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distal cutaneous ischaemia, lower extremity ulceration, necrosis, cutaneous nodules and erythematous and purplish macules of the extremities.6 Chilblains are painful or pruritic erythematous papules or plaques or erythematous swelling of fingers or toes. The main criterion suggestive of chilblain is the triggering by humidity and cold. Histologically, peri-eccrine lymphocytic inflammation, dermal oedema and spongiosis are suggestive of chilblains. Vessels containing organized thrombus like in the antiphospholipid syndrome are rare but can sometimes be found in idiopathic chilblain.4–6 In cases of chronicity, recurrence, associated signs of systemic disease or female sex, laboratory tests should be performed including a full blood count, serum creatinine level, serum protein electrophoresis, antinuclear antibodies, antidouble-stranded DNA, anti-Sm, anti-RNP, anti-SSA ⁄Ro, anti-SSB ⁄La autoantibodies, cryoglobulinaemia, serum haemolytic complement and C3 and C4 components. However, the search for antiphospholipid antibodies is not classically recommended in the initial screening of patients with chilblains.1–3 Thirteen cases of patients with chilblain and antiphospholipid antibodies have been published, involving mainly young women (M ⁄F sex ratio 4 ⁄11), with a mean age of 30 years. Nine had primary antiphospholipid syndrome,4,7,8 including a 4-year-old boy,8 and four had only antiphospholipid antibodies but did not meet the Sapporo criteria. Two of them had systemic lupus erythematosus.9,10 In those patients,4,7–10 however, chilblains were not the initial sign of the disease. In our cases, chilblains were the first sign revealing the presence of antiphospholipid antibodies. In a single case, described by Rustin et al.,9 chilblains revealed the presence of IgG anticardiolipin antibody; this patient had anorexia nervosa and Raynaud phenomenon. Thus, we suggest that the search for antiphospholipid antibodies should be part of the initial screening of patients with chilblains. The prevalence of the syndrome in patients with chilblain is currently unknown, but in some patients it might be the only clinical finding. Some of these patients will eventually develop systemic lupus erythematosus and ⁄or antiphospholipid antibody syndrome, and careful follow up is therefore mandatory. Clinique Dermatologique, Faculte´ de Me´decine, Universite´ de Strasbourg, 1 Place de l’Hoˆpital, BP 426, 67 091 Strasbourg Cedex, France Correspondence: Dan Lipsker. E-mail:
[email protected]
V. LUTZ B. CRIBIER D. LIPSKER
References 1 Dowd PM. Perniosis. In: Texbook of Dermatology (Champion RH, Burton JL, Burns DA, Breathnach SM, eds), 6th edn, Vol. 2. Oxford: Blackwell Science, 1998; 960–1. 2 Ryan TJ. Chilblains. In: Fitzpatrick’s Dermatology in General Medicine (Freedberg IM, Eisen AZ, Wolff K, Austen FK, Goldsmith LA, Katz SI, Fitzpatrick TB, eds), 5th edn, Vol. 1. New York: McGraw-Hill, 1999; 1499–500.
3 Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC. Perniosis. In: Dermatology (Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC, eds), 2nd edn. Berlin: Springer-Verlag, 2000; 531–2. 4 Crowson AN, Magro CM. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases. Hum Pathol 1997; 28:478–84. 5 Cribier B, Djeridi N, Peltre B, Grosshans E. A histologic and immunohistochemical study of chilblains. J Am Acad Dermatol 2001; 45:924–9. 6 Ishikawa O, Takahashi A, Tamura A, Miyachi Y. Cutaneous papules and nodules in the diagnosis of the antiphospholipid syndrome. Br J Dermatol 1999; 140:725–9. 7 Naldi L, Locati F, Marchesi L et al. Cutaneous manifestations associated with antiphospholipid antibodies in patients with suspected primary antiphospholipid syndrome: a case–control study. Ann Rheum Dis 1993; 52:219–22. 8 Olson JC, Esterly NB. Painful digital vesicles and acrocyanosis in a toddler. Pediatr Dermatol 1992; 9:77–9. 9 Rustin MH, Foreman JC, Dowd PM. Anorexia nervosa associated with acromegaloid features, onset of acrocyanosis and Raynaud’s phenomenon and worsening of chilblains. J R Soc Med 1990; 83:495–6. 10 Viguier M, Pinquier L, Cavelier-Balloy B et al. Clinical and histopathologic features and immunologic variables in patients with severe chilblains. A study of the relationship to lupus erythematosus. Medicine (Baltimore) 2001; 80:180–8. Key words: antiphospholipid antibodies, antiphospholipid syndrome, chilblain Conflicts of interest: none declared.
Papillomatosis cutis arising on an immunocompromised district due to paraplegia DOI: 10.1111/j.1365-2133.2010.09833.x MADAM, The immunocompromised district is a novel concept referring to a site in which there is an obstacle to the normal trafficking of immunocompetent cells through lymphatic channels, or an interference with the signals that the neuropeptides and neurotransmitters, released by peripheral nerves, send to cell membrane receptors of immunocompetent cells.1 While congenital and acquired immunodeficiencies represent the prototypes of generalized immunosuppression paving the way to systemic diseases, regional chronic lymphoedema, herpes-infected sites and otherwise damaged areas are clear examples of locally immunocompromised cutaneous districts which are prone to developing circumscribed immunityrelated disorders (malignant tumours, opportunistic infections and immune disorders).1 Cutaneous regions that have been affected by chronic lymphoedema, herpes infection and traumas, such as areas that have undergone various physical injuries (ionizing or ultraviolet radiation, thermal burns, vaccinations), share one common feature: the propensity to harbour a secondary disease, which can appear after an extremely variable lapse of time (days, months, years, decades) on the altered site.2
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The lymphatic system is involved in important immunological functions. Cutaneous dendritic cells, T lymphocytes and macrophages exert their immune functions by migrating from peripheral sites, through dermal lymphatic vessels, to regional lymph nodes. Whatever the cause, inadequate lymph drainage makes the area involved an immunologically vulnerable area; lymphoedematous regions, in time, become sites of altered immunocompetence (also called ‘loci minoris resistentiae’), particularly susceptible to subsequent outbreaks of opportunistic infections, tumours and immune disorders.3,4 We report a 50-year-old paraplegic man who presented chronic hyperproliferative verrucous skin lesions, localized on the feet, that appeared 10 years previously, 2 months after the paraplegic injury (poliomyelitis) (Fig. 1). The patient had no clinical signs of lymphostasis, Stemmer’s sign was negative and there was no evidence of pitting oedema. Diagnosis of papillomatosis cutis ‘lymphostatica’ was postulated by clinical examination. Skin biopsy confirmed the suspected diagnosis by showing thickening of the epidermis, hyperkeratosis with orthokeratosis and hyperacanthosis, and localized epidermal spongiosis; the papillary dermis did not show any lymphangiectasia. Papillomatosis cutis ‘lymphostatica’ is a chronic hyperproliferative verrucous skin disorder, localized on lower legs or feet, usually observed in patients affected by chronic lymphatic congestion.5 The lymphatic disorder can usually be visualized and diagnosed with nondirective lymphogram.6 Lymphoscintigraphic examination in our patient excluded a lymphostasis. Nondirective lymphogram, performed to confirm this finding, did not reveal pathologically widened lymphatics nor valvular insufficiency. Therefore, in this case, papillomatosis cutis ‘lymphostatica’ did not seem related to lymphostasis. Papillomatosis cutis ‘lymphostatica’ and lymphoedema are not so closely correlated events. Papillomatosis cutis is a ‘hamartoma’ while lymphoedema is a condition of localized fluid retention and tissue swelling, caused by an obstacle to the lymphatic network.
In paraplegic patients, local altered nerve release of specific neuromediators, secondary to primarily damaged spinal cords, induces a local immunocompromise. Local alteration of neuroimmunomediator release in involved limbs in paraplegic patients was also shown by Amon and Wolff in 1994, who reported a young boy affected by atopic eczema on the entire skin surface, who, due to a car accident causing trauma of spinal cord and subsequent complete paraplegia, showed the disappearance of the skin lesions, exclusively on the lower paralysed extremities.7 As any interference with the signals that the neurotransmitters, released by peripheral nerves, send to cell membrane receptors of immunocompetent cells, can significantly alter the local immune response, it is conceivable that paraplegia had led to a regional immunocompromise of the limbs involved. The so rapid appearance of papillomatosis cutis ‘lymphostatica’ within 2 months of the paraplegic injury could explain the relationship, not to lymphostasis, still too early to be triggered, but to the known regional immunocompromise due to paraplegia.7 The connection between immunocompromised district and benign proliferative diseases has never been considered. Many clinical events, such as chronic lymphoedema, herpetic infections,8 vaccinations, paraplegia and other physical injuries, could damage the cutaneous district on which they act, causing an altered production of cytokines, growth factors and other neuroimmunomediators. An immunocompromised district becomes a site particularly susceptible to subsequent outbreaks of malignant tumours, opportunistic infections and immune disorders, but is also a site in which benign hyperproliferative cutaneous disease could arise. The altered production of neuroimmunomediators, cytokines and growth factors could explain the genesis of the hyperproliferative stimulus underlying the appearance of a verrucous proliferation like papillomatosis cutis. Lymphostasis and paraplegia have a common denominator: the induction of a regional immunocompromise. There is a well-founded suspicion that papillomatosis cutis ‘lymphostatica’ in patients affected both by lymphostasis and with paraplegia could be hinged upon this common mechanism. In conclusion, according to the possible pathogenetic mechanism, papillomatosis cutis ‘lymphostatica’ should lose the adjective ‘lymphostatica’ and be named ‘papillomatosis cutis of the immunocompromised district’. Department of Dermatology, Second University of Naples, Via Pansini 5, 80131 Naples, Italy E-mail:
[email protected]
A. BARONI V. RUOCCO R. DI MAIO T. NUZZO M. DEL VECCHIO E. RUOCCO
References Fig 1. Papillomatosis cutis: hyperproliferative verrucous skin lesions, localized on the feet, in a paraplegic patient without lymphostasis.
1 Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocompromised district: a unifying concept for lymphoedematous, herpes-
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2 3 4
5 6
7 8
infected and otherwise damaged sites. J Eur Acad Dermatol Venereol 2009; 23:1364–73. Mortimer PS. Managing lymphoedema. Clin Exp Dermatol 1995; 20: 98–106. Vozza A, Palla M, Aiello FS et al. Papillomatosis cutis lymphostatica. G Ital Dermatol Venereol 2009; 144:211–12. Lukas M, Sto¨ssel H, Hefel L et al. Human cutaneous dendritic cells migrate through dermal lymphatic vessels in a skin organ culture model. J Invest Dermatol 1996; 106:1293–9. Stoberl C, Partsch H. Lymphostatische Stauungspapillomatose. Hautarzt 1998; 39:441–6. Partsch H, Urbanek A, Wenzel-Hora B. The dermal lymphatics in lymphoedema visualized by indirect lymphography. Br J Dermatol 1984; 110:431–8. Amon U, Wolff HH. Healing of chronic atopic dermatitis lesions in skin areas of paraplegia after trauma. J Dermatol 1994; 21:982–3. Ruocco V, Ruocco E, Ghersetich I et al. Isotopic response after herpes virus infection: an update. J Am Acad Dermatol 2002; 46:90–4.
(a)
(b)
Key words: immunocompromised district, papillomatosis cutis lymphostatica, paraplegia Conflicts of interest: none declared.
The development of sarcoidosis on antitumour necrosis factor therapy: a paradox DOI: 10.1111/j.1365-2133.2010.09843.x MADAM, We report the case of a man who developed sarcoidosis while on etanercept therapy for chronic plaque psoriasis. This was an unusual and rather unexpected event given that antitumour necrosis factor (TNF)-a therapy has been used successfully to treat refractory sarcoidosis. A 48-year-old man had an 11-year history of chronic plaque psoriasis which had been managed with multiple topical agents, ultraviolet B radiation, methotrexate (1998–2004, up to a dose of 12Æ5 mg, stopped as ineffective) and ciclosporin (2005–2007, up to 300 mg daily, stopped secondary to hypertension). He also had a 5-year history of bronchiectasis [see computed tomography (CT) chest scan in Figure 1a] which had never required treatment. He commenced etanercept (25 mg twice weekly) in September 2007 and his Psoriasis Area and Severity Index score fell from 17 to 3 and his Dermatology Life Quality Index score from 16 to 3 over the following 3 months. In May 2008, 9 months after commencement of etanercept, he became lethargic, febrile and developed a dry cough associated with significant exertional dyspnoea. He had normal inflammatory markers, a corrected serum calcium of 2Æ24 mmol L)1 (normal range 2Æ12–2Æ65 mmol L)1) and a serum angiotensin-converting enzyme level of 116 U L)1 (normal range 40–135 U L)1). A chest X-ray revealed prominent hilar shadows (Fig. 2) and spirometry revealed mild to moderate airway obstruction (forced expiratory volume in 1 s ⁄forced vital capacity 3Æ21 L ⁄4Æ2 L) with a peak expiratory flow rate of 380 L min)1
Fig 1. (a) Computed tomography (CT) chest scan, December 2004. The patient was diagnosed with bronchiectasis. Note: there is no mediastinal or hilar lymphadenopathy. (b) CT chest scan, December 2008, 9 months after starting etanercept. Note: marked hilar lymphadenopathy compared with the previous CT chest scan, consistent with sarcoidosis.
(predicted rate for his age and height 610 L min)1). A CT chest scan revealed extensive mediastinal and hilar lymphadenopathy (which was not present on his previous CT chest scan) with clear lungs, typical of sarcoidosis (Fig. 1b). A mediastinal lymph node biopsy revealed circumscribed, coalescing, noncaseating granulomas with negative fungal stains and no acid-fast bacilli. He was diagnosed with sarcoidosis, his etanercept was stopped and he was commenced on a steroid inhaler. Nine months post-cessation of etanercept he was asymptomatic, had normal lung function and his chest X-ray had almost returned to normal. His psoriasis was well controlled with topical therapy and methotrexate. Sarcoidosis is a multisystem immune disorder characterized by noncaseating granuloma formation, commonly affecting the lungs and lymphatic system. TNF-a is involved in the induction and maintenance of the granuloma formation,1 which explains why anti-TNF-a agents have occasionally been successful in treating refractory disease. Infliximab has been shown to be effective in two randomized controlled trials2,3 2010 The Authors
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