Franz Karlhofer

Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants.

De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection and tumor metastasis. The cellular mechanisms of lymphangiogenesis in human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation. Donor-derived cells were detected by in situ hybridization of the Y chromosome. We compared these tissues with biopsies of essentially normal skin and intestine, and two rare carcinomas with low rates of lymphatic endothelial proliferation that were derived from individuals with gender-mismatched bone marrow transplants. Here, we provide evidence for the participation of recipient-derived lymphatic progenitor cells in renal transplants. In contrast, lymphatic vessels of normal tissues and those around post-transplant carcinomas did not incorporate donor-derived progenitors. This indicates a stepwise mechanism of inflammation-associated de novo lymphangiogenesis, implying that potential lymphatic progenitor cells derive from the circulation, transmigrate through the connective tissue stroma, presumably in the form of macrophages, and finally incorporate into the growing lymphatic vessel.

Recommendations for the use of rituximab (anti-CD20 antibody) in the treatment of autoimmune bullous skin diseases.

Autoimmune bullous skin disorders are induced by autoantibodies against distinct adhesion complexes of the epidermal and dermal‐epidermal junction. Since most of these disorders are characterized by a severe, potentially lethal course,they require long‐term immunosuppressive treatment to reduce the de novo synthesis of pathogenic autoantibodies by B lymphocytes. Rituximab, a chimeric monoclonal antibody against CD20 on B lymphocytes, has shown promise in several case reports or cohort studies in the treatment of paraneo‐plastic pemphigus,refractory cases of pemphigus vulgaris and foliaceus and in other autoimmune bullous disorders.Treatment with rituximab leads to depletion of pathogenic B‐cells which may last up to 12 months resulting in a reduction of plasma cells secreting pathogenic autoantibodies.Rituximab is usually administered in an adjuvant setting at a dose of 375 mg/m2 i.v.in weekly intervals for four consecutive weeks in addition to the standard immunosuppressive treatment.The present consensus statement of German‐speaking derma‐tologists,rheumatologists and oncologists summarizes and evaluates the current evidence for the use and mode of application of rituximab in autoimmune bullous skin disorders.

Efalizumab in routine use: a clinical experience

With the advent of biological therapies, continuous long‐term control of psoriasis is now becoming a reality. We report our experience with biologics based on the treatment of more than 550 psoriatic patients with such compounds at our special outpatient care center of Bio‐Immunotherapy at the Department of Dermatology of the Medical University of Vienna. Approximately 220 of these patients are currently receiving efalizumab. In our hands, efalizumab was generally found to be safe and well tolerated and, after 12 weeks of treatment, resulted in a PASI reduction of 50% or more in approximately two‐thirds of patients treated. In most of these ‘early’ responders, the therapeutic efficacy of efalizumab can be maintained for a prolonged period of time, in certain patients up to 36 months. Flares occurring during long‐term therapy were rare and, in most instances, triggered by infections. During such flares, we usually do not discontinue efalizumab therapy, but rather try to combat the infection by appropriate antibiotics and to control the activity of the cutaneous eruption by the addition of topical (corticosteroids) and, when needed, systemic (e.g. methotrexate 15–20 mg week−1 for 8–10 weeks) medication. In such a situation, it is of utmost importance for the care‐taking physician to closely communicate with the affected patients in a scientifically competent fashion and to have an open ear for their concerns. This helps and improves patient compliance and minimizes the need for treatment discontinuation.

Successful use of acitretin in conjunction with narrowband ultraviolet B phototherapy in a child with severe pustular psoriasis, von Zumbusch type.

Severe pustular psoriasis von Zumbusch type is a therapeutic challenge not only in adults, but even more in children. We report a 3½‐year‐old boy who developed a generalized flare of diffusely scattered pustules on erythematous skin which rapidly progressed to large exuding areas. The clinical presentation and investigations including histopathological examination of a biopsy and negative bacterial cultures were consistent with the diagnosis of pustular psoriasis von Zumbusch type. Upon initial treatment with methylprednisolone, acitretin and antibiotics the extent of the disease declined. However, several attempts to reduce the dose of the oral corticosteroid were followed by immediate severe flares. Additional treatment with narrowband ultraviolet B (NB‐UVB, 311–313 nm UVB) resulted in a rapid arrest of disease activity and allowed the corticosteroid to be tapered off. After 10 irradiations the patient was both off steroid and disease free. NB‐UVB therapy was subsequently reduced to twice‐weekly exposures and acitretin gradually diminished to a maintenance dose of 0·3 mg kg−1 daily. We conclude that NB‐UVB in conjunction with acitretin is a potent therapeutic regimen for the treatment of severe pustular psoriasis von Zumbusch type in childhood.

Combination of an EGFR blocker and a COX-2 inhibitor for the treatment of advanced cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers worldwide. Epidermal growth factor receptor (EGFR) is expressed at the cell surface by more than 90% of SCCs and its activation is responsible for cell cycle progression, proliferation, survival, angiogenesis and metastasis. Cyclooxygenase‐2 (COX‐2) is an enzyme up‐regulated through EGFR signaling and responsible for some of the EGFR‐dependent biological effects. An 88‐year‐old man presented with a recurrent, locoregionally meta‐static SCC of the right parietal region, which was resistant to radiotherapy. With a combination therapy of an EGFR blocker (cetuximab) and a COX‐2 inhibitor (celecoxib), the tumor regressed partially and the patients Karnofsky index improved. We speculate that the combined use of cetuxi‐mab and COX‐2 inhibitors can be a new and effective therapy for advanced and recurrent cutaneous SCCs.

IgA pemphigus--occurrence of anti-desmocollin 1 and anti-desmoglein 1 antibody reactivity in an individual patient.

Background: IgA pemphigus is a rare pustular autoimmune disease with exclusive IgA anti‐keratinocyte cell surface antibody reactivity. Two subtypes have been discerned: in the subcorneal pustular dermatosis type, desmocollin 1 has been identified as a targeted autoantigen, while in few cases of the intraepidermal neutrophilic type, IgA anti‐desmoglein 1 or IgA anti‐desmoglein 3 reactivity has been demonstrated.

Transglutaminases as diagnostically relevant autoantigens in patients with gluten sensitivity.

Background: Patients with gluten sensitivity, i. e. celiac disease and dermatitis herpetiformis have anti‐endomysial antibodies recognizing transglutaminases, which are usually detected on appropriate tissue sections. It would be desirable to have available a reliable, tissue‐independent serological diagnostic tool. We compared disease‐specificity and sensitivity of tTG versus eTG‐based detection systems for the diagnosis of anti‐endomysial IgA‐antibodies.

Successful treatment of poststreptococcal scleredema adultorum Buschke with intravenous immunoglobulins.

Maximilian C. Aichelburg, MD; Robert Loewe, MD; Nikolaus Schicher, MD; Paul-Gunther Sator, MD; Franz M. Karlhofer, MD; Georg Stingl, MD; Ahmad Jalili, MD, PhD; Divisions of Immunology, Allergy, and Infectious Diseases (Drs Aichelburg, Karlhofer, Stingl, and Jalili) and General Dermatology (Drs Loewe and Schicher), Department of Dermatology, Medical University of Vienna, and Department of Dermatology, Hietzing Municipal Hospital (Dr Sator), Vienna, Austria

De novo tuberculosis during infliximab therapy in a patient with Behçet disease

A woman with oculocutaneous Behçet disease developed primary tuberculosis while being treated with infliximab. A latent tuberculosis infection had been excluded before therapy. After more than 80 weeks of treatment, the patient complained of fevers, night sweats, shivering and vigorous cough. The chest x‐ray showed miliary shadowing. Mycobacterium tuberculosis was identified. The history revealed recent contact to an individual with smear‐positive tuberculosis. This constellation speaks in favor of a de novo tuberculosis infection with a fulminant course.

Autoantibodies to the translational suppressors T cell intracytoplasmic antigen 1 and T cell intracytoplasmic antigen 1–related protein in patients with rheumatic diseases: Increased prevalence in systemic lupus erythematosus and systemic sclerosis and correlation with clinical features

OBJECTIVE T cell intracytoplasmic antigen 1 (TIA-1) and TIA-1-related protein (TIAR) are involved in posttranscriptional regulation of the expression of tumor necrosis factor alpha (TNFalpha) and other proteins. Given the pivotal role of TNFalpha in chronic inflammatory diseases, this study was undertaken to analyze sera from patients with systemic autoimmune diseases for the presence of autoantibodies to TIA proteins and to investigate the expression of these proteins in inflamed tissue. METHODS The presence of autoantibodies to TIA proteins in sera from 385 patients with rheumatic diseases and healthy controls was determined by immunoblotting using recombinant antigens. Expression of TIA proteins in skin and kidney tissue was analyzed by immunohistochemistry. Serum levels of TNFalpha were measured by enzyme-linked immunosorbent assay. RESULTS Autoantibodies to TIA-1 and/or TIAR were detected in 61% of patients with systemic lupus erythematosus (SLE), 42% of patients with systemic sclerosis (SSc), 15-31% of patients with other rheumatic diseases, and 6% of healthy controls. Compared with patients negative for anti-TIA antibody, anti-TIA antibody-positive SLE patients had higher disease activity (P = 0.01), elevated antibodies to double-stranded DNA (P = 0.0003), and increased serum TNFalpha levels (P = 0.018). In SLE patients, anti-TIAR antibodies were associated with lupus nephritis (P = 0.02), while in patients with SSc, anti-TIA-1 was associated with lung involvement (P = 0.02). Immunohistochemical analysis of skin and kidney tissue revealed aberrant expression of TIA proteins in skin lesions from SLE and SSc patients, as well as in glomerular cells from SLE patients. CONCLUSION Aberrant expression of TIA proteins in inflammatory tissue may lead to systemic autoantibody responses, particularly in SLE and SSc. Increased occurrence of anti-TIA autoantibodies in patients with severe organ involvement may point to a possible pathogenetic role.