Treatment of Severe Alopecia Areata: DISCUSSION

17 Feb

Cyclosporine A

The effects of CsA for the treatment of AA have been assessed in various in vitro studies. Oliver et al demonstrated that oral CsA restored hair growth in the Dundee Experimental Bald Rat Model of AA by reducing the mononuclear cell infiltrate around the hair follicles and renewing hair growth. Gafter- Gvili et al reported that CsA-induced hair growth in mice was associated with the inhibition of the calcineurin-dependent activation of NFAT in the follicular keratinocytes. They found that CsA delays the duration of the terminal differentiation of hair follicular keratinocytes and it retards catagen induc­tion. They further demonstrated that CsA induced hair regrowth through delaying the regression of hair follicles by inhibiting the apoptosis of follicular keratinocytes.

However, the use of systemic CsA is also limited because its side effect profile is similar to that of systemic corticosteroids. CsA has a narrow therapeu­tic window and many side effects, including nephro- toxicity, neurotoxicity and hyperglycemia. Because of these problems, therapeutic drug monitoring (TDM) is commonly used to optimize the efficacy and safety of CsA and TDM can provide a more optimal dosing strategy.
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Combination therapy using systemic CsA and low-dose corticosteroid to treat AA has been previously reported on, and TDM has helped to reduce the toxicity of these drugs, such as by pre­venting life-threatening infections via administering concentration-oriented therapy rather than dose- oriented therapy. However, the results of pre­vious studies have shown variable success rates and the therapeutic range of the trough CsA con­centration varied from study to study. Teshima et al treated six AU patients using oral CsA at 2.5 mg/kg/day and prednisolone was started at a dose of 5 mg/day for 7 months. The CsA concen­tration was maintained at 30 to 50 ng/ml. An initial response appeared within 1 month and all the patients showed hair regrowth after 7 months of treatment. Ferrando et al treated 15 patients with severe AA by using CsA monotherapy; they administered CsA at a dose of 5 mg/kg/day for 6 to 12 months and they maintained the CsA con­centration at 100 to 350 ng/ml. One patient dis­continued treatment due to hypertension. Seven of the 14 patients had more than 70% hair regrowth, two had complete hair regrowth and five showed no response. CsA induced severe side effects such as gingival hypertrophy and hyperlipidemia. The authors recommended using CsA for 4 months duration for treating refractory AA.

In our study, 77.4% of the patients had hair regrowth exceeding 50%. They maintained the hair regrowth with trough concentrations between 50 and 150 ng/ml and they had lower mean trough concentrations than did the poor responders. Despite administering a higher dose of CsA to the poor responders, they had poorer hair regrowth rates.

In this study, 12 patients showed side effects associated with CsA. However, the side effects were either temporary or well managed. The hyperli- pidemia and hypertension were controlled using hyrdoxymethylglutaryl-coenzyme A reductase inhi­bitors or antihypertensive agents, and the hyper- bilirubinemia and hematuria cleared after tapering the dose of CsA. The weakness in the lower legs disappeared spontaneously within a few weeks. The mean CsA concentration was 195.8 ng/ml in the patients with side effects and 91.2 ng/ml in those patients without side effects. Interestingly, except one patient, most of the patients without side effects maintained trough concentration under 200 ng/ml, and two-third of the patients with side effects showed side effects when the trough concentration was over 200 ng/ml. In the light of these results, we recommend that it is helpful for minimizing side effects to maintain the CsA trough concentration under 200 ng/ml. A further study with a larger number of AA patients is required to establish a more effective, safe treatment strategy with using oral CsA and low dose corticosteroids combination therapy.

Recent studies have reported on the immunologic aspects associated with the severity and prognosis of AA, and so further studies are needed to identify the genetic and immunologic factors that may play a role for the inter-individual variations in the pharmacokinetics of CsA or the prognosis of AA.
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This study demonstrated that systemic CsA and low-dose corticosteroid combination therapy for patients suffering with severe AA led to a high response rate with steroid-sparing effects, and there were no severe side effects. The therapeutic range of the trough CsA concentration for maintenance was 50 ~ 150 ng/ml.

Further concentration-oriented studies with more patients are required to establish the optimal dose regimen of oral CsA and low dose corticosteroids combination therapy for treating patients with AA.