Efectos adversos cutáneos inmunomediados por los anti-TNF: revisión de 30 casos / Immune-Mediated Skin Reactions to Tumor Necrosis α Inhibitors: A Review of 30 Cases

Introducción Los fármacos biológicos inhibidores del factor de necrosis tumoral (TNF) alfa son usados para tratar diferentes enfermedades inflamatorias. A pesar de su adecuado perfil de seguridad, se han descrito reacciones paradójicas asociadas a estos tratamientos. Material y método Se ha realizado una revisión retrospectiva de los pacientes en tratamiento con un anti-TNF que hubiesen presentado una reacción paradójica con afectación cutánea visitados en el Servicio de Dermatología del Hospital Universitari Parc Taulí de Sabadell. Resultados Registramos 30 pacientes en tratamiento con un anti-TNF que desarrollaron un efecto adverso cutáneo inmunomediado en forma de psoriasis (90%), alopecia (6,7%) o dermatitis neutrofílica (3,3%). Adalimumab fue el fármaco más implicado (56,7%), seguido de infliximab (40%). La morfología de la reacción psoriasiforme más descrita es la generalizada en placas (62,9%), seguida de la pustulosis palmo-plantar (37%). El 43,3% de los pacientes mantuvieron el anti-TNF, y de ellos el 92,3% obtuvieron una resolución total y parcial. De los 5 pacientes que iniciaron otro anti-TNF, ninguno obtuvo una resolución total. De los 8 pacientes que cambiaron a un tratamiento biológico diferente al anti-TNF, el 62,5% obtuvieron una resolución total o parcial. Discusión La aparición de una reacción paradójica no siempre obliga al cambio de tratamiento biológico, puesto que se ha observado la resolución de las lesiones cutáneas con un tratamiento tópico y/o sistémico adicional en más de la mitad de los pacientes, sin necesidad de suspender el anti-TNF. Si la afectación es grave, se debe plantear el cambio de tratamiento biológico, siendo más eficaz iniciar un fármaco dirigido a una diana terapéutica distinta al anti-TNF (AU)

Background Tumor necrosis factor α (TNF) inhibitors are used to treat different inflammatory diseases. Although these biologics have an adequate safety profile, they have been associated with paradoxical reactions. Material and methods Retrospective review of patients on TNF inhibitor therapy who developed a paradoxical skin reaction and were seen at the dermatology department of Hospital Universitari Parc Taulí in Sabadell, Spain. Results We collected data on 30 patients under treatment with a TNF inhibitor who developed an immune-mediated skin reaction in the form of psoriasis (90%), alopecia (6.7%), or neutrophilic dermatitis (3.3%). The most common drugs involved were adalimumab (56.7%) and infliximab (40%). Psoriasiform reactions mostly manifested as generalized plaques (62.9%) or palmoplantar pustulosis (37%). Thirteen patients (43.3%) continued on the same TNF inhibitor and 12 of them (92.3%) achieved partial or complete resolution of lesions. Five patients were switched to a different TNF inhibitor, but none of them achieved complete resolution. Eight patients were switched to a biologic with a different target, and 5 of them (62.5%) achieved partial or complete resolution. Conclusions Paradoxical reactions during TNF inhibitor therapy do not always require a change of treatment. In our series, the addition of a topical and/or systemic treatment resolved the skin lesions in more than half of the patients, and switching to a drug with a different target was more effective. A change of strategy should be contemplated in more serious cases (AU)

[Translated article] Immune-Mediated Skin Reactions to Tumor Necrosis α Inhibitors: A Review of 30 Cases / Efectos adversos cutáneos inmunomediados por los anti-TNF: revisión de 30 casos

Background Tumor necrosis factor α (TNF) inhibitors are used to treat different inflammatory diseases. Although these biologics have an adequate safety profile, they have been associated with paradoxical reactions. Material and methods Retrospective review of patients on TNF inhibitor therapy who developed a paradoxical skin reaction and were seen at the dermatology department of Hospital Universitari Parc Taulí in Sabadell, Spain. Results We collected data on 30 patients under treatment with a TNF inhibitor who developed an immune-mediated skin reaction in the form of psoriasis (90%), alopecia (6.7%), or neutrophilic dermatitis (3.3%). The most common drugs involved were adalimumab (56.7%) and infliximab (40%). Psoriasiform reactions mostly manifested as generalized plaques (62.9%) or palmoplantar pustulosis (37%). Thirteen patients (43.3%) continued on the same TNF inhibitor and 12 of them (92.3%) achieved partial or complete resolution of lesions. Five patients were switched to a different TNF inhibitor, but none of them achieved complete resolution. Eight patients were switched to a biologic with a different target, and 5 of them (62.5%) achieved partial or complete resolution. Conclusions Paradoxical reactions during TNF inhibitor therapy do not always require a change of treatment. In our series, the addition of a topical and/or systemic treatment resolved the skin lesions in more than half of the patients, and switching to a drug with a different target was more effective. A change of strategy should be contemplated in more serious cases (AU)

Introducción Los fármacos biológicos inhibidores del factor de necrosis tumoral (TNF) alfa son usados para tratar diferentes enfermedades inflamatorias. A pesar de su adecuado perfil de seguridad, se han descrito reacciones paradójicas asociadas a estos tratamientos. Material y método Se ha realizado una revisión retrospectiva de los pacientes en tratamiento con un anti-TNF que hubiesen presentado una reacción paradójica con afectación cutánea visitados en el Servicio de Dermatología del Hospital Universitari Parc Taulí de Sabadell. Resultados Registramos 30 pacientes en tratamiento con un anti-TNF que desarrollaron un efecto adverso cutáneo inmunomediado en forma de psoriasis (90%), alopecia (6,7%) o dermatitis neutrofílica (3,3%). Adalimumab fue el fármaco más implicado (56,7%), seguido de infliximab (40%). La morfología de la reacción psoriasiforme más descrita es la generalizada en placas (62,9%), seguida de la pustulosis palmo-plantar (37%). El 43,3% de los pacientes mantuvieron el anti-TNF, y de ellos el 92,3% obtuvieron una resolución total y parcial. De los 5 pacientes que iniciaron otro anti-TNF, ninguno obtuvo una resolución total. De los 8 pacientes que cambiaron a un tratamiento biológico diferente al anti-TNF, el 62,5% obtuvieron una resolución total o parcial. Discusión La aparición de una reacción paradójica no siempre obliga al cambio de tratamiento biológico, puesto que se ha observado la resolución de las lesiones cutáneas con un tratamiento tópico y/o sistémico adicional en más de la mitad de los pacientes, sin necesidad de suspender el anti-TNF. Si la afectación es grave, se debe plantear el cambio de tratamiento biológico, siendo más eficaz iniciar un fármaco dirigido a una diana terapéutica distinta al anti-TNF (AU)

Soluble Immune Response Suppressor (SIRS): Reassessing the immunosuppressant potential of an elusive peptide.

A previously studied immunosuppressive cytokine, Soluble Immune Response Suppressor (SIRS), may have relevance to current studies of immune suppression in a variety of human disease states. Despite extensive efforts using experimental models, mainly in mice, much remains to be discovered as to how autoimmune cells in mice and humans escape normal regulation and, conversely, how tumor cells evade evoking an immune response. It is the contention of this commentary that the literature pre-2000 contain results that might inform current studies. The broadly immunosuppressive protein, SIRS, was studied extensively from the 1970s to 1990s and culminated in the determination of the n-terminal 21mer sequence of this 15kDa protein which had high homology to the short neurotoxins from sea snakes, that are canonical members of the three finger neurotoxin superfamily (3FTx). It was not until 2007 that the prophylactic administration of the synthetic N-terminal peptide of the SIRS 21mer, identical to the published sequence, was reported to inhibit or delay the development of two autoimmune diseases in mice: experimental allergic encephalomyelitis (EAE) and type I diabetes (T1D). These findings were consistent with other studies of the 3FTx superfamily as important probes in the study of mammalian pharmacology. It is the perspective of this commentary that SIRS, SIRS peptide and the anti-peptide mAb, represent useful, pharmacologically-active probes for the study of the immune response as well as in the potential treatment of autoimmune, inflammatory diseases and cancer.

[Retroperitoneal postoperative necrotizing fasciitis]. / Retroperitonealen sledoperativen nekrotichen fastsiit.

This is a report on clinical experience had with 17 patients presenting necrotizing fasciitis--a complication ever more frequently encountered. The case material is distributed in two group differing by origin and clinical course of the complication. In group one (n = 11) it is a matter of postoperative development of postoperative complication, consistent with the classical "per continuitatem" and "per contiguitatem" mechanisms, while in group two (n = 6) the process originates, evolves and speads within the retroperitoneal space proper. Comprehensive microbiological examinations performed in 13 cases show that in either group different microorganisms are identified. In group one aerobic-anaerobic mixed infection is documented in all patients, with predominance of Enterobacteroidaceae among aerobic ones. In group two, anaerobic bacterial species, mainly Clostridium sp, prevail in all the isolates. The clinical study points to a substantial difference in the time of septic complication occurrence, as well as between the clinical picture of the two species. Accordingly, the final results are radically different--in group one survivorship amounts to 62.6%, whereas in group two--to 16.6% only.

[Control of autoimmune processes by natural and other non-harmful methods]. / Kontrola autoagresivních procesu pomocí prirozených a dalsích pro organismus neskodných postupu.

At present an increase of some autoaggressive diseases can be observed. The commonly used treatment consists of the administration of some immunosuppressive drug of some hormonal preparations. This type of therapy is accompanied by some undesired side effects, as these drugs influence also some other cell systems besides the immunologically active cells. These drugs are also known to lower the resistance to some intercurrent infections. Due to these undesired side effects some naturally occurring factors are introduced into the therapy. These are e.g., TGF-beta, or some interleukins (IL-10 etc.). In our department and immunosuppressively acting substance was isolated from DHL which had the ability to inhibit the AA (adjuvant arthritis) in rats. In humans this SF (suppressive factor) stimulates the CD 8+ cells which are known to have suppressoric activity. This SF was successfully applied in some autoaggressive diseases, e.g., atopic eczema, multiple sclerosis, some polyradiculoenuritis, amyotropic lateral sclerosis etc. In this paper the results in the ALS patients are given. Amongst other possibilities of the therapy the application of antilymphocyte sera, monoclonal antibodies to some CD markers of lymphocytes and some methods of hyposensitizations of tolerance induction are mentioned. Further, an original method using antigen bound to isosoluble carrier is described. This administration of encephalitogen bound onto Sforon (polyacrylate spheres) sis not only inhibit the EAE manifestations but also enable the survival of guinea-pigs which had already manifested the clinical signs of EAE.

An attempt to inhibit the course of amyotrophic lateral sclerosis (ALS) by suppressor factor.

Forty amyotrophic lateral sclerosis (ALS) patients were treated with suppressor factor. The therapy led to the normalization of the immunoregulatory index in approximately two thirds of the patients. The responder patients had a better clinical response, i.e. the degenerative process slowed down or it was even arrested. This favourable effect was accompanied with a significant increase in the patients' life span. When the therapy had no effect on the CD8 cells, it was discontinued. Stopping the therapy led to disease progression and death; thus, in some patients, therapy was carried out despite its failure to increase the CD8 cell numbers. Substantial clinical improvement was noticed in these patients. The mean survival of patients with ALS was 2-3 years, whereas ALS patients treated with the suppressor factor survived on the average more than 5 years.

[Treatment of lupus erythematosus disseminatus]. / Traitement du lupus érythémateux disséminé.

Corticosteroids have transformed the prognosis of systemic lupus erythematosus (SLE), but no further advance has been achieved during the last few years. Treatment of SLE rests on the use, as rational as possible, of those therapeutic tools that are available. However, diagnosing SLE does not necessary, they must be given promptly in effective doses whilst preventing their side-effects, notably by the simultaneous management of atheroma factors. Non-steroidal anti-inflammatory agents and synthetic antimalarial drugs may be used to replace corticosteroids or reduce their dosage. Severe forms of SLE which are function- or life-threatening require immunosuppressants, the best one being cyclophosphamide administered monthly as intravenous bolus injections, as this drug has been shown to be effective and to have low morbidity. Plasmapheresis is exceptionally needed. The risk of thrombogenesis due to the frequently associated "antiphospholipid syndrome" can be avoided by anticoagulants or antiplatelets the respective indications of which have not yet been clearly determined. SLE being a chronic disease, patient's compliance with treatment is very important and justifies the efforts made to train and inform these young male or female patients.

Función inmunosupresora de las glicoproteínas de VIH-1, agente causal del SIDA / HIV-1 glycoprotein immunosuppression function

En este trabajo se demuestra que el virus VIH-1 inactivado por la luz ultravioleta inhibe la proliferación de linfocitos humanos estimulados con mitógenos; estos datos concuerdan con reportes de otros grupos. Además se observó que no es necesaria la presencia del virus completo ya que membranas celulares aisladas de células infectadas también tienen efecto supresor. Existen indicios de que la glicoproteína de transmembrana (gp41) de VIH-1 induce un efecto supresor, pero los experimentos aquí descritos usando gp41 purificada no pudieron confirmar esas observaciones. El efecto supresor de VIH-1 pudo ser bloqueado con anticuerpos monoclonales anti-CD4 (epitopio OKT4a) lo que implica que la interacción entre el receptor de los linfocitos T con la glicoproteína de superficie (gp120) juega un papel importante. Esto sugiere y confirma resultados de otros grupos que la gp120 tiene efecto inmunosupresor. Los sueros de pacientes positivos no mostraron efecto neutralizante sobre el virus aun cuando el suero contiene anticuerpos contra todas las proteínas estructurales del virus

Prevention of tumor growth and enhancement of cell-mediated immunity by an antigen-specific contrasuppressor factor from a T cell hybridoma.

We have produced a contrasuppressor T cell hybridoma which has positive effects on multiple forms of cell-mediated immunity. First of all, it protects the adoptive transfer of contact sensitivity from suppressor cells and factors. In addition, TcsF modifies the response to normally tolerogenic administrations of hapten, leading mice to develop contact sensitivity and CTL activity instead of tolerance. Most relevant to this conference, mice which have been both treated with AF5.C6 TcsF and painted with TNCB resist challenge with highly malignant TNP-modified tumors. These experiments suggest a decisive role for contrasuppression in tumor rejection.

Action of a thymic cytokine TsIF in reversing the autoimmune disease state of the MRL/1pr mouse.

T suppressor cells differentiate from bone marrow precursors when cocultured with thymic epithelium, a thymic-derived cytokine TsIF, or mixture of both. (TsIF is a trademark of Ventrex Laboratories, Inc., Portland, ME, and is the subject of a U.S. patent by Ventrex Laboratories, Inc., Portland, ME.) These cells, when transplanted into the lupus-rheumatoid arthritis-prone mouse, prevent acquisition of disease as assessed by lack of both antinuclear antibody, rheumatoid factor, and survival beyond mean time for MRL/lpr mice. When TsIF is administered directly into these lupus-rheumatoid arthritis-prone mice, an equivalent sparing effect is manifested.

Murine interstitial nephritis. VII. Suppression of renal injury after treatment with soluble suppressor factor TsF1.

We prepared soluble suppressor T cell factor (TsF1) from donor spleens harvested from mice primed with tubular antigen-derivatized lymphocytes to analyze both its functional interactions with a larger suppressor T cell network and its influence on the nephritogenic effector T cell response producing interstitial nephritis to a parenchymal antigen. Our findings indicate that TsF1 is antigen-specific, genetically restricted by I-J in its direct mediation of suppression, and capable of inhibiting the development of interstitial lesions. TsF1 also provides an inducing signal for the activation of effector Ts-2 suppressors following presentation by accessory cells. The induction of a Ts-2 effect, however, requires that the factor-presenting cell and the recipient of such cells share homology at I-J, and that the TsF1, the precursor Ts-2 cells, and the recipient of the Ts-2 effect share the same Igh-V allotype. Finally, the results of this current report clearly demonstrate a possible therapeutic role for soluble suppressor factors in the management of interstitial renal disease.