Nonsecretory IgA1 autoantibodies targeting desmosomal component desmoglein 3 in intraepidermal neutrophilic IgA dermatosis

Intraepidermal neutrophilic IgA dermatosis, a rare skin disease entity manifested with blisters and pustules clinically and lower epidermal blister, acantholysis, and neutrophilic infiltration pathologically, was first reported in 1985. Although the disease is characterized by IgA autoantibodies targeting the epithelial cell surface component, the target antigen has not been determined. We investigated a patient with this disease by histopathology, direct and indirect immunofluorescence, immunoblotting, and immunoadsorption studies. The pustular lesion was characterized by blister at the lower epidermis, acantholysis, and neutrophilic infiltration. Nonsecretory IgA1 subclass autoantibodies targeting the lower epithelial cell surfaces were detected in the patient's skin and serum. The patient's IgA autoantibodies labeled a recombinant desmosomal protein desmoglein 3 on immunoblotting and the immunolabeling of epithelial cell surfaces was eliminated by preadsorption with desmoglein 3. Thus, desmoglein 3 is identified as a target antigen in intraepidermal neutrophilic IgA dermatosis. The ability of IgA1 autoantibodies to bind neutrophils may be responsible for the prominent neutrophilic infiltration observed histopathologically and for the pustular lesions observed clinically.     

Powered wheelchairs: are we enabling or disabling?

The sonographic diagnosis of malignant lymphoma in childhood is described. Malignant lymphomas are sonographically relatively uniform: initial enlargement of the lymph nodes and organs involved and disturbance of normal echo texture by mainly hypoechoic lesions can be found. Generally, four sonographic patterns of infiltration are described: diffuse, small nodular, large nodular and bulky type. Secondary, tumor-related or inflammatory complications (e.g. dislocation or compression of vessels, thoracic inlet syndrome, venous thrombosis, ileus, urinary retention, abscess and effusion) can be sonographically evaluated. Response to therapy correlates with normalization of size and echo texture and recovery from tumor-related complications. Differential diagnosis with ultrasound is based on the topographic distribution and echo pattern of infiltration and, with certain restrictions, on the echogenicity of lesions and perfusion feasible with Doppler sonography. The primary diagnosis has to be established histologically.     

Cutaneous histopathology of Rocky Mountain spotted fever

The dermatologic diagnosis of Rocky Mountain spotted fever (RMSF) is often presumptive; the clinical presentation includes skin rash and febrile illness with or without a clear history of tick bite. The characteristic cutaneous manifestations include a generalized skin eruption with purpuric, blanching or non-blanching macules and papules usually involving the extremities. Although skin biopsies are often performed to confirm the diagnosis, the spectrum of cutaneous histopathology in RMSF has not been well described. We studied a series of 26 cases of RMSF, of which 10 were surgical specimens and 16 were autopsies. The microscopic changes were correlated with the duration of illness. The main histopathologic feature was lymphohistiocytic capillaritis and venulitis with extravasation of erythrocytes, edema, predominantly perivascular and some interstitial infiltrate. Leukocytoclastic vasculitis (LCV) with neutrophilic infiltrate and nuclear dust was seen in 11 of 15 (73%) specimens from involved skin. These lesions with LCV also showed notable epidermal change including basal layer vacuolar degeneration with mild dermoepidermal interface lymphocytic exocytosis. Six lesions with LCV displayed focal fibrin thrombi and capillary wall necrosis. Apoptotic keratinocytes were noted in 3 lesions with LCV. Subepidermal blister was observed in the skin lesion of an autopsied patient with LCV changes. Another lesion of a fatal case with LCV also contained features of acute neutrophilic eccrine hidradenitis. Focal small nerve twig inflammation was noted in a third autopsy case with LCV. Plasma cells were seen in 6 of 34 specimens (18%); and eosinophils were observed in 3 (9%). The subcutaneous fat contained a mild perivascular inflammation and one case revealed focal lobular neutrophilic inflammation. Immunohistologic (IH) staining using polyclonal rabbit anti-Rickettsia rickettsii demonstrated positive staining of the organisms in the affected endothelial cells in all 12 cases tested. The cutaneous histopathology of RMSF is caused by endothelial damage by the rickettsial organisms which elicit an initial lymphohistiocytic small vessel vasculitis with progression to LCV. The vasculitis in RMSF is, therefore, considered to be a form of septic vasculitis.     

Transitional cell carcinoma of the bladder in patients under 30 years of age

Large haemorrhagic and necrotic cutaneous lesions developed after two low dose (5 mg) methotrexate injections in a patient suffering from long standing rheumatoid arthritis. Differential clinical diagnosis included factitia dermatitis, infectious processes, pyoderma gangrenosum, rheumatoid neutrophilic dermatitis, necrotizing arteritis and vasculitis. Histological and direct immunofluorescent examinations of skin biopsies supported the diagnosis of leucocytoclastic vasculitis. We discuss the respective roles of methotrexate and rheumatoid arthritis in the outbreak of leucocytoclastic vasculitis. Hypersensitivity is strongly suspected.     

Target effector role of vascular endothelium in the inflammatory response: insights from the clinical trial of anti-TNF alpha antibody in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterised by chronic joint inflammation and infiltration by cells from the blood, especially activated T cells and macrophages, together with formation of new blood vessels. The overgrowth of the synovial lesion results eventually in destruction of cartilage and bone. Cytokines play a major role in RA, both in systemic inflammatory processes, such as induction of acute phase protein synthesis, and in the stimulation of new blood vessel development and recruitment of leucocytes to developing lesions. The focus for the interplay of many cytokines is the endothelium, the lining layer of the vasculature. This is the primary target for circulating mediators, and it controls the traffic of cells and molecules from the bloodstream into underlying tissues. Targeting the action of individual cytokines--for example, using antibody against tumour necrosis factor alpha (TNF alpha), has been shown to be very effective in the treatment of RA. Blockade of TNF alpha activity results in deactivation of the endothelium, manifested as reduced expression of adhesion molecules and chemoattractant cytokines, leading to diminished trafficking of inflammatory cells to synovial joints. In addition anti-TNF alpha decreases circulating levels of the potent angiogenic cytokine VEGF, suggesting that new blood vessel formation, and hence the supply of nutrients to the growing synovial lesion, is also affected. These observations lend further support to the hypothesis that interruption of a component of the cytokine network in RA may modulate disease progression, and point the way towards the development of new therapeutic strategies for the treatment of chronic inflammatory disease states.     

Neutrophilic dermatoses: pyoderma gangrenosum and Sweet's syndrome

Pyoderma gangrenosum and Sweet's syndrome are classified as neutrophilic dermatoses as they exhibit intense dermal inflammatory infiltrates composed of neutrophils with little evidence of a primary vasculitis. They share several characteristics and respond to immunosuppressives. Aetiology is felt to represent a manifestation of altered immunologic reactivity. Patients with both conditions concurrently have been described. Diagnosis is based on clinical and histopathological findings. However, clinically the typical forms of the two conditions are quite distinct: pyoderma showing cutaneous ulceration with a purple undermined border and Sweet's syndrome having tender, erythematous, nonulcerated plaques and nodules. Approximately 50% of cases of pyoderma are associated with a specific systemic disorder. These include inflammatory bowel disease, rheumatoid arthritis, non-Hodgkin's lymphoma and myeloproliferative disorders. Many associations with Sweet's syndrome have been described, including acute myeloid leukaemia, myeloma and adenocarcinomas, and haematological malignancy. There is overlap between the two conditions with lesions categorised as Sweet's syndrome being clinically more characteristic of atypical pyoderma and vice versa. We believe that pyoderma and Sweet's syndrome represent a continuum of spectrum of disease. The reason for the clinical differences between the conditions is unclear and merits further investigation but may be explained by varying levels of intensity and extent of the inflammatory process. This review will describe the pathogenesis, clinical features, diagnosis, associations and treatment of the two conditions.     

Neutrophilic eccrine hidradenitis associated with relapse of acute myeloblastic leukemia

BACKGROUND: Neutrophilic eccrine hidradentitis is a recently described clinical entity. Most reported cases have occurred in patients given chemotherapy for acute myelogenous leukemia, suggesting a drug induced mechanism. Some authors have considered however that neutrophilic eccrine hidradenitis belongs to the group of neutrophilic dermatoses. CASE REPORT: We observed neutrophilic eccrine hidradentitis in a 48-year-old man which developed when he suffered a relapse of acute leukemia. He had not been given chemotherapy in the preceding months. DISCUSSION: This case favors the hypothesis that neutrophilic eccrine hidradenitis is associated with myeloid hemotology disorders and not a complications secondary to treatment.     

Okadaic acid enhances prostaglandin E1-induced alkaline phosphatase activity in osteoblast-like cells: regulation at a point downstream from protein kinase A

A variety of pharmacologic agents have been known to induce pustular psoriasis. We describe a patient with a positive personal and family history of psoriasis who developed an extensive annular pustular eruption 3 weeks after starting hydroxychloroquine (Plaquenil) for arthritis. The drug was discontinued, and she received 3 weeks of systemic and topical corticosteroids; in spite of the therapeutic intervention, showers of new lesions appeared daily, and progressed to involve 75% of the body. The development of new lesions stopped, and the older lesions began to clear after one dose of 7.5 mg of methotrexate. Subsequently, methotrexate therapy was stopped because of mild transaminase elevation; the pustular lesions then flared. New lesions stopped appearing after four doses of weekly methotrexate. The patient remains clear of lesions 6 months later.     

Amicrobial pustulosis of the folds. A cutaneous manifestation associated with connective tissue disease

Amicrobial pustulosis (AP) is a recently defined entity associated with connective tissue diseases. Few cases have appeared in the literature. We report a case of AP coexisting with a systemic lupus erythematosus-scleroderma overlap syndrome and marked photosensitivity. The patient presented prominent pustular skin lesions and a few discoid lupus ones. No significant differences in the inflammatory infiltrate were found between the two clinical variants. The infiltrate consisted mainly of CD4+ lymphocytes and many neutrophils. CD1a+ dendritic cells were few in both epidermis and dermis. AP introduces a potential source of diagnostic confusion, but increasing experience of this syndrome will improve the awareness and diagnostic potential among dermatologists.     

The effect of acebutolol on the cerebral circulation of man

The term dyshidrosis describes a nonspecific tissue pattern reaction characterized by a noninflammatory, pruritic (and sometimes burning) intraepidermal vesicular dermatosis involving selected areas of the fingers, palms, and soles. It should be distinguished from various pustular and vesicular dermatoses of the palms and soles with or without associated lesions elsewhere. When dyshidrotic lesions appear in areas where friction or pressure from the handling or wearing of sport gear occurs, the discomforting symptoms are noticeably accentuated and can thus interfere with the participant's effectiveness in the performance of the sport. A composite approach of dermatologic therapeutic acumen and physician-sponsored emotional support is essential in effectively handling this problem so that dyshidrosis does not "handicap" the patient.     

Psychotherapy for intractable inflammatory dermatoses

BACKGROUND: Most patients with inflammatory dermatoses respond to conventional treatment. Recalcitrance may indicate underlying emotional factors after infection, contact allergy, and noncompliance have been ruled out. Psychiatric treatment has been reported to be effective. OBJECTIVE: The purpose was to determine whether insight-oriented psychotherapy, by effecting last change, would provide long-term cutaneous and psychiatric improvement. METHODS: On the basis of emotional distress attributed to a recalcitrant inflammatory dermatosis, four patients were referred for psychiatric evaluation. The effect of adding insight-oriented psychotherapy as the only change in the treatment regimen of each patient was studied. Each patient served as his or her own control. RESULTS: In each patient clearing of the previously recalcitrant dermatosis accompanied psychiatric improvement. CONCLUSION: In selected cases of recalcitrant inflammatory dermatoses, insight-oriented psychotherapy may provide lasting cutaneous improvement and improved life adjustment and psychologic well-being.     

A patient with psoriatic arthritis due to generalized pustular psoriasis (von Zumbusch type)

Pustular psoriasis is a rare skin disease that is observed in about 1% of all patients with psoriasis. We encounted a patient with psoriatic arthritis (PsA) due to pustular psoriasis. The patient was a 31-year old male. He visited our hospital due to generalized eruption and pain in multiple joints. Treatment was initiated under a diagnosis of psoriasis vulgaris and associated PsA. However, eruption extended to the entire body and became pustular, and fever developed. Since PsA symptoms were simultaneously aggravated, and body movements become difficult, he was admitted. A diagnosis of generalized pustular psoriasis (von Zumbusch) and associated symmetrical polyarthritis was made. Local therapy was performed. As systemic treatment, oral administration of an corticosteroid and weekly low-dose pulse methotrexate therapy were performed. The skin symptoms and PsA symptoms rapidly improved. At present, about one year after the initiation of treatment, the eruption almost completely disappeared, and joint pain does not present any problem in daily life.     

An increased ratio of interleukin-1 receptor antagonist to interleukin-1alpha in inflammatory skin diseases

IL-1 receptor antagonist (IL-1ra) is a cytokine that competitively binds the IL-1 receptor to antagonize IL-1 activity without any agonist function. Previous experiments indicated that the ratio of IL-1ra to IL-1alpha in the normal stratum corneum (SC) was much higher in the sun-exposed face than in the sun-protected area, upper arms. It was also reported by another laboratory that IL-1ra is increased in the lesional skin of psoriatic patients. This study was designed to measure the contents of IL-1alpha and IL-1ra in non-lesional and pathological SC obtained from inflammatory skin diseases including psoriasis and non-psoriatic dermatoses such as atopic dermatitis. The SC materials were obtained with a non-invasive tape-stripping method. Their soluble fractions were prepared and assayed for IL-1alpha and IL-1ra by enzyme-linked immunosorbent assays. As a result we confirmed the previous findings that the ratio of IL-1ra to IL-1alpha in the normal SC was much higher in the face than in the sun-protected sites, the trunk as well as extremities. Next, we found that IL-1alpha contents were significantly reduced in the SC samples obtained from inflammatory skin regardless of whether their IL-1ra contents increased or unchanged. Moreover, we noted that an increased ratio of IL-1ra to IL-1alpha in the SC was not specific to psoriasis, but was also found in other inflammatory skin diseases including atopic dermatitis. This ratio was found to become lower after successful treatment of these skin lesions with topical glucocorticoids. We conclude from these observations that the increased ratio of IL-1ra to IL-1alpha in the SC is a non-specific phenomenon that can occur in any inflammatory skin diseases regardless of the inflammatory pattern, probably reflecting a skin regulation process against various kinds of inflammation.     

Oligoclonal expansion of HIV-specific cytotoxic CD8 T lymphocytes in the skin of HIV-1-infected patients with cutaneous pseudolymphoma

A massive infiltration of the skin by activated CD8+ T lymphocytes involving both the dermis and the epidermis has been found in HIV-1-infected patients presenting with a chronic skin rash. We characterized the T cell receptor (TCR) BV-BJ junctional diversity of the skin-infiltrating lymphocytes (SILs) in four patients. The SILs expressed a limited set of TCRBV gene segments. Complementarity determining region 3 length analysis further emphasized their oligoclonality, suggesting that antigen stimulation might be responsible for the cutaneous T cell expansion. Furthermore, independent skin biopsies obtained from the same individual were shown to harbor distinct T cell repertoires, possibly reflecting the spatial heterogeneity of the antigenic stimuli. The CD8+ cytotoxic T lymphocyte (CTL) lines isolated from the skin rash in one patient exhibited a specific, class I MHC-restricted cytotoxic activity against HIV-1 Gag- and Pol-expressing target cells, whereas CTL lines derived from the skin lesions of a second patient were shown to be predominantly Env-specific. Taken together, these data demonstrate the infiltration of HIV-specific CTLs in the skin of HIV-infected patients, and suggest that in addition to their known role in controlling the retroviral infection, these CTLs may also be involved in the pathogenesis of cutaneous inflammatory disorders occurring during the course of HIV infection.     

Neutrophilic dermatosis

We present this neutrophilic dermatoses review, showing the importance and pluripotential function of neutrophils: its special proliferation way or its association with immune complexes, that make them express in most different ways, such entities were consider till recently as no related. We are here including uncommon neutrophilic dermatoses, infrequently seen in dermatological departments that make them extremely interesting and a need to be known by dermatologist., looking forward to find new therapeutically concepts.     

Multiple pulmonary nodules in association with pyoderma gangrenosum

This report describes a patient with extensive pyoderma gangrenosum in whom there were co-existent lung abnormalities. The patient's X-ray showed peripherally sited multiple pulmonary lesions bilaterally. A lung biopsy showed chronic non-specific inflammatory changes with neutrophil and lymphocyte infiltration which were similar to the skin lesions. This case was diagnosed as multiple aseptic nodules in pyoderma gangrenosum. The pulmonary infiltrative shadows were controlled only with prednisolone treatment. Steroid therapy is considered to be the first choice to control pulmonary lesions of this disease.     

The viable motheaten (mev) mouse--a new model for arthritis

Homozygous mev mice are first identified at the age of 3-4 days by focal depigmentation of the skin, followed by patchy absence of hair and by necrotic lesions on paws, tail and ears. Of particular interest are the inflammatory reactions in the paws of these animals which consist mainly of polymorphonuclear and mononuclear cell infiltration in the subcutaneous tissue extending to the periosteum and joint, resulting in focal destructive arthritis and osteomylitis. These lesions are to some extent reminiscent of an acute form of rheumatoid-like arthritis. Since mev mice are sterile, a limited number of symptomatic offspring can be obtained by cross-breeding their heterozygous siblings which are phenotypically not distinguishable from mice lacking this mutation. In order to produce a sufficient number of diseased animals for performing pharmacological studies, we have established a model by transferring this disease in lethally irradiated, 8- to 10-week-old syngeneic mice which were grafted with mev spleen cells. Such reconstituted recipients develop first inflammatory symptoms of the paws 2 to 3 weeks after cell transfer. The arthritic inflammation finally affects all paws and toes by 30 to 50 days. This procedure increased the number of mev-like mice expressing arthritis, allowing assessment of the effects of standard reference drugs used in the therapy of rheumatoid arthritis (RA). The immunosuppressants cyclosporin and rapamycin and the steroid dexamethasone at therapeutic concentrations exert a strong inhibitory effect on the development of arthritis in this novel model. In contrast, the non-steroidal anti-inflammatory drug phenylbutazone shows only a moderate effect. These results indicate the particular sensitivity of this model for efficacy of potentially new therapeutic but non-cytostatic compounds for clinical use.     

A case of papillary cystadenoma of the epididymis]

BACKGROUND: In AIDS, nodular skin disease can result from various causes. OBJECTIVE: To report a new manifestation of microsporidial infection presenting as nodular skin disease with underlying osteomyelitis. DESIGN: Case report. SETTING: Tertiary-care military medical center in Washington, D.C. PATIENT: A 36-year-old woman with late-stage AIDS who presented with disseminated, nodular cutaneous lesions and underlying osteomyelitis. MEASUREMENTS: Disseminated microsporidial infection with an Encephalitozoon-like species was diagnosed by electron microscopic examination of material obtained from the skin lesions. INTERVENTION: The patient received long-term oral clindamycin therapy, which cured her disseminated infection. CONCLUSIONS: Microsporidia can cause disseminated cutaneous infections in AIDS patients. The response of this patient to long-term clindamycin therapy merits further evaluation.     

Monoarthritis

By definition, monoarticular arthritis means one-joint involvement, even though, in fact, such a condition is often an oligoarthritis because as many as two or three separate joints will be involved. Arthritis is often limited and may regress, so that it is frequently misdiagnosed. Sometimes, a monoarticular condition may be a polyarthritis onset (i.e., rheumatoid arthritis). Monoarticular arthritis can be caused by many factors, such as infections (septic arthritis), nonspecific inflammatory processes (reactive arthritis), crystals deposition (gout, CPPD crystal deposition disease), trauma, neoplasm (pigmented villonodular synovitis), immunologic conditions (amyloidosis) and hormonal changes (parathyroid disease). Its onset is usually acute and sometimes dramatic, with fever, pain and joint swelling, so that a decision must be made promptly to stop rapid illness evolution and to prevent the irreversible destruction of cartilage and bone (especially in septic arthritis). Diagnostic studies are performed with mono-bilateral radiographs of the joint. Radiographic findings (i.e., soft tissue swelling, joint effusion, widening and thinning of joint spaces, bone erosions and destruction of bone surface) are typical of the disease, but some findings (e.g., type of evolution and progression), laboratory tests, synovial biopsy and arthroscopy can differentiate infectious from inflammatory forms. Scintigraphy can depict isotopic joint uptake, before articular abnormalities are demonstrated with radiography, thanks to its high sensitivity; nevertheless, because of its low specificity, scintigraphy may miss some kinds of lesions (including osteoarthritis) and cannot easily differentiate osteomyelitis from septic arthritis. CT and MRI play a secondary, though not negligible, role, especially to study such deep infections as psoas abscesses, which may mimic arthritides.     

Mucocutaneous reactions to antineoplastic agents

Mucocutaneous reaction patterns in patients receiving cancer therapy are not only variable, but in many instances identical patterns are produced by different pathologic mechanisms. For example, patients with leukemia or lymphoma may present with nodular skin lesions that may represent malignant infiltration, septic emboli, vasculitis, or a drug eruption. The most banal skin eruption may signal an impending or ongoing catastrophe. If one is able to make some clinical evaluation regarding the likelihood of a drug being responsible for the mucocutaneous eruption, it may help avoid further clinical or laboratory investigation and patient discomfort. Unfortunately, only a few antineoplastic agents have "characteristic" skin manifestations. If, however, these are kept in mind they may be helpful in the diffential diagnosis of mucocutaneous eruptions occurring in patients treated with cancer chemotherapeutic agents.