Rituximab is a chimeric anti-CD20 monoclonal antibody that was first used for the treatment of B-cell lymphomas. In the last years there has been a growing interest in using its B-cell-depleting effect in treating different autoimmune diseases (those that are mediated by autoantibodies in particular). It has been used in rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, idiopathic thrombocytopenic purpura, acquired hemophilia, autoimmune hemolytic anemia, mixed cryoglobulinemia, Wegener’sgranulomatosis, myasthenia gravis, dermatomyositis, and multiple sclerosis. Rituximab has also been used increasingly in autoimmune blistering skin diseases when these became refractory to systemic corticosteroids and immunosuppressants.

In a recent paper Peterson and Chan have reviewed 71 cases with different autoimmune blistering dermatoses treated with Rituxumab published in the world literature in the recent years.

They found that 51 patients had pemphigus vulgaris, one had pemphigus vegetans, nine had pemphigus foliaceus, five had paraneoplastic pemphigus, four with epidermolysis bullosa acquisita, and one patient had bullous pemphigoid simultaneously with graft versus host disease. Of these 71 patients, 49 showed a complete response to rituximab, 18 had a partial response, and 4 did not respond and had a progression of their disease. Overall, 94% (67 out of 71) of the reported patients showed a complete or partial clinical improvement to rituximab. There were 4 patients (6%) that were non-responders to rituximab, and these included 1 patient with pemphigus foliaceus, 1 with pemphigus vegetans, and 2 with paraneoplastic pemphigus.

Important complications (including death) associated with rituximab were seen in only 14% of the patients (10 out of 71). There were six deaths in total. Four of these patients had paraneoplastic pemphigus, 1 pemphigus vulgaris, and 1 bullous pemphigoid and graft versus host disease. Interestingly all these deaths were in patients that had been treated without combining rituximab with intravenous immune globulin (IVIg). Most causes of death were attributed to sepsis, congestive heart failure, or pneumonia. Ten patients developed infections: 4 cases of sepsis/bacteremia, 2 cases of pneumonia, and 1 case each of infective arthritits, ocular herpes simplex, varicella, and Mycobacterium chelonae cutaneous infection. Other complications included atrial fibrillation with congestive heart failure (leading to death) and deep venous thrombosis.

Therefore, according to this review rituximab seems to be highly effective and has a good safety profile. We should also take into consideration that the reported cases might show a bias to report only succesful cases or series. And you, what is your experience with rituximab in autoimmune blistering diseases.

(more…)

Drug eruptions are a frequent complication seen in approximately 2% to 3 % of hospitalized patients. Some of these eruptions have a characteristic clinical picture such as erythema multiforme, fixed drug eruption, vasculitis, or acute generalized exanthematic pustulosis. However, most patients present with less specific rashes such as morbilliform drug eruptions, or urticaria that can account for up to 95% of cutaneous drug reactions. The diagnosis of drug eruptions is based on clinical history, particularly when the rash is temporally related to the introduction of a new drug, in the last days or weeks. Most drugs that the patient had been taking for years can usually be excluded as triggering agents. In addition, the clinical features of the rash, and, in some cases, the histopathologic examination of a cutaneous biopsy can help in diagnosis.

Although some drug eruptions have histologic patterns that make them easily diagnosed, in most patients histology is ‘‘non-specific’’ or ‘‘non-diagnostic’’. In a study published in the December issue of the Journal of the American Academy of Dermatology the authors have made a revision of the of cutaneous drug eruptions diagnosed over a 5-year period. A total of 104 cases were included in the study. In 83% of the cases, the suspected drug or drugs could be narrowed to 3 or fewer. The two most frequent classes of drug associated with the appearance of a rash were antibiotics (45%) and antiepileptics (15%). 94% of the rashes were morbiliform. Most of the biopsies (80%) showed superficial dermal inflammatory infiltrates in a combined perivascular and interstitial pattern. There were interface changes in 53% of the biopsies. The inflammatory infiltrates was composed of lymphocytes only in 32% of the cases, lymphocytes and eosinophils in 29% of the cases, lymphocytes and neutrophils in 10% of the cases, and lymphocytes, neutrophils and eosinophils in 21% of the cases. Therefore, 50% of the cases contained eosinophils in the infiltrate. In summary, the finding of superficial infiltrates with or without interface changes, with the presence of eosinophils is the most frequent histologic pattern observed in morbilliform drug eruptions. (more…)

Infantile hemangiomas are benign vascular neoplasms formed by endothelial cells that lose their ability to organize in regular vascular structures and form proliferating masses of cells. These tumors are not present at birth and appear during the neonatal period or early infancy. Most infantile hemangiomas are small lesions that are only of cosmetical concern. However some lesion can grow as disfiguring masses that can sometimes be life-threatening.

In the November issue of Nature Medicine, a group of researchers from the United States and Belgium have found that there is an imbalanced vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) function in hemangiomas that could be one of the implicated mechanisms underlying endothelial cell growth in these tumors. In normal endothelial cells VEGF usually binds to VEGFR1 with higher affinity than to VEGFR2. VEGFR1 would act as a regulator of VEGF levels and would decrease VEGFR2 activity on endothelial cells. By contrast, the endothelial cells in hemangiomas have mutations in several genes and this results in the expression of several aberrant proteins complexes (that contain beta-1 integrin, mutated VEGFR2, and TEM8 among others).These aberrant protein complexes in turn decrease the activity of nuclear factor of activated T cells (NFAT), and this results in turn in that much less VEGFR1 is expressed on these cells. As VEGFR1 is a regulator of VEGF levels, then there is more VEGF that is going to bind to VEGFR2, resulting in an increased endothelial cell growth.

All these findings suggest that antibodies directed against the VEGF, inhibitors of VEGFR2 tyrosine kinase or other agents inhibiting the different components of these signaling pathway (VEGFR2, TEM8, beta1 integrin and NFAT) could be used in the future as promising target-directed therapies for hemangiomas. (more…)

In a recent paper published online first in October 20th in the Journal of Experimental Medicine a group of French researchers have found a new antigenic protein that can be very important in the immune response against melanoma cells.

They studied a patient that had remained free of melanoma 10 years after the infusion of a clone of tumor-infiltrating lymphocytes (TIL). These T-cells cells are obtained from the tumor of a patient with late-stage melanoma. They are cultured in vivo, expanded in sufficient numbers, and then infused to different melanoma patients. In this patient the researchers found that the T-cell line recognized a specific antigen that could be found in all melanoma cell lines and, to a lower extent, melanocytes. They named this protein MELOE-1 (melanoma-over expressed antigen-1).

Subsequently, they found that 5 out of 9 patients treated with TILs that did not had relapse had been infused with TILs that contained MELOE-1–specific T cells. In contrast none of the 21 patients treated with TILs who relapsed had been infused with MELOE-1–specific T cells.

These interesting findings suggest that MELOE-1 can be a promising antigenic target for immunotherapy of melanoma in the near future. (more…)

Two recent separate studies that have been published on-line in the journal Nature Genetics have identified new genetic risk factors for male-pattern baldness. Both studies have found similar results, and they found that there is a susceptibility locus for male-pattern baldness at chromosome 20p11. These studies add a new candidate gene for androgenetic alopecia. Previous studies had shown that variants in the androgen receptor gene on the X chromosome were associated with androgenetic alopecia. These investigators found that the combination of both gene variants (the one on chromosome X and the new one found in chromosome 20) were present in 1 out of 7 caucasian men, and that this increased seven-fold their risk of having androgenetic alopecia.

The gene on chromosome 20p11 has not been identified but it is probable that it harbors an androgen-independent pathway in androgenetic alopecia that may be the target of future therapies. (more…)