with type III minocycline-induced pigmentation (MP).1Mouton R.W. Jordaan H.F. Schneider J.W. A new type of minocycline-induced cutaneous hyperpigmentation.Clin Exp Dermatol. 2004; 29: 8-14Crossref PubMed Scopus (69) Google Scholar There was no pigmentation of sun-protected areas. Two different laser modalities were tested before treatment: Q-switched 755 nm (Qs755nm) alexandrite (3.4 J/cm2 with 4-mm spot size, 4.8 J/cm2 with 3-mm spot size) and Q-switched 1064 nm (Qs1064nm) neodymium:YAG (yttrium aluminum garnet) (4.8 J/cm2 with 3-mm spot size, 3 J/cm2 with 4-mm spot size). Qs755nm at 2.0 Hz/4-mm spot/3.4 J/cm2 showed the most improvement, with immediate pigment clearing, and was used for full facial treatment (3450 pulses). This setting was also selected because it had the largest spot size with lowest fluence, thus limiting the number of pulses and treatment time required. As observed with the test treatment, pigment resolution occurred immediately on the same day after therapy. There were no significant postoperative complications. Pigment resolution was maintained at 13 months despite continued minocycline use, and the patient was highly satisfied (Fig 1, B). The patient continued taking minocycline 100 mg 3 times weekly and re-presented 3 times over the next 13 years with facial hyperpigmentation (total cumulative dose of minocycline, 202.8 g). Each time, immediate pigment clearing was achieved with the Qs755nm alexandrite laser. Every visit concluded with a discussion that hyperpigmentation would recur with continued minocycline ingestion. At the time of this article's writing, he continues to take minocycline. The pretreatment biopsy showed intracellular and extracellular type III MP in the dermis1Mouton R.W. Jordaan H.F. Schneider J.W. A new type of minocycline-induced cutaneous hyperpigmentation.Clin Exp Dermatol. 2004; 29: 8-14Crossref PubMed Scopus (69) Google Scholar (Fig 2, A), with notably no detectable change in the posttreatment biopsy (Fig 2, B). However, in contrast to the pretreatment biopsy, the extracellular pigment in the posttreatment sample was no longer highlighted by Fontana-Masson (FM) stain, but intracellular pigment continued to stain with FM (Fig 2, C and D). The change in melanin staining is consistent with the clinically observed reduction in pigment intensity. Although minocycline is generally safe, cutaneous pigmentation is a common adverse effect.2La Placa M. Infusino S.D. Balestri R. Vincenzi C. Minocycline-induced blue-gray discoloration.Skin Appendage Disord. 2017; 3: 161-162Google Scholar Type III is the least common MP, involving sun-exposed areas and staining positively only for melanin. It is often unremitting or requires multiple treatments to achieve improvement.2La Placa M. Infusino S.D. Balestri R. Vincenzi C. Minocycline-induced blue-gray discoloration.Skin Appendage Disord. 2017; 3: 161-162Google Scholar Although we are not the first to document successful Qs laser treatment of MP,3Alster T.S. Gupta S.N. Minocycline-induced hyperpigmentation treated with a 755-nm Q-switched alexandrite laser.Dermatol Surg. 2004; 30: 1201-1204Crossref PubMed Scopus (31) Google Scholar, 4Green D. Friedman K.J. Treatment of minocycline-induced cutaneous pigmentation with the Q-switched alexandrite laser and a review of the literature.J Am Acad Dermatol. 2001; 44: 342-347Scopus (58) Google Scholar, 5Nisar M.S. Iyer K. Brodell R.T. Lloyd J.R. Shin T.M. Ahmad A. Minocycline-induced hyperpigmentation: comparison of 3 Q-switched lasers to reverse its effects.Clin Cosmet Investig Dermatol. 2013; 31: 159-162Google Scholar our case is notable for the rapidity of pigment resolution repeated on multiple occasions over 13 years. In contrast to previous cases requiring multiple treatments,3Alster T.S. Gupta S.N. Minocycline-induced hyperpigmentation treated with a 755-nm Q-switched alexandrite laser.Dermatol Surg. 2004; 30: 1201-1204Crossref PubMed Scopus (31) Google Scholar, 4Green D. Friedman K.J. Treatment of minocycline-induced cutaneous pigmentation with the Q-switched alexandrite laser and a review of the literature.J Am Acad Dermatol. 2001; 44: 342-347Scopus (58) Google Scholar our patient experienced immediate and sustained cosmetic improvement after only 1 treatment. Although successful treatment of minocycline-related pigmentation has also been reported with newer picosecond lasers,6Sasaki K. Ohshiro T. Ohshiro T. et al.Type 2 minocycline-induced hyperpigmentation successfully treated with the novel 755nm picosecond alexandrite laser – a case report.Laser Ther. 2017; 26: 137-144Google Scholar, 7Rodrigues M. Bekhor P. Treatment of minocycline-induced cutaneous pigmentation with the picosecond alexandrite (755-nm) laser.Dermatol Surg. 2015; : 1179-1182Google Scholar these devices are more expensive and less accessible than the Qs alexandrite laser. Other reports have also described the treatment of minocycline-associated pigmentation with combination laser modalities.8Vangipuram R.K. DeLozier W.L. Geddes E. Friedman P.M. Complete resolution of minocycline pigmentation following a single treatment wit non-ablative 1550-nm fractional resurfacing in combination with the 755-nm Q-switched alexandrite laser.Lasers Surg Med. 2016; 48: 234-237Google Scholar However, this is less convenient and more costly than using a single device such as the Qs alexandrite, as shown in our case. Because our patient continued to take minocycline, he did experience re-pigmentation; however, each recurrence resolved immediately with 1 treatment using the Qs755nm alexandrite laser, showing its effectiveness in achieving MP clearing. The findings of our case are reminiscent of immediate pigment darkening resulting from ferric oxide (red-brown) reduction to ferrous oxide (black).9Fitzpatrick R.E. Lupton J.R. Successful treatment of treatment-resistant laser-induced pigment darkening of a cosmetic tattoo.Lasers Surg Med. 2000; 27: 358-361Crossref PubMed Scopus (55) Google Scholar We term our outcome immediate pigment lightening, which may be another example of Q-switched laser alteration of dermal pigmentation through a physicochemical mechanism. The pigment in our case may be an insoluble minocycline-cation coordination complex, with calcium or magnesium as central metal ions. Because tetracyclines are susceptible to heat and photodecomposition,10Hassani M. Lazaro R. Perez C. Condon S. Pagan R. Thermostability of oxytetracycline, tetracycline, and doxycycline at ultrahigh temperatures.J Agric Food Chem. 2008; 56: 2676-2680Crossref PubMed Scopus (63) Google Scholar a physicochemical process that disrupts these complexes could explain our findings. Specifically, the discrepancy between H&E and FM stains suggests that extracellular pigment is still present after treatment but in an altered chemical state, such that it can no longer absorb visible light. To our knowledge, this is the first case to show immediate pigment lightening of type III MP repeated over multiple instances using only the Qs755nm alexandrite laser. We propose that an insoluble minocycline-cation coordination complex with selective sensitivity to the Qs755nm alexandrite laser may be deposited within the dermis. Our case shows that the Qs755nm alexandrite laser may be a preferable treatment modality for type III MP, especially because it is a single device and may be more convenient and cost effective compared with other laser modalities or combination laser treatments. Further studies investigating the mechanisms of MP deposition and resolution are warranted to clarify our findings.