Treatment options in pemphigus.

The therapy of pemphigus is one of the miracles of modern medicine, having transformed an almost invariably fatal disease into one whose mortality is now approximately 5%. Nonetheless, major challenges remain in further decreasing mortality and reducing the side effects of the potent medications used to treat this disease. The cornerstone of treatment remains the use of systemic steroids. The role of adjuvants, such as immunosuppressive and anti-inflammatory drugs, as ''steroid-sparing'' agents, remains to be defined, as there are little randomized trial data that provides objective evidence of their effectiveness. More recently, biologicals, such as IVIg and rituximab, have been introduced; the first to speed the control of active disease unresponsive to conventional treatment and the second to increase the proportion of patients in whom a complete clinical remission can be induced.

Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris, or just "witnesses of disease"?

Pemphigus vulgaris (PV) is fascinating to dermatologists, epithelial biologists and immunologists alike, as its pathogenesis has been clarified to a much greater extent than that of most other organ-specific autoimmune diseases, and as it has provided abundant novel insights into desmoglein biology and pathology along the way. Historically, the most influential PV pathogenesis concept is that of Stanley and Amagai. This concept holds that autoantibodies against desmogleins are both essential and sufficient for epidermal blister formation (acantholysis) by impeding the normal functioning of these major adhesion proteins. However, as with most good theories, this landmark concept has left a number of intriguing and important questions open (or at least has not managed to answer these to everyone's satisfaction). Moreover, selected dissenting voices in the literature have increasingly called attention to what may or may not be construed as inconsistencies in this dominant PV pathogenesis paradigm of the recent past. The present debate feature therefore bravely rises to the challenge of re-examining the entire currently available evidence, as rationally and as undogmatically as possible, by provocatively asking a carefully selected congregation of experts (who have never before jointly published on this controversial topic!) to discuss how essential anti-desmoglein autoantibodies really are in the immunopathogenesis of PV. Not surprisingly, some of our expert "witnesses" in this animated debate propose diametrically opposed answers to this question. While doing so, incisive additional questions are raised that relate to the central one posed, and our attention is called to facts that may deserve more careful consideration than they have received so far. Together with the intriguing (often still very speculative) complementary or alternative pathogenesis scenarios proposed in the following pages, this offers welcome "food for thought" as well as very specific suggestions for important future research directions--within and beyond the camp of PV aficionados. The editors trust that this attempt at a rational public debate of the full evidence that is currently at hand will constructively contribute to further dissecting the exciting--and clinically very relevant!--immunopathogenesis of PV in all its complexity.

Double-blind trial of a polyvalent, shed-antigen, melanoma vaccine.

A polyvalent melanoma vaccine prepared from shed antigens stimulates humoral and cellular immune responses and improves survival compared with historical controls. We conducted a double-blind, prospectively randomized, placebo-controlled trial to assess whether this vaccine could slow the progression of resected melanoma. Thirty-eight patients with resected melanoma metastatic to regional nodes (American Joint Committee on Cancer stage III) who had a particularly poor prognosis on the basis of the nodes being clinically positive or two or more histologically positive nodes were randomly assigned in a 2:1 ratio to treatment with 40 microg of melanoma or placebo (human albumin) vaccine, both of which were bound to alum as an adjuvant. Immunizations were given intradermally into the extremities every 3 weeks x 4, monthly x 3, every 3 months x 2, and then every 6 months for 5 years or until disease progression. Twenty-four patients were treated with the melanoma, and 14 patients were treated with the placebo vaccine. The groups were evenly balanced with respect to prognostic factors. Median length of observation was 2.5 years. There was no local or systemic toxicity. By Kaplan-Meier analysis, median time to disease progression was two and a half times longer in patients treated with melanoma vaccine compared with that in patients treated with placebo vaccine, i.e., 1.6 years (95% confidence interval, 1.0-3.0 years) compared with 0.6 year [95% confidence interval, 0.3-1.9 year(s)]. By Cox proportional hazards analysis, this difference was significant at P = 0.03. Overall survival was 40% longer in the melanoma vaccine-treated group (median overall survival of 3.8 years versus 2.7 years), but this difference was not statistically significant. In a double-blind and placebo-controlled trial, these results suggest that immunization with a melanoma vaccine may be able to slow the progression of melanoma. Although statistically significant, these results must be interpreted with caution because they are based on a small number of patients.

Laryngeal and nasal involvement in pemphigus vulgaris.

BACKGROUND: The presence of lesions of pemphigus vulgaris in the larynx and nasal cavity has been reported in individual case reports. However, the frequency with which these sites are involved is not known. OBJECTIVE: Our purpose was to investigate the incidence of laryngeal and nasal disease involvement in patients with pemphigus vulgaris. METHODS: This was a retrospective analysis conducted in a referral private practice in an academic department of dermatology. A total of 53 sequential patients with pemphigus vulgaris diagnosed by clinical, histologic, and immunofluorescence criteria were selected on the basis of having been treated by one of us (J. C. B.) during most of their illness. Patients' charts were reviewed for documentation of laryngeal and nasal symptoms, ear/nose/throat evaluation, and response to treatment. RESULTS: Twenty-six (49%) of the patients complained of laryngeal or nasal symptoms at some time during the course of their disease. Twenty-one patients had laryngeal symptoms and 12 had nasal symptoms. More than 80% of patients with laryngeal or nasal symptoms had evidence of pemphigus involvement based on ear/nose/throat examination or rapid response to increased doses of corticosteroids, and 2 patients had candidiasis confirmed by fungal culture. CONCLUSION: These observations indicate that laryngeal and nasal symptoms are common in pemphigus vulgaris. In the majority of cases, this appears to be a result of involvement with the disease or with candidiasis.

Decrease in circulating tumor cells as an early marker of therapy effectiveness.

As melanoma cells are present in the circulation of many patients with this cancer, decreases in their number could provide an early indication of therapy effectiveness. To evaluate this possibility, we examined the effect of treatment with a melanoma vaccine on the number of melanoma cells present in the circulation. PCR was used to detect melanoma cells that expressed the melanoma-associated antigens MART-1, MAGE-3, tyrosinase and/or gp100 in 91 patients with melanoma. Melanoma cells that expressed one or more of these markers were present more often in advanced disease, i.e. in 80% of patients with advanced stage IV compared to in less than one-third of patients with less advanced disease. We then measured circulating melanoma cells in a subset of 43 of these patients who were treated with a polyvalent, shed antigen, melanoma vaccine. The vaccine contains multiple melanoma-associated antigens including MART-1, MAGE-3, tyrosinase and gp100. Immunizations were given intradermally q2-3 weeks x4 and then monthly x3. Prior to vaccine treatment, circulating melanoma cells were detected in 14 (32%) patients. Following 4 and 7 months of vaccine treatment, melanoma cells that expressed any of these markers were present in only nine (21%) and three (7%) of patients, respectively. Thus, vaccine therapy was associated with clearance of melanoma cells from the circulation in 78% of initially positive patients. As the number of these cells declined steadily with increasing length of therapy, it is unlikely that this was due to a random change in their number. Rather it suggests that the decline was a result of the therapy. These observations suggest that the presence of melanoma cells in the circulation is related to the extent of the melanoma, and that their disappearance may provide an early marker of the efficacy of therapy. However, the practical utility of assaying circulating tumor cells as a guide to the effectiveness of therapy or of prognosis will need to be confirmed by correlations with clinical outcome.

Identification of HLA-A*03, A*11 and B*07-restricted melanoma-associated peptides that are immunogenic in vivo by vaccine-induced immune response (VIIR) analysis.

With the discovery of increasing numbers of tumor antigens, there is a need to rapidly determine whether these antigens and the individual peptides they express are able to stimulate immune responses in vivo and thus, can be used to construct cancer vaccines. In this study we used the method of vaccine-induced immune response (VIIR) analysis to identify multiple immunogenic peptide epitopes derived from several melanoma associated antigens and presented by HLA-A*03, A*11 and B*07. Thirty-one patients with melanoma were immunized to a polyvalent vaccine containing multiple antigens, including MAGE-3, Melan A/MART-1, gp100 and tyrosinase. Their peripheral blood was tested for peptide-specific, vaccine-induced CD8+ T cell responses before and after immunization using an enzyme-linked immune spot (ELISPOT) assay with panels of peptides restricted by these three alleles. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*03, A*11 or B*07. Overall, 60% of the 20 peptides studied were recognized by at least one patient and 50% of the patients showed a vaccine-induced CD8+ T cell response to at least one peptide that matched their HLA specificity. We conclude that VIIR analysis is an effective strategy to directly identify immunogenic peptides that are good candidates for vaccine construction.

Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus.

OBJECTIVE: To compare the effectiveness and the adverse effects of 2 different regimens for the treatment of pemphigus: corticosteroids alone compared with a combination of corticosteroids and cyclosporine. DESIGN: Concurrently randomized trial. SETTING: Tertiary care medical center. PATIENTS AND METHODS: We studied 33 sequential hospitalized patients with newly diagnosed pemphigus vulgaris (n=29) or pemphigus foliaceous (n=4) based on clinical, histological, and immunofluorescence criteria who had not previously been treated with systemic corticosteroids or immununosuppressive drugs. Patients were randomly assigned to treatment with methylprednisolone or prednisolone plus cyclosporine. INTERVENTION: Both groups were treated with similar initial doses of prednisolone (prednisone equivalent, 1 mg/kg), which were increased 50% every 5 to 10 days based on persistence of disease activity. One group was treated in addition with cyclosporine (5 mg/kg). MAIN OUTCOME MEASURES: Patients were followed up closely for clinical outcome based on time required to control active manifestations of the disease, induction of partial and complete remissions, total amount of corticosteroids administered, frequency of relapses, and development of complications. RESULTS: The 2 groups were similar in terms of demographics and baseline disease severity. There was no difference between groups in any of the variables used to measure response to treatment or total amount of corticosteroids administered. Complications were more common in patients who received combination therapy. CONCLUSION: Combination treatment with corticosteroids and cyclosporine, 5 mg/kg, offers no advantage over treatment with corticosteroids alone in patients with pemphigus.

Dermatology manpower needs.

The future need for dermatologists is difficult to predict, as it depends on the structure of our health care delivery system, which is still rapidly evolving, and whose future shape is unknown. The best strategy to deal with this unpredictable situation is to de-emphasize trying to predict the future and focus on responding as rapidly as possible to whatever changes in dermatologic manpower needs the future may bring. From that perspective, it is best to train fewer rather than more dermatologists, as it is much quicker to rectify a shortage than an excess in medical manpower. Other issues that impact on dermatologist manpower include a very rapid increase in nonphysicians taking care of skin diseases, the maldistribution of dermatologists, the decreasing proportion of common skin diseases treated by dermatologists, and the need to upgrade the residency training to master the explosion in medical knowledge which has occurred, and to gain a greater expertise in the medical and cosmetic aspects of the specialty.

Expression of SS-A/Ro and SS-B/La antigens in skin biopsy specimens of patients with photosensitive forms of lupus erythematosus.

CONTEXT: The reason that only some patients with lupus erythematosus (LE) develop autoantibodies to SS-A/Ro and SS-B/La antigens and photosensitivity is unknown. One hypothesis is that both events are related to the level of expression of these antigens in the skin. OBJECTIVE AND DESIGN: To test this hypothesis, we measured the expression of the 52-kd SS-A/Ro, 60-kd SS-A/Ro, and 48-kd SS-B/La antigens in normal sun-protected and sun-exposed skin in 14 patients with LE with photosensitivity, 12 patients with LE without photosensitivity, and 4 normal individuals. The presence of circulating antibodies to these antigens was measured in all patients. SETTING: Outpatient clinic in an academic medical center. RESULTS: We found that the expression of the 52-kd SS-A/Ro, 60-kd SS-A/Ro, and 48-kd SS-B/La antigens in skin biopsy specimens obtained from the same site was 4- to 10-fold higher in patients with LE with photosensitivity than in those patients with LE without photosensitivity (P<.001). Antigen expression was highly correlated with the presence and titer of circulating anti-SS-A/Ro and anti-SS-B/La antibodies (P<.001). CONCLUSIONS: These findings indicate that photosensitivity and the presence and titer of circulating anti-SS-A/Ro and anti-SS-B/La antibodies are both directly correlated with the expression of accessible and immunoreactive SS-A/Ro and SS-B/La antigens in the skin specimens of patients with LE. Thus, the expression of these antigens in keratinocytes may be an important determinant of the development of both SS-A/Ro and SS-B/La autoantibodies and of photosensitive forms of LE.

Patterns of remission in pemphigus vulgaris.

BACKGROUND: The incidence of remissions in pemphigus is unclear because these are usually reported at a single point in the evolution of the disease. Thus it is uncertain whether treatment simply suppresses the manifestations of the disease and consequently must be continuously administered, or induces complete and long-lasting remissions that permit therapy to be discontinued. OBJECTIVE: To answer this question, we investigated the incidence of remission in a long-term longitudinal study. METHODS: The induction of complete and long-lasting remissions (lesion free with no systemic therapy for at least 6 months) was studied in 40 patients with pemphigus vulgaris treated conventionally and followed up for an average of 7.7 years by the same investigator. RESULTS: Five (5%) of the patients died of the disease. Complete and long-lasting remissions were induced in 25%, 50%, and 75% of patients 2, 5, and 10 years, respectively, after diagnosis. Most of the remaining patients were in partial remission or had mild disease controlled with a small dose of steroids. The course of the disease followed different patterns, with some patients rapidly entering complete and long-lasting remissions, whereas others never entered into a complete remission. The induction of complete remission was related to the initial severity and extent of disease and to early response to treatment. CONCLUSION: It is possible to eventually induce complete and durable remissions in most patients with pemphigus that permit systemic therapy to be safely discontinued without a flare in disease activity. The proportion of patients in whom this can be achieved increases steadily with time, and therapy can be discontinued in approximately 75% of patients after 10 years.

Alopecia areata: an autoimmune disease?

A wide range of hypotheses such as focal infection, trophoneuroses, and endocrine dysfunction, have been previously proposed to explain the pathogenesis of alopecia areata (AA). Currently, the most widely held belief is that AA is an autoimmune disease with cellular and/or humoral immunity directed against anagen hair follicle antigen(s). However, until recently evidence in support of an autoimmune mechanism of AA has been largely circumstantial. More fundamental evidence has recently been amassed in support of AA as an autoimmune disease by using animal models. These data include: 1) identification of cross-species hair follicle specific IgG autoantibodies, 2) The ability to induce AA in an animal model with transfer of skin from affected to naive individuals, and 3) the induction of disease by transfer of lymphocytes to human skin grafted to severe combined immunodeficiency mutant mice. A review of the previous and current data related to the autoimmune basis of AA is provided to put into perspective the future studies needed to definitively determine whether AA is an autoimmune disease.