Giampiero Brunetti

Pemphigus: Associations and management guidelines: Facts and controversies

Pemphigus, a prototypical organ-specific human autoimmune disease, may be associated with other immunity-related disorders, viral infections, and different types of tumors. Coexistence with immune diseases is fairly frequent and, for some of them (eg, myasthenia gravis, Basedows disease, rheumatoid arthritis, or lupus erythematosus), common pathogenic mechanisms can be considered. The association with viral infections (mainly herpesvirus infections) raises the question of whether the virus triggers the outbreak of the disease or simply complicates its clinical course. Neoplastic proliferations coexisting with pemphigus have a different histogenesis and the pathogenic link may vary according to the associated tumor (thymoma, lymphoma, carcinoma, or sarcoma). A subset of pemphigus-neoplasia association is represented by Anhalts paraneoplastic pemphigus, with peculiar clinical, histologic, and immunologic features characterizing it. Coexistence of pemphigus with Kaposis sarcoma, albeit not frequent, offers an intriguing speculative interest. The cornerstone of management in pemphigus is the combination of systemic corticosteroids and immunosuppressants. The conventional treatment used in most cases is based on oral administration of deflazacort and azathioprine. In selected cases, mycophenolate mofetil is preferred to azathioprine. Severe forms of pemphigus require intravenous pulse therapy with dexamethasone (or methylprednisolone) and cyclophosphamide. In the recent years, the use of high-dose intravenous immunoglobulin therapy has gained several consents. Rituximab, a monoclonal anti-CD 20 antibody, which affects both the humoral and cell-mediated responses, has proved to give a good clinical response, often paralleled by decrease of pathogenic autoantibodies. The combination with intravenous immunoglobulin offers the double advantage of better clinical results and a reduced incidence of infection. Interventional treatments, such as plasmapheresis and extracorporeal immunoadsorption, are aimed at patients with life-threatening forms of pemphigus and high levels of circulating autoantibodies, a circumstance where the medical therapy alone risks failing. Second-line treatments include gold salts (which we do not favor because of the acantholytic potential inherent in thiol structure) and the association of oral tetracyclines with nicotinamide, which is rather safe. Local treatments, supplementary to the systemic therapy, are aimed at preventing infections and stimulating reepithelialization of eroded areas. Innovative topical treatments are epidermal growth factor, nicotinamide gel, pimecrolimus, and a proteomics-derived desmoglein peptide. Pemphigus patients should be warned against over-indulging in unnecessary drug intake, prolonged exposure to ultraviolet rays, intense emotional stress, and too spiced or too hot foods. Cigarette smoking is not contraindicated in pemphigus patients because of the nicotine anti-acantholytic properties.

The immunocompromised district in dermatology: A unifying pathogenic view of the regional immune dysregulation

Besides the systemic immune deficiency, a sectorial default in immune control may occur in immunocompetent subjects. This regional immune defect can appear and remain confined to differently damaged skin areas, lately labeled immunocompromised districts (ICDs). An ICD is a skin area more vulnerable than the rest of the body for genetic or acquired reasons. Its vulnerability mainly consists in a local dysregulation of the immune control, which often facilitates (but sometimes hinders) the local onset of immunity-related eruptions or skin disorders. The factors responsible for localized immune dysregulation are multifarious, being represented by chronic lymphatic stasis, herpetic infections, ionizing or ultraviolet (UV) radiations, burns, all sorts of trauma (especially amputation), tattooing, intradermal vaccinations, and others of disparate nature (eg, paralytic stroke, poliomyelitis). Whatever the cause, in time an ICD may become a vulnerable site, prone to developing opportunistic infections, tumors, or dysimmune reactions (often of granulomatous type), strictly confined to the district itself; however, the opposite may also occur with systemic immune disorders or malignancies that selectively spare the district. In any case, the immunologic behavior of an ICD is different from that of the rest of the body. The pathomechanisms involved in this sectorial immune destabilization may reside in locally hampered lymph drainage that hinders the normal trafficking of immunocompetent cells (eg, chronic lymphedema, posttraumatic lymph stasis) or in a damage to sensory nerve fibers that release immunity-related peptides (eg, herpetic infections, carpal tunnel syndrome), or in both conditions (eg, amputation stump, radiation dermatitis). The ICD is a conceptual entity with no definite shape or dimension. It may take an extremely variable form and extent depending on the causative agent, ranging from a minimal area (eg, intradermal vaccination) or a small area (eg, herpes simplex infection), through a wide area (eg, radiotherapy), a bandlike segment (eg, skin mosaicism, herpes zoster infection), or an acral area (eg, carpal tunnel syndrome), up to a whole limb (eg, Stewart-Treves syndrome) or even an entire half body (eg, brain stroke). Varied newly coined terminology can be used to indicate the specific cause each time that it is responsible for a regional immune dysregulation. The advantage of the umbrella term ICD is that it encompasses all the possible causes involved in a local immune destabilization. An ICD may have a congenital or a postnatal origin, and interesting similarities between the two forms exist. An ICD may also take place in patients with a preexisting systemic immune deficiency, thus creating a more vulnerable site in an already vulnerable patient. Identifying a cutaneous ICD in a given patient is an important standpoint for both diagnostic and prevention purposes. This can be proven by the educative clinical examples that are reported here.

Beyond zoster: sensory and immune changes in zoster-affected dermatomes: a review*.

Neuroepidermal tropism of varicella-zoster virus accounts for cutaneous and nerve lesions following herpes zoster. Skin lesions heal in a few weeks and may or may not leave visible scars. Nerve lesions involve peripheral sensory fibres, sometimes causing permanent damage that results in partial denervation of the affected dermatome. The effects of the nerve injury involve the sensibility function, thus causing neuralgia, itch, allodynia, hypo- or anaesthesia, as well as the immune function that is related to neuropeptide release, thus altering immune control in the affected dermatome. The neuro-immune destabilization in the zoster-infected site paves the way for the onset of many and various immunity-related disorders along the affected dermatome.

Wolf's post-herpetic isotopic response: Infections, tumors, and immune disorders arising on the site of healed herpetic infection

Herpes simplex viruses (HSV-1/HSV-2) and varicella-zoster virus (VZV) have several characteristics in common. Both are epidermoneurotropic, cause skin eruptions accompanied by sensory symptoms (itch, pain), damage peripheral sensory nerve fibers and cutaneous nerve endings, and interfere with neuromediator release, which can alter local mechanisms of immune control. For this reason, herpes-infected areas may become a preferential location for the subsequent onset of immunity-related skin disorders (infections, tumors, and dysimmune reactions), an event first reported by a neurologist and focused on by two brothers, a dermatologist and a pediatrician. The phenomenon therefore named Wolfs post-herpetic isotopic response (PHIR) refers to the occurrence of a new skin disorder at the site of a previous and already healed herpetic eruption (herpes zoster in most cases). Until now, we have been able to gather 189 well-documented cases of PHIR (all reported in the reference section), but our list is far from being complete. Some of the most emblematic cases are briefly described here. In some circumstances, the opposite of PHIR occurs, with diffuse skin disorders or eruptions that selectively spare herpes-infected areas (Wolfs post-herpetic isotopic nonresponse). Experimental investigations with patch testing have been performed in seven patients who were sensitized to nickel and had had herpes zoster in the past years. The tests were carried out bilaterally on the affected dermatomes and on the unaffected contralateral ones. The uneven immune responses we obtained have shown that the immune behavior of an herpes zoster-affected dermatome can be different from that of the corresponding contralateral dermatome, thus supporting the existence of immune dysregulation in herpes-infected areas.

Discoid lupus erythematosus at a site of previous injury.

A 71‐year‐old man with three patches of discoid lupus erythematosus (DLE) confined to the right preauricular region drew our attention because of the unusual linear arrangement of the lesions. Twenty‐five years previously, the patient had suffered a trauma in the same area from falling off his motorcycle. We believe that, despite the great lapse in time, this injury may have facilitated the onset of DLE in the very same area, through long‐term destabilization of the local neuroimmune network. The case fits the recently coined concept of the immunocompromised district, a cutaneous region with altered immune control, more susceptible to harbouring opportunistic infections, tumours, and immune disorders.

Coexistence of malignancy (skin cancer) and immune disorder (discoid lupus erythematosus) on a burn scar: a concrete example of ‘immunocompromised district’

Features of psychopathological disorders could not be found. Nevertheless, when approached on the subject of suspicions concerning the origin of the haematomas, the children kept silent. However, the three siblings on request independently answered a question for psychic stress in the past, that their beloved cat had died 1 week before appearance of the haematomas. Blood tests and immunology were unremarkable, and serology for toxocariasis was negative. Analysis of blood clotting revealed an extended collagen–epinephrine bleeding time in all three children without any increase in the collagen–ADP bleeding time; plasma clotting parameters were within the normal reference range. There was no evidence that the children had taken nonsteroidal anti-inflammatory drugs or other drugs that could affect the test results. A typical autosensitivity test was undertaken with autologous and washed erythrocytes and showed a positive result only in the 12-year-old girl. Based on the dermatological examination, Gardner–Diamond syndrome (GDS) was considered. The syndrome was named after Frank H. Gardner und Louis K. Diamond, who in 1955 were the first who systematically reported cases of painful bruising. Women are predominantly affected; only a few cases describe affected men. Furthermore, GDS is associated with symptoms such as abdominal pain, nausea, vomiting, diarrhoea and headache. Prodromal symptoms such as pain, heat, burning, itching and pulsating are described before the intradermal bruising appears, which correlates with the symptoms reported by the children. The pathogenesis is still uncertain; a role of erythrocyte antibodies was suspected by Gardner and Diamond. Latest publications define GDS as an autoimmune vasculopathy with sensitization to phosphatidylserine, a component of the erythrocyte stroma. It is assumed that tissue-bound erythrocytic antibodies lead to the development of immune complexes and complement activation. In several publications, a psychogenic component has been discussed as an inducing factor. No curative therapy has been established, but it is considered that medications influencing the capillary tonus, the permeability of vessels and the rheological properties of blood might be advisable. Some authors assert a positive effect of psychiatric therapy, particularly in younger patients. The three siblings were discharged from the hospital after 6 days of inpatient stay when the results of the additional examination arrived. Although GDS is a rare disease, a case in which three siblings develop co-occurring symptoms is extraordinary, especially as very few male cases are known. This could constitute an argument against internal causes (in the case that it is not infectious). Because of the patterned arrangement of the haematomas, an interaction of an exogenous and endogenous component, possibly self-adduction through some trigger, must be assumed, but cannot be proved. As the main diagnostic criterion (skin test) was negative in the two younger siblings, GDS could not be proved but was strongly suspected. Results of interdisciplinary cooperation revealed clearly that there was no evidence for maltreatment, and any allegation of child abuse was lifted from the parents.

Achilles' heel in dermatology.

criteria for systemic mastocytosis. However, it is important to underline the presence of the aberrant CD25 and CD2 immunophenotype, as this is present in virtually all patients with systemic mastocytosis. Additionally, CD25 seems to be a marker for neoplastic MCs and its expression indicates histologically occult bone marrow infiltration, which could be an indication for additional investigation. In conclusion, we would like to emphasize that this is the first time that M541L KIT mutation is reported in an adult patient with mastocytosis. Although the role of this mutant form of KIT in the pathogenesis of the disease is still unclear, in our patient, it is associated with aberrant MC immunophenotype. From our point of view, although without systemic mastocytosis criteria, these patients should maintain regular clinical evaluation. Further studies will be required as all these are important prognosis factors determining these patients’ follow-up.

Contact pemphigus: a side‐effect of imiquimod therapy

carcinoma. Akiyama et al. have recognized the development of squamous cell carcinomas on chronic ulcers, scars, and burns, but association with this fungal infection is not completely understood. Associations with melanoma are rare; yet, we found this one previous report of chromoblastomycosis in association with melanoma. With both malignant tumors, we only found a description that appeared on a burn scar. Fonsecaea pedrosoi is the most common etiological agent in chromoblastomycosis, but it rarely affects nails. We did not find cases of onychomycosis caused by F. pedrosoi in the literature.

Phlebolymphedema: Disregarded cause of immunocompromised district

Recurrent lymphangitis, deep trauma, malignancy, and related treatments (ie surgery and radiotherapy) are usually considered the commonest causes of lymphedema. The role of chronic venous disease in this context is often overlooked; yet, all patients with advanced venous disease (stasis dermatitis) have some degree of lymph circulation impairment.1 Venous edema is assumed to be the sole consequence of increased capillary filtration from venous hypertension. Because lymph drainage is the main buffer against the formation of edema, a compensation for the increased lymph load does occur at the beginning. In the long run, however, when the transport capacity is exceeded, the lymphatics fail to keep their buffer function, and interstitial fluid accumulates. This leads to a clinical condition of mixed venous and lymphatic insufficiency that causes a progressive swelling of soft tissues, which is termed phlebolymphedema.2 There is clinical and laboratory evidence confirming the presence of microangiopathy of the lymphatic network in patients with chronic venous disease.3 Further causes of phlebolymphedema are vein stripping (saphenectomy) for varicosities, vein-harvesting procedures for coronary bypass grafting or other vascular surgery, orthopedic surgery, or penetrating trauma involving the medial aspect of a lower limb (Brodell syndrome).4 In all of these conditions, lymph stasis occurs in the involved district as a consequence of the almost inevitable surgical cutting of the lymph collectors

The correct meaning of the term ‘immunocompromised’: a necessary explanation

Editor We appreciated Simon et al.’s reply to our letter to the Editor concerning acne and local immunity and completely agree with them that in the patient they reported there was hyperactivation (and not suppression) of immunity. Based on the activation of local immunity, Simon et al. have expressed their belief that their clinical case could not fall within the novel concept of immunocompromised district. All the same, in our opinion, the case remains an instance of immunocompromised district because the term ‘immunocompromised’ generically indicates an alteration of the immune response, and not necessarily reduction of it. In fact, this alteration, depending on the neurotransmitters and immune cells each time involved, can be either defective or excessive, as precisely it occurred in Simon et al.’s patient. We thought we have made it clear in our previously published articles, in particular in the lowest box of Fig. 4, that the immunocompromised district can be identified as a peculiar site of regional destabilization of the neuroimmunocutaneous system (an intriguing subject extensively dealt with by Misery) where many and various disorders can take place and remain confined. Among these disorders, some clearly indicate local reduction of immunity (e.g. opportunistic infections and tumours), some point to a locally exaggerated activation of immunity (e.g. bullous pemphigoid, pemphigus, lichen planus, discoid lupus erythematosus, drug eruptions and acne). This is the reason why we have always talked of immunocompromised (and not immunosuppressed) district in our articles and oral presentations on the topic.