http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, 2014; 25(6): 489–494 ! 2014 Informa UK Ltd. DOI: 10.3109/09546634.2013.848259
REVIEW ARTICLE
Acrodermatitis continua of Hallopeau (ACH): Two cases successfully treated with adalimumab Luisa Di Costanzo, Maddalena Napolitano, Cataldo Patruno, Mariateresa Cantelli, and Nicola Balato
Abstract
Keywords
Acrodermatitis continua of Hallopeau (ACH), also known as dermatitis repens or acrodermatitis perstans, is a rare acropustular eruption, characterized by sterile pustules, paronychia and atrophic skin changes, onychodystrophy and osteolysis of the distal phalanges of the fingers and toes. While some consider ACH a distinct entity, many believe it to be a variant of pustular psoriasis, especially as cases of ACH progressing to generalized pustular psoriasis. The treatment options used are various; however, its typical cyclic recurrences, which induce important physical and psychological morbidity, may render this pathology difficult to treat. Hence, it was considered important to review the evolution of treatment options available thus far including use of biologics. Hereby, we report two patients with ACH who were successfully treated with adalimumab. By analogy to the efficacy of TNF-a antagonists in the treatment of generalized pustular psoriasis, the two patients we report illustrate the long-term efficacy and safety of adalimumab in the treatment of Hallopeau’s acrodermatitis refractory to therapies.
acrodermatitis continua of Hallopeau, adalimumab, anti-TNF-a agents
Introduction Acrodermatitis continua of Hallopeau (ACH), also known as dermatitis repens or acrodermatitis perstans, is a rare form skin disease predominantly affecting middle-aged women, characterized by chronic and recurrent pustular eruption of the distal phalanges of the fingers and toe (1). ACH can involve the nail matrix with onychodystrophy, possibly progressing to anonychia and rarely to mutilation of the distal phalanges. Mutilation arises from involvement of the bone, radiographically visible as osteolysis of the distal phalange, often perceived by the patient as joint pain and stiffness. Quality of life of patients suffering from ACH is greatly impaired because fragility and tenderness of the skin on the hands limits the daily activities. The etiology of ACH is unknown. However, the eruption onset is sometimes associated with trauma or infection, such an episode is not always reported. Different etiopathological hypotheses have been proposed for ACH; some authors classify this dermatosis as a variant of pustular psoriasis because of the histopathological features, others consider ACH as a separate entity based on its unique clinical picture. Differential diagnosis based on clinical appearance includes chronic bacterial, fungal or viral paronychia, superinfected malignancy, secondarily infected contact dermatitis and vesicular eczema (1). Treatment is difficult, limited success is reported with numerous agents including topical treatments, photochemotherapy, cyclosporin, methotrexate, retinoids, dapsone and tetracyclines (2). Recently, effective treatment with biologic agents (3–6) as well as successful combined therapies (7) is reported. Spontaneous remission of the disease is sometimes Correspondence: Mariateresa Cantelli, Department of Dermatology, University of Naples Federico II, Via S. Pansini n.5, 80131 Napoli, Italy. Tel: þ39-3491337336. Fax: þ39-081-7462442. E-mail: [email protected]
History Received 27 June 2013 Accepted 5 September 2013 Published online 11 November 2013
seen (1). Herein, we report two cases of ACH successfully treated with adalimumab.
Case report 1 A 53-year-old man presented with a 10-year history of erythema and pustular eruption on the fourth finger of his right hand, showing periungual erythema, scaling and severe nail dystrophy; the nail plate appeared edematous, thickened and covered by crusts, associated with chronic arthralgy of the interphalangeal joints and osleolysis of the distal phalanx of the affected digits (Figure 1A). No other lesions were noted over the patient body surface area. The patient was otherwise in good health with the exception of heart attack that occurred 4 years before and currently in treatment with acetylsalicylic acid. Bacterial and fungal cultures of pustules were negative. Histopathology showed epidermal hyperplasia, parakeratosis with neutrophils in the stratum corneum and spinous layer, absence of granular layer and suprapapillary thinning. The superficial dermis revealed dilated capillaries and sparse perivascular lymphohistiocytic infiltrate. Staining with periodicacid–Schiff was negative for fungal elements. These findings confirmed our diagnosis of ACH. Previous treatments with topical cream (clobetasol propionate 0.05%), topical and systemic antibiotics, systemic retinoids (acitretin 50 mg daily for 24 weeks), cyclosporine A (200 mg daily for 24 weeks) and methotrexate (15 mg/week for 12 weeks) had all been unsuccessful. Because of the lack of efficacy of previous treatments and severe disability, we decided to use the recombinant, fully human, antitumor necrosis factor (anti-TNF), a monoclonal IgG1 antibody adalimumab (8). Pretreatment screening included full blood count, urea and electrolytes, liver function tests and antinuclear antibodies (ANA). A personal and family history of tuberculosis
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Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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Figure 1. Case report 1. The fourth finger of the right hand of patient (A) before adalimumab treatment and (B) after 40 weeks of adalimumab treatment.
was taken and patient was screened for tuberculosis with the tuberculin test (Mantoux), in particular two tuberculin units were used, and a chest X-ray. Adalimumab was introduced (subcutaneous injection – at the dose of 40 mg every other week). The patient’s joint symptoms disappeared completely, and within 40 weeks there was complete clearance of skin lesions of the hands (Figure 1B). Because of complete resolution, the therapy was discontinued, but after 28 weeks, erythema of the skin returned again, including postules and fingers fissures. Adalimumab therapy was started again (at the same dose) and the patient is still under treatment.
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Figure 2. Case report 2. Hands of the patient (A) before adalimumab treatment and (B) after 12 weeks of adalimumab treatment.
dose followed by 1 mg/kg weekly) was administered to the patient with improvement (3). After efalizumab withdrawal in medical markets (because of a potential risk to patients of developing progressive multifocal leukoencephalopathy), the patient discontinued the therapy and had a rapid worsening of ACH. Therefore, adalimumab was introduced (40 mg every other weeks). After 3 months of therapy, she showed a remarkable amelioration of the symptoms and the growth of the nail was increased (Figure 2A,B).
Discussion Case report 2 A 62-year-old woman presented to our department with a 2-year history of multiple, asymptomatic pustules, erythema and scales between the proximal nail fold and the distal interphalangeal joint on third finger of her right hand. A slight onychodystrophy of the same digit was observed. No other lesions were noted over the patient body surface area. There was no personal or familial history of psoriasis. The patient was otherwise in good health with the exception of a lower limb occlusive arteriopathy, treated with surgery 4 years before, and in treatment with acetylsalicylic acid. Bacterial and fungal cultures of pustules were carried out showing the growth of normal saprophytic flora. A 3-mm punch biopsy was performed confirming our clinical suspected diagnosis of ACH. Previous treatments with potent topical steroids, calcipotriol, and oral and topical antibiotics had all been unsuccessful. Systemic retinoids (acitretin 50 mg daily for 24 weeks) did not lead to any improvement. Efalizumab (0.7 mg/kg conditioning
ACH was first reported in 1888 by Radcliffe-Crocker named as ‘‘dermatitis repens’’ (10). In 1890, Hallopeau described a series of cases to which he applied the term ‘‘acrodermatitis suppurativa continua’’ and which he considered to arise from a suppurative process caused by Staphylococcus albus or Staphylococcus aureus (11). In 1925, Strandberg suggested for the first time that this disorder might be associated with pustular psoriasis (12) and Ingram put in relationship psoriasis with ACH (13). In 1944, Lever described the clinical and histopathological features of acrodermatitis continua (14). According to some authors, acrodermatitis is a unique and separate clinical entity, distinct from psoriasis (15). However, other authors believed that the disease was indistinguishable from pustular psoriasis on histopathology. Over the years, many studies have attempted to assess the relationship of ACH with psoriasis. Hence, it has been concluded that ACH is a variant of pustular psoriasis (16–18).
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ACH treatments The treatment of ACH is difficult because of the typical course of the disease, characterized by chronic and frequent relapses at the cessation of therapy. Numerous therapies have been published as case study in the literature (Tables 1, 2, and 3) but there remains that there is no standard therapy for this disease.
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unresponsiveness to ACH in three weeks of monotherapy with 50 mg/g calcipotriol applied twice daily (29) . All these studies are listed in Table 1. A positive response of ACH to topical combined therapy with calcipotriol þ tacrolimus 0.1% highlighted by Brill et al. (30) and Brunasso et al. (31) or with calcipotriol þ bethamethasone dipropionate by Sotiriadis et al. (32) is also reported in literature (Table 2).
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Topical treatments White and Main reported a 63-year-old man suffering from ACH with widespread pustulation of the fingers. Topical combination therapy comprising 0.05% clobetasol propionate, 0.5% neomycin sulfate and 100 000 units of nystatin per gram was given under occlusion twice daily along with oral cloxacillin. Dramatic regression of the lesions was observed within 12 hours, with no recurrence (19). Piquero-Casals et al. reported a 65-year-old woman suffering from ACH treated with oral tetracycline 500 mg four times daily, and topical betamethasone valerate cream, after one week (20). Notowicz et al. and Tsuji and Nishimura reported the efficacy of topical cytostatic agents (mechlorethamine hydrochloride and fluorouracil, respectively) (21,22). Wilsmann-Theis et al. successfully used topical 0.1% tacrolimus, applied once during the night, in two patients suffering from ACH refractory to other topical and oral medications (23). Tacrolimus 0.1% ointment was, therefore, recommended for use in the initial phase of ACH, twice daily under occlusion overnight for 1–2 weeks, then once daily under occlusion overnight for 1–2 weeks and finally once weekly as maintenance therapy (24). Calcipotriol, a synthetic vitamin D analogue, was used first in 1996 by Emtestam and Wede´n in a 71-year-old woman with ACH who showed only partial response to the administration of local remedies (25). She was successfully treated with topical application of calcipotriol, which resulted in the cessation of pustule formation and clinical improvement of skin fragility, tender edema and erythema. Piraccini et al. reported that 9 of their 15 patients with ACH of the nail responded to topical calcipotriol (26). Mozzanica and Cattaneo reported a 40-year-old man with ACH, successfully treated with twice daily application of 50 lg/g calcipotriol ointment. Reduction in lesions and symptoms was observed after four weeks of therapy, and complete remission was noted at four months (27). Kokelj et al. reported seven patients resistant to topical calcipotriol (28). Kuijpers et al. also reported
Systemic treatments Phototherapy and photochemotherapy have been used in five cases only, also in children (33,34). Kiszewski et al. reported the utility of UVB þ thalidomide (50 mg/day for 2 months) in a 2-year-old boy suffering from ACH, with excellent response (35). Bordignon et al. successfully treated a 9-year-old boy with a two-year history of ACH with nb-UVB phototherapy, twice per week at a starting dose of 80% MED and increased in increments of 20% every session. Complete remission of the lesions was achieved after 36 treatment sessions (36). Methotrexate has been used for the treatment of ACH with varying responses. Harland et al. reported a case of ACH in which partial response to oral methotrexate was seen (37). Chowdhury et al. reported a patient who was treated with methotrexate 15 mg/week and oral propylthiouracil (PTU) 100 mg for 14 weeks (38). Zachariae and Thestrup-Pedersen reported the first successful use of cyclosporine (CSA) in a 58-year-old woman with a history of severely disabling ACH (39). CSA, at a dose of 14 mg/kg/day, resulted in the cessation of new pustule formation after one week of therapy. However, when the dose was reduced to 5 mg/kg, the patient developed a few pustules. Resolution of pustules was apparent as soon as the dose was increased to 7.5 mg/kg/day. Many other cases are also reported (37,40). Few reports have demonstrated the role of oral retinoids (etretinate and acitretin) administered either as monotherapy or in combination with other topical and systemic agents for the treatment of ACH (24). Pearson et al. reported the first demonstration of the role of etretinate in a 38-year-old woman with ACH refractory to treatment with topical steroids, topical and oral antibiotics, whirlpool baths, topical tars, oral hydroxyurea, colchicines, dapsone and UVB light (15).
Table 1. Overview of literature of the possible topical treatments used in ACH. Year of report
Topical treatment
Notowicz et al. (21) White and Main (19) Tsuji and Nishimura (22) Emtestam and Wede´n (25) Kuijpers et al. (29) Mozzanica and Cattaneo (27)
Mechloretamine Clobetasol propionate Topical fluorouracil Topical calcipotriol Topical calcipotriol Topical calcipotriol
Kokelj et al. (28) Piraccini et al. (26) Piquero-Casals et al. (20) Wilsmann-Theis (23)
Topical calcipotriol Topical calcipotriol Bethametasone valerate Tacrolimus 0.1%
Number of patients 1 1 1 1 1 1 7 15 1 2
Results Remission Remission Remission Remission Unresponsiveness Remission
Follow-up recurrences No recurrence No recurrence Recovery after 3 months No recurrence Two recurrence in the next 26 months, also treated with calcipotriol
Unresponsiveness Regression on nine patients No recurrence Regression Controlled with topical SS Regression No recurrence
Table 2. Overview of literature of some topical combination therapies used in ACH. Year of report Brill et al. (30) Brunasso et al. (31) Sotiriadis et al. (32)
Combination therapy
Number of patient
Results
Follow-up recurrences
Calcipotriol þ tacrolimus 0.1% Calcipotriol þ tacrolimus 0.1% Calcipotriol þ bethamethasone dipropionate
1 1 1
Remission Remission Remission
No recurrence No recurrence No recurrence
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Table 3. Overview of literature of systemic therapies used in ACH.
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Year of report
Systemic therapy
Number of patients
Results
Follow-up recurrence
Pearson et al. (15)
Etretinate (20 mg/die)
1
Remission
Zachariae and Thestrup-Pedersen (39) Korstanje et al. (54) Van Dooren-Greebe et al. (42) Peter et al. (55) Slawsky and Libow (41)
Cyclosporine (7.5 mg/kg/die)
1
Remission
Cyclosporine (8 mg/kg/die) þ prednisolone Acitretin (45 mg/die) Cyclosporine (4.8 mg/kg/die) Etretinate (25 mg twice daily)
1 1 1 1
Remission Remission Remission Remission
Gupta et al. (56) Harland et al. (37)
Cyclosporine (6 mg/kg/die) Cyclosporine (5 mg/kg/die)
1 1
Remission Remission
Van der Kerkhof et al. (43) Kuijpers et al. (29) Behrens et al. (33) Chowdhury and Motley (38)
Acitretin (35–40 mg/die) Acitretin (35 mg/die) þ topical calcipotriol PUVA MTX (15 mg/week) þ PTU (300 mg/die)
1 1 1 1
Remission Remission Remission Remission
Mang et al. (4) Tobin and Kirby (7)
Infliximab (5 mg/kg) Adalimumb (40 mg/weekly) þ acitretin (50 mg/die) Etanercept (25 mg twice/week) þ acitretin (75 mg/die) Infliximab (5 mg/kg)
1 1
Remission Remission
Recurrence after 1 week of stopping etretinate responding to CsA Recurrence a dose reduction to 5 mg/kg/die No recurrence No recurrence No recurrence Recurrence a dose reduction 35 mg/die No recurrence Recurrence a dose reduction to 3 mg/Kg/die No recurrence No recurrence No recurrence No recurrence but the patient developed PTUinduced pancytopenia No recurrence No recurrence
1
Remission
No recurrence
1
Remission
Etanercept Etanercept (50 mg bi-weekly) Etanercept (25 mg twice per week) Broad-band UVB þ thalidomide Infliximab (5 mg/kg) þ acitretin (0,25 mg/kg/die) þ prednisone 10 mg/die 8-methoxypsoralen þ nb-UVB Adalimumab (40 mg/weekly) Efalizumab (0.7 mg/kg) nb-UVB phototherapy Etanercept (25 mg twice/week)
1 1 1 1 1
Remission Remission Remission Remission Remission
After 40 months, the patient developed high ANA titers No recurrence No recurrence No recurrence No recurrence No recurrence
1 3 1 1 1
Remission Remission Remission Remission Remission
Kazinski et al. (46) Ahmad and Rogers (50) Nikkels et al. (57) Bonish et al. (58) Thielen et al. (59) Kiszewaki et al. (35) Rubio et al. (44) Durmazlar et al. (34) Ryan et al. (6) Balato et al. (3) Bordignon et al. (36) Puig et al. (45)
Slawsky and Libow recorded a dramatic improvement with etretinate 25 mg twice daily for one month in a 24-year-old patient who had suffered from ACH since early childhood (41). Van Dooren-Greebe et al. reported the complete clearance of lesions with oral acitretin at a dose of 45 mg/day (42). Van der Kerkhof et al. treated a 53-year-old man with ACH and myelodysplastic syndrome with acitretin at a dose of 35–40 mg/day and noted improvement after one month of treatment (43). Recent publications report the use of anti-TNF-a agents, sometimes added to conventional treatments to treat ACH. In 2004, Mang et al. reported the efficacy of infliximab in ACH for the first time (4). They had successfully treated a 54-year-old woman with 23 monthly infusions without any side effects. Also, Rubio et al. successfully treated with infliximab a 60-year-old woman affected with ACH of 15 years’ duration which was refractory to multiple topical and oral treatments (44). A combination therapy of oral acitretin 0.25 mg/kg/day, prednisone 10 mg/day, and infliximab 5 mg/kg by IV infusion was administered once and again after a two week interval. A remarkable improvement in the lesions was seen after two weeks, and at this point acitretin and prednisone were stopped. Another dose of infliximab was administered at week 6, followed by a maintenance dose administered at eight-week intervals. No relapse was observed during a follow-up of 32 months (44). In 2005, Tobin and Kirby reported a case of a 54-year-old woman initially treated with infliximab (7); however, a second
No recurrence No recurrence No recurrence No recurrence Recurrence 3 weeks after discontinuation of treatment
infusion was ineffective because the patient developed infusion reaction and high titers of ANA. Among TNF-a blockers, etanercept is the most widely used to treat ACH. Puig et al. used etanercept (in combination with methotrexate) to treat ACH in a 72-year-old woman with a twoyear history of a severe pustular eruption affecting her nails and periungual areas of all fingers and toes, and with plaques of psoriasis elsewhere (45). After the first positive effects, for the recovery of disease, etanercept was replaced with adalimumab. Methotrexate was discontinued five months later, and the patient was reported to be asymptomatic and free of relapse over a follow-up of nine months. Kazinski et al. successfully treated an ACH patient with a combination therapy of acitretin and etanercept (46). This combination therapy was confirmed by Silpa-archa et al. who report a case of recalcitrant ACH who previously failed to topical corticosteroid, methotrexate, acitretin and phototherapy and rapidly responded to etanercept in combination with acitretin (47). On the other hand, six reports have shown reduced response or failure of treatment with etanercept administered either alone or in combination with other drugs (6,45,48–50). In the literature, only one case of ACH treated with efalizumab has been reported (3). Adalimumab elicited an excellent response in ACH. In 2009, Ryan et al. reported two ACH patients successfully treated with adalimumab (6). Tobin and Kirby treated a patient with a combination of adalimumab 40 mg weekly and acitretin 50 mg
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daily within one month (7). Its safety was also confirmed by Dini et al. who used adalimumab to treat refractory paediatric ACH (51) and its validity by Sopkovich et al. who treated ACH in a 79year-old man with a history of gout and chronic obstructive pulmonary disease (52). Furthermore a case of ACH treated with ustekinumab is reported, even if further studies are needed (53). All these studies are listed in Table 3. Our cases confirm the efficacy and the safety of adalimumab as a monotherapy for a continuous treatment of ACH in a patient that was unresponsive to previous therapies. The quality of life was impaired because of pain and immobility. Therefore, we decided to give adalimumab in accordance with the literature. These cases support the observation that adalimumab may represent a promising alternative in multidrug-resistant ACH.
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Conclusion ACH is an interesting entity, its clinical diagnosis is sometimes difficult and even dermatologists often fail to recognize this condition because various conditions may masquerade as ACH, clinically and/or histologically. The disease is notoriously difficult to treat and limited success is reported with numerous topical e/o systemic agents. We described our cases and summarized the literature because it would be important to have outcomes of treatment with topical and systemic, monotherapy and combination therapy, and with the recently emerged biologics.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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38. Chowdhury MM, Motley RJ. Treatment of acrodermatitis continua of Hallopeau with oral propylthiouracil and methotrexate. Clin Exp Dermatol. 2001;26:657–60. 39. Zachariae H, Thestrup-Pedersen K. Cyclosporin A in acrodermatitis continua. Dermatologica. 1987;175:29–32. 40. Baker H. Localized pustular psoriasis. In: Roenigk HH, Maibach HI, eds. Psoriasis. New York: Dekker, 1986. p 40–5. 41. Slawsky LD, Libow LF. Successful treatment of acrodermatitis continua of Hallopeau with etretinate. J Am Acad Dermatol. 1990; 23:1176–8. 42. Van Dooren-Greebe RJ, van de Kerkhof PC, Chang A, Happle R. Acitretin monotherapy in acrodermatitis continua Hallopeau. Acta Derm Venereol. 1989;69:344–6. 43. Van der Kerkhof PC, Steijlen PM, Raymakers RA. Acrodermatitis continua of Hallopeau in a patient with myelodysplastic syndrome. Br J Dermatol. 1996;134:754–7. 44. Rubio C, Martin MA, Arranz Sa´nchez DM, et al. Excellent and prolonged response to infliximab in a case of recalcitrant acrodermatitis continua of Hallopeau. J Eur Aca Dermatol Venereol. 2009;23:707–8. 45. Puig L, Barco D, Vilarrasa E, Alomar A. Treatment of acrodermatitis continua of Hallopeau with TNF blocking agents: case report and review. Dermatology. 2010;220: 154–8. 46. Kazinski K, Joyce KM, Hodson D. The successful use of etanercept in combination therapy for treatment of acrodermatitis continua of Hallopeau. J Drugs Dermatol. 2005;4:360–4. 47. Silpa-archa N, Wongpraparut C. A recalcitrant acrodermatitis continua of Hallopeau successfully treated with etanercept. J Med Assoc Thai. 2011;94:1154–7. 48. Ahmad K, Rogers S. Two years of experience with etanercept in recalcitrant psoriasis. Br J Dermatol. 2007;156: 1010–14.
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49. Adis en E, Oztas M, Gu¨rer MA. Lack of efficacy of etanercept in acrodermatitis continua of Hallopeau. Int J Dermatol. 2007;46: 1205–7. 50. Ahmad K, Rogers S. Three years’ experience with infliximab in recalcitrant psoriasis. Clin Exp Dermatol. 2006;31:630–3. 51. Dini V, Barbanera S, Romanelli M. Efficacy of Adalimumab for the Treatment of Refractory Paediatric Acrodermatitis Continua of Hallopeau. Acta Derm Venereol. 2013 Feb 14. doi: 10.2340/ 00015555-1540. 52. Sopkovich JA, Anetakis Poulos G, Wong HK. Acrodermatitis continua of hallopeau successfully treated with adalimumab. J Clin Aesthet Dermatol. 2012;5:60–2. 53. Allegue F, Pardo J, Ruffin J, et al. Treatment of acrodermatitis continua of hallopeau with ustekinumab. J Eur Acad Dermatol Venereol. 2010;24(Suppl 4):1–83. 54. Korstanje MJ, Bessems PJ, Hulsmans RF, et al. Pustular psoriasis and acrodermatitis continua (Hallopeau) need high doses of systemic ciclosporin A. Dermatologica. 1989;179:90–1. 55. Peter RU, Ruzicka T, Donhauser G, et al. Acrodermatitis continuatype of pustular psoriasis responds to low-dose cyclosporine. J Am Acad Dermatol. 1990;23(3 Pt 1):515–6. 56. Gupta AK, Ellis CN, Nickoloff BJ, et al. Oral cyclosporine in the treatment of inflammatory and noninflammatory dermatoses. A clinical and immunopathologic analysis. Arch Dermatol. 1990;126:339–50. 57. Nikkels AF, Pie´rard GE. Etanercept and recalcitrant acrodermatitis continua of Hallopeau. J Drugs Dermatol. 2006;5:705–6. 58. Bonish B, Rashid RM, Swan J. Etanercept responsive acrodermatitis continua of Hallopeau: is a pattern developing? J Drugs Dermatol. 2006;5:903–4. 59. Thielen AM, Barde C, Marazza G. Long-term control with etanercept (Enbrel) of a severe acrodermatitis continua of Hallopeau refractory to infliximab (Remicade). Dermatology. 2008;217:137–9.
REVIEW ARTICLE
Acrodermatitis continua of Hallopeau (ACH): Two cases successfully treated with adalimumab Luisa Di Costanzo, Maddalena Napolitano, Cataldo Patruno, Mariateresa Cantelli, and Nicola Balato
Abstract
Keywords
Acrodermatitis continua of Hallopeau (ACH), also known as dermatitis repens or acrodermatitis perstans, is a rare acropustular eruption, characterized by sterile pustules, paronychia and atrophic skin changes, onychodystrophy and osteolysis of the distal phalanges of the fingers and toes. While some consider ACH a distinct entity, many believe it to be a variant of pustular psoriasis, especially as cases of ACH progressing to generalized pustular psoriasis. The treatment options used are various; however, its typical cyclic recurrences, which induce important physical and psychological morbidity, may render this pathology difficult to treat. Hence, it was considered important to review the evolution of treatment options available thus far including use of biologics. Hereby, we report two patients with ACH who were successfully treated with adalimumab. By analogy to the efficacy of TNF-a antagonists in the treatment of generalized pustular psoriasis, the two patients we report illustrate the long-term efficacy and safety of adalimumab in the treatment of Hallopeau’s acrodermatitis refractory to therapies.
acrodermatitis continua of Hallopeau, adalimumab, anti-TNF-a agents
Introduction Acrodermatitis continua of Hallopeau (ACH), also known as dermatitis repens or acrodermatitis perstans, is a rare form skin disease predominantly affecting middle-aged women, characterized by chronic and recurrent pustular eruption of the distal phalanges of the fingers and toe (1). ACH can involve the nail matrix with onychodystrophy, possibly progressing to anonychia and rarely to mutilation of the distal phalanges. Mutilation arises from involvement of the bone, radiographically visible as osteolysis of the distal phalange, often perceived by the patient as joint pain and stiffness. Quality of life of patients suffering from ACH is greatly impaired because fragility and tenderness of the skin on the hands limits the daily activities. The etiology of ACH is unknown. However, the eruption onset is sometimes associated with trauma or infection, such an episode is not always reported. Different etiopathological hypotheses have been proposed for ACH; some authors classify this dermatosis as a variant of pustular psoriasis because of the histopathological features, others consider ACH as a separate entity based on its unique clinical picture. Differential diagnosis based on clinical appearance includes chronic bacterial, fungal or viral paronychia, superinfected malignancy, secondarily infected contact dermatitis and vesicular eczema (1). Treatment is difficult, limited success is reported with numerous agents including topical treatments, photochemotherapy, cyclosporin, methotrexate, retinoids, dapsone and tetracyclines (2). Recently, effective treatment with biologic agents (3–6) as well as successful combined therapies (7) is reported. Spontaneous remission of the disease is sometimes Correspondence: Mariateresa Cantelli, Department of Dermatology, University of Naples Federico II, Via S. Pansini n.5, 80131 Napoli, Italy. Tel: þ39-3491337336. Fax: þ39-081-7462442. E-mail: [email protected]
History Received 27 June 2013 Accepted 5 September 2013 Published online 11 November 2013
seen (1). Herein, we report two cases of ACH successfully treated with adalimumab.
Case report 1 A 53-year-old man presented with a 10-year history of erythema and pustular eruption on the fourth finger of his right hand, showing periungual erythema, scaling and severe nail dystrophy; the nail plate appeared edematous, thickened and covered by crusts, associated with chronic arthralgy of the interphalangeal joints and osleolysis of the distal phalanx of the affected digits (Figure 1A). No other lesions were noted over the patient body surface area. The patient was otherwise in good health with the exception of heart attack that occurred 4 years before and currently in treatment with acetylsalicylic acid. Bacterial and fungal cultures of pustules were negative. Histopathology showed epidermal hyperplasia, parakeratosis with neutrophils in the stratum corneum and spinous layer, absence of granular layer and suprapapillary thinning. The superficial dermis revealed dilated capillaries and sparse perivascular lymphohistiocytic infiltrate. Staining with periodicacid–Schiff was negative for fungal elements. These findings confirmed our diagnosis of ACH. Previous treatments with topical cream (clobetasol propionate 0.05%), topical and systemic antibiotics, systemic retinoids (acitretin 50 mg daily for 24 weeks), cyclosporine A (200 mg daily for 24 weeks) and methotrexate (15 mg/week for 12 weeks) had all been unsuccessful. Because of the lack of efficacy of previous treatments and severe disability, we decided to use the recombinant, fully human, antitumor necrosis factor (anti-TNF), a monoclonal IgG1 antibody adalimumab (8). Pretreatment screening included full blood count, urea and electrolytes, liver function tests and antinuclear antibodies (ANA). A personal and family history of tuberculosis
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Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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Figure 1. Case report 1. The fourth finger of the right hand of patient (A) before adalimumab treatment and (B) after 40 weeks of adalimumab treatment.
was taken and patient was screened for tuberculosis with the tuberculin test (Mantoux), in particular two tuberculin units were used, and a chest X-ray. Adalimumab was introduced (subcutaneous injection – at the dose of 40 mg every other week). The patient’s joint symptoms disappeared completely, and within 40 weeks there was complete clearance of skin lesions of the hands (Figure 1B). Because of complete resolution, the therapy was discontinued, but after 28 weeks, erythema of the skin returned again, including postules and fingers fissures. Adalimumab therapy was started again (at the same dose) and the patient is still under treatment.
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Figure 2. Case report 2. Hands of the patient (A) before adalimumab treatment and (B) after 12 weeks of adalimumab treatment.
dose followed by 1 mg/kg weekly) was administered to the patient with improvement (3). After efalizumab withdrawal in medical markets (because of a potential risk to patients of developing progressive multifocal leukoencephalopathy), the patient discontinued the therapy and had a rapid worsening of ACH. Therefore, adalimumab was introduced (40 mg every other weeks). After 3 months of therapy, she showed a remarkable amelioration of the symptoms and the growth of the nail was increased (Figure 2A,B).
Discussion Case report 2 A 62-year-old woman presented to our department with a 2-year history of multiple, asymptomatic pustules, erythema and scales between the proximal nail fold and the distal interphalangeal joint on third finger of her right hand. A slight onychodystrophy of the same digit was observed. No other lesions were noted over the patient body surface area. There was no personal or familial history of psoriasis. The patient was otherwise in good health with the exception of a lower limb occlusive arteriopathy, treated with surgery 4 years before, and in treatment with acetylsalicylic acid. Bacterial and fungal cultures of pustules were carried out showing the growth of normal saprophytic flora. A 3-mm punch biopsy was performed confirming our clinical suspected diagnosis of ACH. Previous treatments with potent topical steroids, calcipotriol, and oral and topical antibiotics had all been unsuccessful. Systemic retinoids (acitretin 50 mg daily for 24 weeks) did not lead to any improvement. Efalizumab (0.7 mg/kg conditioning
ACH was first reported in 1888 by Radcliffe-Crocker named as ‘‘dermatitis repens’’ (10). In 1890, Hallopeau described a series of cases to which he applied the term ‘‘acrodermatitis suppurativa continua’’ and which he considered to arise from a suppurative process caused by Staphylococcus albus or Staphylococcus aureus (11). In 1925, Strandberg suggested for the first time that this disorder might be associated with pustular psoriasis (12) and Ingram put in relationship psoriasis with ACH (13). In 1944, Lever described the clinical and histopathological features of acrodermatitis continua (14). According to some authors, acrodermatitis is a unique and separate clinical entity, distinct from psoriasis (15). However, other authors believed that the disease was indistinguishable from pustular psoriasis on histopathology. Over the years, many studies have attempted to assess the relationship of ACH with psoriasis. Hence, it has been concluded that ACH is a variant of pustular psoriasis (16–18).
Acrodermatitis continua of Hallopeau and adalimumab
DOI: 10.3109/09546634.2013.848259
ACH treatments The treatment of ACH is difficult because of the typical course of the disease, characterized by chronic and frequent relapses at the cessation of therapy. Numerous therapies have been published as case study in the literature (Tables 1, 2, and 3) but there remains that there is no standard therapy for this disease.
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unresponsiveness to ACH in three weeks of monotherapy with 50 mg/g calcipotriol applied twice daily (29) . All these studies are listed in Table 1. A positive response of ACH to topical combined therapy with calcipotriol þ tacrolimus 0.1% highlighted by Brill et al. (30) and Brunasso et al. (31) or with calcipotriol þ bethamethasone dipropionate by Sotiriadis et al. (32) is also reported in literature (Table 2).
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Topical treatments White and Main reported a 63-year-old man suffering from ACH with widespread pustulation of the fingers. Topical combination therapy comprising 0.05% clobetasol propionate, 0.5% neomycin sulfate and 100 000 units of nystatin per gram was given under occlusion twice daily along with oral cloxacillin. Dramatic regression of the lesions was observed within 12 hours, with no recurrence (19). Piquero-Casals et al. reported a 65-year-old woman suffering from ACH treated with oral tetracycline 500 mg four times daily, and topical betamethasone valerate cream, after one week (20). Notowicz et al. and Tsuji and Nishimura reported the efficacy of topical cytostatic agents (mechlorethamine hydrochloride and fluorouracil, respectively) (21,22). Wilsmann-Theis et al. successfully used topical 0.1% tacrolimus, applied once during the night, in two patients suffering from ACH refractory to other topical and oral medications (23). Tacrolimus 0.1% ointment was, therefore, recommended for use in the initial phase of ACH, twice daily under occlusion overnight for 1–2 weeks, then once daily under occlusion overnight for 1–2 weeks and finally once weekly as maintenance therapy (24). Calcipotriol, a synthetic vitamin D analogue, was used first in 1996 by Emtestam and Wede´n in a 71-year-old woman with ACH who showed only partial response to the administration of local remedies (25). She was successfully treated with topical application of calcipotriol, which resulted in the cessation of pustule formation and clinical improvement of skin fragility, tender edema and erythema. Piraccini et al. reported that 9 of their 15 patients with ACH of the nail responded to topical calcipotriol (26). Mozzanica and Cattaneo reported a 40-year-old man with ACH, successfully treated with twice daily application of 50 lg/g calcipotriol ointment. Reduction in lesions and symptoms was observed after four weeks of therapy, and complete remission was noted at four months (27). Kokelj et al. reported seven patients resistant to topical calcipotriol (28). Kuijpers et al. also reported
Systemic treatments Phototherapy and photochemotherapy have been used in five cases only, also in children (33,34). Kiszewski et al. reported the utility of UVB þ thalidomide (50 mg/day for 2 months) in a 2-year-old boy suffering from ACH, with excellent response (35). Bordignon et al. successfully treated a 9-year-old boy with a two-year history of ACH with nb-UVB phototherapy, twice per week at a starting dose of 80% MED and increased in increments of 20% every session. Complete remission of the lesions was achieved after 36 treatment sessions (36). Methotrexate has been used for the treatment of ACH with varying responses. Harland et al. reported a case of ACH in which partial response to oral methotrexate was seen (37). Chowdhury et al. reported a patient who was treated with methotrexate 15 mg/week and oral propylthiouracil (PTU) 100 mg for 14 weeks (38). Zachariae and Thestrup-Pedersen reported the first successful use of cyclosporine (CSA) in a 58-year-old woman with a history of severely disabling ACH (39). CSA, at a dose of 14 mg/kg/day, resulted in the cessation of new pustule formation after one week of therapy. However, when the dose was reduced to 5 mg/kg, the patient developed a few pustules. Resolution of pustules was apparent as soon as the dose was increased to 7.5 mg/kg/day. Many other cases are also reported (37,40). Few reports have demonstrated the role of oral retinoids (etretinate and acitretin) administered either as monotherapy or in combination with other topical and systemic agents for the treatment of ACH (24). Pearson et al. reported the first demonstration of the role of etretinate in a 38-year-old woman with ACH refractory to treatment with topical steroids, topical and oral antibiotics, whirlpool baths, topical tars, oral hydroxyurea, colchicines, dapsone and UVB light (15).
Table 1. Overview of literature of the possible topical treatments used in ACH. Year of report
Topical treatment
Notowicz et al. (21) White and Main (19) Tsuji and Nishimura (22) Emtestam and Wede´n (25) Kuijpers et al. (29) Mozzanica and Cattaneo (27)
Mechloretamine Clobetasol propionate Topical fluorouracil Topical calcipotriol Topical calcipotriol Topical calcipotriol
Kokelj et al. (28) Piraccini et al. (26) Piquero-Casals et al. (20) Wilsmann-Theis (23)
Topical calcipotriol Topical calcipotriol Bethametasone valerate Tacrolimus 0.1%
Number of patients 1 1 1 1 1 1 7 15 1 2
Results Remission Remission Remission Remission Unresponsiveness Remission
Follow-up recurrences No recurrence No recurrence Recovery after 3 months No recurrence Two recurrence in the next 26 months, also treated with calcipotriol
Unresponsiveness Regression on nine patients No recurrence Regression Controlled with topical SS Regression No recurrence
Table 2. Overview of literature of some topical combination therapies used in ACH. Year of report Brill et al. (30) Brunasso et al. (31) Sotiriadis et al. (32)
Combination therapy
Number of patient
Results
Follow-up recurrences
Calcipotriol þ tacrolimus 0.1% Calcipotriol þ tacrolimus 0.1% Calcipotriol þ bethamethasone dipropionate
1 1 1
Remission Remission Remission
No recurrence No recurrence No recurrence
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Table 3. Overview of literature of systemic therapies used in ACH.
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Year of report
Systemic therapy
Number of patients
Results
Follow-up recurrence
Pearson et al. (15)
Etretinate (20 mg/die)
1
Remission
Zachariae and Thestrup-Pedersen (39) Korstanje et al. (54) Van Dooren-Greebe et al. (42) Peter et al. (55) Slawsky and Libow (41)
Cyclosporine (7.5 mg/kg/die)
1
Remission
Cyclosporine (8 mg/kg/die) þ prednisolone Acitretin (45 mg/die) Cyclosporine (4.8 mg/kg/die) Etretinate (25 mg twice daily)
1 1 1 1
Remission Remission Remission Remission
Gupta et al. (56) Harland et al. (37)
Cyclosporine (6 mg/kg/die) Cyclosporine (5 mg/kg/die)
1 1
Remission Remission
Van der Kerkhof et al. (43) Kuijpers et al. (29) Behrens et al. (33) Chowdhury and Motley (38)
Acitretin (35–40 mg/die) Acitretin (35 mg/die) þ topical calcipotriol PUVA MTX (15 mg/week) þ PTU (300 mg/die)
1 1 1 1
Remission Remission Remission Remission
Mang et al. (4) Tobin and Kirby (7)
Infliximab (5 mg/kg) Adalimumb (40 mg/weekly) þ acitretin (50 mg/die) Etanercept (25 mg twice/week) þ acitretin (75 mg/die) Infliximab (5 mg/kg)
1 1
Remission Remission
Recurrence after 1 week of stopping etretinate responding to CsA Recurrence a dose reduction to 5 mg/kg/die No recurrence No recurrence No recurrence Recurrence a dose reduction 35 mg/die No recurrence Recurrence a dose reduction to 3 mg/Kg/die No recurrence No recurrence No recurrence No recurrence but the patient developed PTUinduced pancytopenia No recurrence No recurrence
1
Remission
No recurrence
1
Remission
Etanercept Etanercept (50 mg bi-weekly) Etanercept (25 mg twice per week) Broad-band UVB þ thalidomide Infliximab (5 mg/kg) þ acitretin (0,25 mg/kg/die) þ prednisone 10 mg/die 8-methoxypsoralen þ nb-UVB Adalimumab (40 mg/weekly) Efalizumab (0.7 mg/kg) nb-UVB phototherapy Etanercept (25 mg twice/week)
1 1 1 1 1
Remission Remission Remission Remission Remission
After 40 months, the patient developed high ANA titers No recurrence No recurrence No recurrence No recurrence No recurrence
1 3 1 1 1
Remission Remission Remission Remission Remission
Kazinski et al. (46) Ahmad and Rogers (50) Nikkels et al. (57) Bonish et al. (58) Thielen et al. (59) Kiszewaki et al. (35) Rubio et al. (44) Durmazlar et al. (34) Ryan et al. (6) Balato et al. (3) Bordignon et al. (36) Puig et al. (45)
Slawsky and Libow recorded a dramatic improvement with etretinate 25 mg twice daily for one month in a 24-year-old patient who had suffered from ACH since early childhood (41). Van Dooren-Greebe et al. reported the complete clearance of lesions with oral acitretin at a dose of 45 mg/day (42). Van der Kerkhof et al. treated a 53-year-old man with ACH and myelodysplastic syndrome with acitretin at a dose of 35–40 mg/day and noted improvement after one month of treatment (43). Recent publications report the use of anti-TNF-a agents, sometimes added to conventional treatments to treat ACH. In 2004, Mang et al. reported the efficacy of infliximab in ACH for the first time (4). They had successfully treated a 54-year-old woman with 23 monthly infusions without any side effects. Also, Rubio et al. successfully treated with infliximab a 60-year-old woman affected with ACH of 15 years’ duration which was refractory to multiple topical and oral treatments (44). A combination therapy of oral acitretin 0.25 mg/kg/day, prednisone 10 mg/day, and infliximab 5 mg/kg by IV infusion was administered once and again after a two week interval. A remarkable improvement in the lesions was seen after two weeks, and at this point acitretin and prednisone were stopped. Another dose of infliximab was administered at week 6, followed by a maintenance dose administered at eight-week intervals. No relapse was observed during a follow-up of 32 months (44). In 2005, Tobin and Kirby reported a case of a 54-year-old woman initially treated with infliximab (7); however, a second
No recurrence No recurrence No recurrence No recurrence Recurrence 3 weeks after discontinuation of treatment
infusion was ineffective because the patient developed infusion reaction and high titers of ANA. Among TNF-a blockers, etanercept is the most widely used to treat ACH. Puig et al. used etanercept (in combination with methotrexate) to treat ACH in a 72-year-old woman with a twoyear history of a severe pustular eruption affecting her nails and periungual areas of all fingers and toes, and with plaques of psoriasis elsewhere (45). After the first positive effects, for the recovery of disease, etanercept was replaced with adalimumab. Methotrexate was discontinued five months later, and the patient was reported to be asymptomatic and free of relapse over a follow-up of nine months. Kazinski et al. successfully treated an ACH patient with a combination therapy of acitretin and etanercept (46). This combination therapy was confirmed by Silpa-archa et al. who report a case of recalcitrant ACH who previously failed to topical corticosteroid, methotrexate, acitretin and phototherapy and rapidly responded to etanercept in combination with acitretin (47). On the other hand, six reports have shown reduced response or failure of treatment with etanercept administered either alone or in combination with other drugs (6,45,48–50). In the literature, only one case of ACH treated with efalizumab has been reported (3). Adalimumab elicited an excellent response in ACH. In 2009, Ryan et al. reported two ACH patients successfully treated with adalimumab (6). Tobin and Kirby treated a patient with a combination of adalimumab 40 mg weekly and acitretin 50 mg
DOI: 10.3109/09546634.2013.848259
daily within one month (7). Its safety was also confirmed by Dini et al. who used adalimumab to treat refractory paediatric ACH (51) and its validity by Sopkovich et al. who treated ACH in a 79year-old man with a history of gout and chronic obstructive pulmonary disease (52). Furthermore a case of ACH treated with ustekinumab is reported, even if further studies are needed (53). All these studies are listed in Table 3. Our cases confirm the efficacy and the safety of adalimumab as a monotherapy for a continuous treatment of ACH in a patient that was unresponsive to previous therapies. The quality of life was impaired because of pain and immobility. Therefore, we decided to give adalimumab in accordance with the literature. These cases support the observation that adalimumab may represent a promising alternative in multidrug-resistant ACH.
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Conclusion ACH is an interesting entity, its clinical diagnosis is sometimes difficult and even dermatologists often fail to recognize this condition because various conditions may masquerade as ACH, clinically and/or histologically. The disease is notoriously difficult to treat and limited success is reported with numerous topical e/o systemic agents. We described our cases and summarized the literature because it would be important to have outcomes of treatment with topical and systemic, monotherapy and combination therapy, and with the recently emerged biologics.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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