Dermatology

Pemphigus Vegetans (Pemphigus vegetans of Hallopeau, pemphigus vegetans of Neumann, pemphigus vulgaris)

Pemphigus vegetans (Pemphigus vegetans of Hallopeau, pemphigus vegetans of Neumann, pemphigus vulgaris; ICD-9 694.4)

Are You Confident of the Diagnosis?

Pemphigus vegetans is considered to be a subset of pemphigus vulgaris. Pemphigus vegetans of Hallopeau has been used to describe a form of indolent disease with good prognosis. Pemphigus vegetans of Neumann is associated with more extensive and refractory disease.

What you should be alert fer in the history

Determine the scope of mucosal and cutaneous disease: Ask whether patients have pain with eating or sexual intercourse. Ask about aggravating factors, which can include stress, ultraviolet radiation, menses, recent vaccinations, or cessation of smoking. Although rare, determine if any underlying factors may be present. Ask about recent changes in medications. Ask about trouble speaking or swallowing, eyelid droop, or double vision (the earliest signs of myasthenia gravis). In children, ask about cough, chest pain, hoarseness, or difficulty swallowing (symptoms of thymoma; thymoma in adults is usually asymptomatic early on.)

Characteristic findings on physical examination

The characteristic finding in pemphigus vegetans is the presence of vegetating plaques at the site of cutaneous erosions. Vegetative lesions occur more often in the scalp, face, and in intertriginous areas (Figure 1). In the Hallopeau variant, vegetative and often pustular lesions are present from the outset of disease, are not preceded by bullae, and favor flexural regions. In the Neumann variant, typical pemphigus vulgaris erosions heal with vegetative plaques and often remain for long periods of time.

Figure 1.

Erosive vegetative plaques of pemphigus vegetans in the inguinal fold. Photo courtesy of Dr. Michael Hertl.

Otherwise, the clincial exam findings in pemphigus vegetans are identical to pemphigus vulgaris. In mucosal disease, areas of involvement can include the oropharyngeal, upper esophageal, vaginal, nasal, and less often the conjunctival mucosa (areas with stratified squamous epithelia). Oropharyngeal mucosae (including gingiva, tongue, and hard and soft palates) are most often affected. A common finding is desquamative gingivitis (friability of gingiva with erosions, often at the interdental papillae). Scalp, face, trunk, and extremities are commonly affected in mucocutaneous disease. Skin blisters are most often flaccid or eroded, with a thicker scale crust and beefy red base.

Patients with widespread disease may demonstrate the Nikolsky sign, where blisters can be extended into normal-appearing skin by fingertip pressure lateral to the edge of a blister, or induced in normal-appearing skin distant from areas of blistering by mechanical shear force, indicating the loss of cell adhesion throughout the epidermis. The Nikolsky sign is not specific for pemphigus vulgaris and may also be observed in other skin blistering diseases such as pemphigus foliaceus, staphylococcal scalded skin syndrome, and toxic epidermal necrolysis.

Expected results of diagnostic studies

Skin or mucosal biopsy for histology. A punch or shave biopsy for histology should be obtained at the lateral edge of a fresh lesion. Biopsy of vegetative lesions may or may not demonstrate epidermal blister formation. Biopsies from patients with pemphigus vegetans will usually show suprabasal acantholysis (loss of intercellular adhesion between intact keratinocytes), resulting in a blister just above the basal cell layer. The basal keratinocytes remain attached to the basement membrane zone by their hemidesmosomes, but lose attachment to each other, resulting in the “row of tombstones” that is characteristic of pemphigus vulgaris.

Most blisters in pemphigus vegetans demonstrate inflammation with neutrophils and/or eosinophils. Some biopsies of vegetative plaques show no epidermal blister formation, instead desmonstrating epidermal acanthosis with neutrophilic and/or eosinophilic epidermal abscesses (Figure 2).

Figure 2.

Pemphigus vegetans histology, with epidermal acanthosis and prominent eosinophilic and neutrophilic infiltrate.

Autoantibodies to the keratinocyte cell surface should be documented, either by direct immunofluorescence, indirect immunofluorescence, or ELISA.

Skin or mucosal biopsy for direct immunofluorescence (DIF). A punch or shave biopsy should be obtained from normal-appearing perilesional skin or mucosa and submitted in Michel’s or other appropriate fixative for direct immunofluorescence analysis. Pemphigus vegetans often demonstrates both IgG and IgA cell surface staining of keratinocytes. C3 is rarely positive. Even if all skin lesions have healed because of recent therapy, DIF should remain positive for at least several weeks. Cell surface-bound IgG is typically internalized by keratinocytes within the blister cavity, leading to false negative results if samples for DIF are taken from blistered skin.

Serum sample for indirect immunofluorescence (IIF). Serum is incubated with epithelial substrates (typically monkey esophagus or normal human skin). Similar to DIF, IIF for pemphigus vegetans will often demonstrate both IgG and IgA cell surface staining (Figure 3), less often C3, and will remain positive for at least several weeks after skin lesions have healed. Indirect immunofluorescence is a semi-quantitative test, with titer roughly correlating with disease activity.

Serum sample for desmoglein ELISA. Antigen-specific ELISAs are more sensitive and specific (100% and 94%, respectively) for pemphigus than indirect immunofluorescence and may replace the latter as the preferred diagnostic test. However, desmoglein ELISA is not always available from major national reference laboratories, and some cases of pemphigus vegetans are associated with antibodies against desmocollin 3 rather than desmoglein 3.

Pemphigus vegetans is usually associated with both a positive desmoglein 3 and desmoglein 1 ELISA, similar to the serologic findins in mucocutaneous pemphigus vulgaris. Desmoglein index values roughly correlate with disease activity. However, because the desmoglein ELISA measures both pathogenic as well as nonpathogenic antibodies (see “Pathophysiology” below), positive desmoglein ELISA index values may still be observed in patients in remission.

Diagnosis confirmation

Desquamative gingivitis from mucosal pemphigus can also be seen in herpesvirus infection, oral lichen planus, and erythema multiforme/Stevens-Johnson syndrome. The clinical differential diagnosis for pemphigus vegetans includes Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous pemphigoid, epidermolysis bullosa acquisita and other rare subepidermal autoimmune blistering diseases, porphyria, pemphigus foliaceus, paraneoplastic pemphigus, and disseminated herpes simplex or zoster.

Who is at Risk for Developing this Disease?

The epidemiology of pemphigus vegetans has not specifically been investigated. Pemphigus vulgaris is more common among Ashkenazi Jewish, Mediterranean, and Middle Eastern populations. Incidence estimates range from 0.5 per million person years in central European countries to 0.7 per 100,000 person years in the United Kingdom, 1.6 per 100,000 person years in Jerusalem, and 10.0 per 100,000 person years in Iran.

Average age of onset for pemphigus vulgaris varies by region, ranging from 40 in Iran to 50-60 in the United States. Children rarely develop pemphigus vulgaris. Pemphigus vulgaris is slightly more common in women, with sex ratios in women versus men ranging from 1.33 to 2.25. Women often notice flares around the time of their menses.

Pemphigus vulgaris has been associated with both myasthenia gravis and thymoma. It is more common for patients with thymoma to have pemphigus than for patients with pemphigus to have thymoma.

Penicillamine and captopril have been associated with pemphigus. The prevalence of pemphigus (including vulgaris and foliaceus) in penicillamine users is estimated at 7%. Although angiotensin-converting enzyme inhibitors other than captopril are not as strongly associated with pemphigus, it is reasonable to change these medications. Diet has also been proposed as a risk factor for pemphigus (eg, garlic, onions). However, discontinuation of penicillamine or other medications and modification of diet rarely result in disease remission.

What is the Cause of the Disease?

Etiology

Pemphigus vegetans, like pemphigus vulgaris, is caused by autoantibodies against desmoglein 3 and +/- desmoglein 1. Mucosal dominant disease is associated with autoantibodies to desmoglein 3, and mucocutaneous disease is associated with autoantibodies to both desmoglein 3 and desmoglein 1. Some cases of pemphigus vegetans are also associated with IgG and IgA antibodies against desmocollins, although the pathogenicity of these anti-desmocollin antibodies has not been well investigated.

Desmogleins and desmocollins are transmembrane proteins of the desmosome, which is the major cell adhesive junction in keratinocytes. Anti-desmoglein antibodies are necessary and sufficient for blister formation in animal and human skin models of pemphigus vulgaris; IgA antibodies may be mediating neutrophilic inflammation in the case of pemphigus vegetans.

Pathophysiology

The immune mechanisms causing the loss of tolerance to desmogleins are unknown, although certain MHC class II alleles are more often associated with pemphigus vulgaris (HLA DRB1*0402 and DQB1*0503). Structural studies have shown that these MHC class II molecules can bind and present desmoglein 3 peptides to T cells. However, T cells from unaffected individuals can respond just as well to desmoglein 3 peptides as those from pemphigus patients, indicating that T cell reactivity to desmoglein 3 is not sufficient for disease onset.

Why some patients with anti-desmoglein antibodies demonstrate typical pemphigus vulgaris blisters and erosions and others demonstrate vegetative plaques is unclear. Most pathogenic antibodies target the desmoglein extracellular domain that is predicted to form the trans-adhesive interface between cells, while nonpathogenic antibodies more often target other extracellular domains. These studies suggest that pathogenic autoantibodies cause blisters by steric hindrance of desmoglein adhesive interactions.

In addition, keratinocyte signaling pathways such as p38 mitogen activated protein kinase regulate the cell surface internalization of desmogleins, which may also contribute to disease pathology. Corticosteroids upregulate desmoglein expression in keratinocytes, which may account for their rapid therapeutic effect (within days, even when circulating antibody titers have not yet changed), as well as their efficacy when used topically.

Systemic Implications and Complications

Pemphigus vulgaris is rarely associated with thymoma or myasthenia gravis. Myasthenia gravis would be best evaluated by a neurologist, who can complete a full neurologic examination and may test for serum acetylcholine receptor autoantibodies. Posteroanterior and lateral chest radiographs with or without computerized tomography follow up can detect most thymomas.Thymic irradiation or removal, although beneficial for myasthenia gravis, may not lead to remission of pemphigus.

Acantholytic cells in the cervicovaginal mucosa may be misinterpreted as cervical dysplasia on pap smears.

Left untreated, pemphigus vulgaris was uniformly fatal within 5 years due to severe blistering of the skin and mucous membranes leading to malnutrition, dehydration, and sepsis.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Treatment options for pemphigus vegetans
Medical Treatment
Topical or intralesional corticosteroids
Oral corticosteroids
Mycophenolate mofetil
Azathioprine
Dapsone
Rituximab
Intravenous immunoglobulin
Plasmapheresis
Tetracyclines plus niacinamide
Cyclophosphamide

Optimal Therapeutic Approach for this Disease

Class I steroids such as clobetasol can be applied twice daily to new blisters and erosions on both the face and body. Topical tacrolimus ointment may also be helpful, particularly for lesions on the face where chronic steroid therapy is undesirable. Intralesional triamcinolone acetonide (5 mg/cc) can be injected directly into refractory vegetative lesions.

For mucosal disease, dexamethasone elixir, swish and spit 5 cc once to twice daily, is easy to use. Clobetasol ointment or gel can also be applied directly to mucosal erosions. Dental trays (fitted by oral medicine) facilitate occlusion of topical steroids to the gingiva at night. For mild disease (transient lesions that heal within one week), monotherapy with topical corticosteroids may be sufficient. Mild mucosal or mucocutaneous disease may also respond to tetracyclines plus niacinamide (doxycycline 100mg twice daily plus

With persistent or widespread disease, oral corticosteroids such as prednisone are indicated. For moderate disease, 0.5mg/kg/day of prednisone or equivalent may be sufficient. Doses generally do not need to exceed 1mg/kg/day of prednisone. If patients flare on 1mg/kg/day of prednisone, the dose can be split to twice daily or three times daily dosing, which increases the therapeutic efficacy without increasing the total daily dose.

Before starting high-dose steroids, tuberculosis screening should be performed (via tuberculin skin testing or Quantiferon-gold blood assay). If patients will be on chronic corticosteroids (at least 5mg daily prednisone equivalent for at least 3 months), osteoporosis counseling and prevention is indicated. Additionally, Pneumocystis prophylaxis should be considered for patients on chronic prednisone, particularly with daily prednisone doses of 15mg or higher. Patients should remain on high-dose steroids until new lesions cease to form, and then the dose can be gradually tapered to the minimum required to control disease. If patients can be managed with 10mg (or ideally 5mg) daily prednisone or less, corticosteroid monotherapy is feasible.

Dapsone (100-200mg daily) can be effective in mucosal disease, to lower the daily corticosteroid dose in patients with stable disease, and in patients with evidence of IgA deposition or neutrophilic inflammation on biopsy. Dapsone can be used in addition to mycophenolate mofetil or azathioprine. As an advantage, dapsone 100mg daily provides Pneumocystis prophylaxis.

Glucose-6-phosphate dehydrogenase (G6PD) activity should ideally be measured before starting therapy, particularly in men of African-American and Middle Eastern descent. Most patients will experience a 1-2 g/dL drop in hemoglobin due to hemolysis, although some patients can experience a severe pancytopenia with or without systemic hypersensitivity reaction. Laboratory monitoring should be performed at least every other week for the first 8 weeks.

In patients requiring greater than 10mg daily prednisone for control of disease activity, or in patients with contraindications to systemic corticosteroid therapy, other immunosuppressants are necessary to reduce or replace systemic corticosteroids. Mycophenolate mofetil and azathioprine have shown approximately equal efficacy and safety in clinical trials for pemphigus vulgaris, although there is a trend toward both greater efficacy and safety with mycophenolate mofetil.

Mycophenolate mofetil (30-40 mg/kg/day divided twice daily) is generally well tolerated, although side effects of fatigue, gastrointestinal upset, and tremor are not uncommon, particularly at higher doses, and there is a small long-term risk of lymphoma and fatal infection or reactivation from JC virus with progressive multifocal leukencephalopathy. Reduction of corticosteroid dose can be initiated as early as 1 month after starting mycophenolate mofetil, although maximal effect is not achieved until 2-3 months.

Azathioprine can be started at 50mg daily and titrated upward by 50mg every 1-2 weeks until side effect, therapeutic effect, or the target dose of 2.5mg/kg/day occurs. Measurement of serum thiopurine methyltransferase (TPMT) level prior to start of azathioprine therapy can be performed, although some studies suggest that TPMT levels do not correlate with the incidence of adverse effects or efficacy of azathioprine therapy. Nevertheless, if serum TPMT levels are very low or very high, azathioprine may not be a good choice for therapy, due to an increased likelihood for adverse effects or lack of effect, respectively. The active metabolites for azathioprine do not significantly accumulate until 6-8 weeks after initiation of therapy, leading to a delayed therapeutic effect.

In patients who have severe or persistent disease that cannot be controlled with corticosteroids and/or other immunosuppressives, other therapies such as rituximab, intravenous immunoglobulin, plasmapheresis, and cyclophosphamide can be considered.

B-cell depletion therapy with rituximab (anti-CD20 monoclonal antibody) is an effective therapy for pemphigus, and some experts have proposed that it should be considered for first-line therapy. Both lymphoma (375 mg/m 2 IV weekly x 4 weeks) and rheumatoid arthritis (1000mg IV on days 1 and 15) dosing regimens can be used. In vivo studies from lymphoma patients indicate that peripheral blood B cells disappear from the circulation within days, although antibody production by plasma cells (which are not well targeted by rituximab) can persist for months; therefore maximal results are not observed until 3-6 months after infusion, and re-infusion every 6 months may be required.

Fatal infection has occurred with rituximab therapy, including bacterial sepsis, hepatitis B reactivation, and progressive multifocal leukencephalopathy from JC virus, although fatal infection is also a potential side effect of first-line therapies, including prednisone and mycophenolate mofetil.

Intravenous immunoglobulin (IVIG, 2mg/kg, divided over 3-5 days) is effective for PF therapy and can be provided by hospital or home infusion. IVIG induces catabolism of endogenous serum antibodies and offers the advantage of being immunoprotective. A disadvantage of IVIG is that the temporary serum viscosity associated with the infusion can cause stroke or other complications from clotting.

The serum half life of IVIG has been reported to range from 8-39 days (average 3-4 weeks). Treatment guidelines for autoimmune blistering disease with IVIG suggest an initial frequency of every 4 weeks until disease remits, increasing to 6, 8, 10, 12, 14, then 16 weeks, the latter being the proposed end point for an initial course of therapy.

Plasmapheresis allows for the rapid removal of antibodies from the circulation, but must always be used in conjunction with adjunctive immunosuppressants to prevent new antibody production.

Cyclophosphamide (50-200mg daily) is among the fastest agents for treating pemphigus. However, its risk of blood count and liver test abnormalities, infertility, and hemorrhagic cystitis with bladder carcinoma, together with the advent of other effective therapies such as rituximab, have led to the decreased use of cyclophosphamide in the management of severe pemphigus.

Patient Management

The goal of treatment is to obtain a complete remission off therapy, although many patients may only achieve a partial remission off therapy, or a complete remission on minimal therapy. When starting patients on therapy, risks of medications should be discussed. There is no systemic medication that for pemphigus that is 100% safe. However, the natural history of untreated pemphigus vulgaris is to progress to life-threatening disease; therefore the risk-benefit ratio favors treatment.

Open erosions can become superinfected with Staphylococcus aureus or herpesviruses; culture of refractory or worsening lesions should be considered.

Remind patients that their skin during active disease is fragile, so crusted blisters should not be scrubbed and use of massage or other high pressure showerheads should be avoided.

Patients should receive regularly scheduled dental cleaning from a hygienist experienced with oral blistering disease. Patients often avoid cleanings due to painful mucosal disease; however, over time plaque buildup leads to chronic gingival inflammation that aggravates pemphigus. If necessary, patients can take a short (1-2 week) course of prednisone surrounding their cleanings to prevent flares of disease.

Patients should ideally be maintained in complete remission for at least 1 year before all immunosuppressive therapy is discontinued. Often patients want to taper off their medications quickly, but then flare and have to go back on high doses of medications for disease control, which may reduce the chance for disease remission. Typically, corticosteroids are tapered off first, then adjunctive immunosuppressants are slowly tapered over the course of one year. However, the tapering regimen should be tailored for each patient depending on side effects and response to therapy. It is common for patients to have a small flare with each dose taper; as long as lesions heal within one week and no further lesions form, the taper can be continued.

The Centers for Disease Control recommends that all patients on immunosuppressive therapy receive influenza and other regularly scheduled vaccinations. While on immunosuppressive therapy, patients should be reminded that they should not receive live vaccines (e.g. nasal influenza or zoster.)

Unusual Clinical Scenarios to Consider in Patient Management

Pregnant patients with pemphigus vegetans should be referred for high-risk obstetrical care. Maternal pemphigus vulgaris (and likely, pemphigus vegetans) is associated with low birthweight and rarely stillbirths in newborns. Additionally, neonatal pemphigus vulgaris can result from placental transfer of disease-causing IgG from the maternal circulation. Pregnant patients are usually treated with prednisone monotherapy, as most other immunosuppressive agents are pregnancy category D, including mycophenolate mofetil, azathioprine, tetracyclines, and cyclophosphamide. Dapsone is pregnancy category C.

There are sparse data regarding the safety of immunosuppressives in men whose pregnant wives can be exposed to drugs in seminal fluid. Rare cases of birth defects with azathioprine use by fathers has been reported. An ongoing registry of male transplant patients receiving mycophenolate mofetil has shown no significant increase in birth defects.

In hospitalized patients with severe disease, blood should be cultured so that bacteremia can be identified and treated. A thin layer of triamcinolone 0.1% ointment can be spread on sterile linens and wrapped around patients twice daily. Unfortunately, there is no single consensus regimen among experts about how to treat severe pemphigus, owing to the sparsity of randomized controlled trials in this rare disease. Historically, these patients were treated with corticosteroids, cyclophosphamide, and plasmapheresis due to their rapid therapeutic effect. Several other regimens can be considered for the hospitalized patient, including:

-intravenous corticosteroids (as high as 60mg methylprednisolone four times daily), adjunctive immunosuppressant such as mycophenolate mofetil, and IVIG (which is immunoprotective)

-intravenous corticosteroids (+/- adjunctive immunosuppressant) and rituximab for long term control

-intravenous corticosteroids (+/- adjunctive immunosuppressant), plasmapheresis to immediately remove serum antibodies, followed by rituximab for long term control

The timing of certain combinations of medications should be considered. For example, rituximab infusion should not be administered immediately before plasmapheresis or IVIG, as the former would clear the rituximab and the latter may induce its catabolism. However, rituximab is thought to rapidly bind and deplete circulating B cells (within days), and peripheral B cell counts begin to recover 8 days after infusion.

Theoretically therefore, plasmapheresis and IVIG could be considered as early as 1-4 weeks after completion of rituximab infusion, although studies indicate that rituximab half-life progressively increases with subsequent weekly infusions (suggesting saturation of in vivo binding sites), and that a higher serum concentration is associated with better treatment outcome in B cell lymphomas. Conversely, plasmapheresis can be performed immediately prior to rituximab, but the ideal timing of rituximab infusion after a course of IVIG is unknown, with recommendations ranging from 1-6 weeks based on the serum half life of IVIG.

What is the Evidence?

Nelson, CG, Apisarnthanarax, P, Bean, SF, Mullins, JF. "Pemphigus vegetans of Hallopeau: immunofluorescent studies". Arch Dermatol. vol. 113. 1977. pp. 942-5.

(Histologic and immunofluorescence analysis of lesions of pemphigus vegetans suggests that these cases are clinical variants of pemphigus vulgaris.)

Payne, AS, Stanley, JR, Wolff, K, Goldsmith, LA, Katz, SI, Gilchrest, B, Paller, AS, Leffell, DJ. "Dermatology in general medicine". McGraw Hill. 2011.

(A more complete review of the clinical presentation and management of pemphigus.)

Murrell, DF, Dick, S, Ahmed, AR, Amagai, M, Barnadas, MA, Borradori, L. "Consensus statement on definitions of disease endpoints and therapeutic response for pemphigus". J Am Acad Dermatol. vol. 58. 2008. pp. 1043-6.

(An international consensus of definitions for disease endpoints [such as remission, relapse, and treatment failure]).

Amagai, M, Komai, A, Hashimoto, T, Shirakata, Y, Hashimoto, K, Yamada, T. "Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus". Br J Dermatol. vol. 130. 1999. pp. 351-7.

(Describes the development of the desmoglein ELISA, including sensitivity and specificity.)

Beissert, S, Werfel, T, Frieling, U, Bohm, M, Sticherling, M, Stadler, R. "A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus". Arch Dermatol. vol. 142. 2006. pp. 1447-54.

(This prospective randomized trial of 40 pemphigus patients demonstrated equal efficacy and safety between mycophenolate mofetil [2g daily] and azathioprine [2mg/kg/day] as steroid-sparing agents in pemphigus, with a trend toward greater efficacy and safety for mycophenolate mofetil.)

Chams-Davatchi, C, Esmaili, N, Daneshpazhooh, M, Valikhani, M, Balighi, K, Hallaji, Z. "Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris". J Amer Acad Dermatol. vol. 57. 2007. pp. 622-8.

(This trial compared prednisolone alone to prednisolone plus azathioprine [2.5mg/kg/day], mycophenolate mofetil, [2g/day] or pulse IV cyclophosphamide among 120 patients with PV. All agents were effective as steroid-sparing agents, although azathioprine was associated with a significantly lower mean total prednisolone dose as compared to mycophenolate mofetil.)

Beissert, S, Mimouni, D, Kanwar, A, Solomons, N, Kalia, V, Anhalt, GJ. "Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a randomized, placebo-controlled trial". J Invest Dermatol. vol. 130. 2010. pp. 2041-8.

(This trial randomized patients to mycophenolate mofetil [MMF] 2 or 3g daily versus oral corticosteroids (1-2mg/kg/day). Treatment with MMF was not associated with a significantly improved treatment response, although time to relapse and length of sustained response was significantly increased. There were several caveats to this study, including the fact that after randomization, the placebo-treated group had significantly milder disease than the MMF-treated group.)

Joly, P, Mouquet, H, Roujeau, JC. "A single cycle of rituximab for the treatment of severe pemphigus". New Engl J Med. vol. 357. 2007. pp. 545-52.

(Largest published case series of 21 pemphigus patients treated with rituximab. 18 patients achieved complete remission within 3 months, and 20 patients achieved complete remission within 12 months. After treatment with corticosteroids or a second cycle of rituximab, 18 patients remained disease-free at 34 months, with 8 patients completely off corticosteroid therapy. Two patients had severe complications including pyelonephritis and fatal sepsis.)

Ahmed, AR, Spigelman, Z, Cavacini, LA, Posner, MR. "Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin". New Engl J Med. vol. 355. 2006. pp. 1772-9.

(Nine out of 11 pemphigus vulgaris patients had sustained remissions lasting 22-37 months, and the two who relapsed had sustained remissions after a second course of rituximab only. No infections occurred. The authors propose that IVIG replaces the beneficial antibodies otherwise depleted by rituximab. However, the safety and efficacy of the combined regimen compared to rituximab or IVIG alone, as well as the optimal timing of rituximab and IVIG infusions, remains unknown.)

Ahmed, AR, Dahl, MV. "Consensus statment on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases". Arch Dermatol. vol. 139. 2003. pp. 1051-9.

(Provides guidelines for the use of IVIG, including indications, prescreening, premedications, dose, frequency, monitoring, and therapeutic endpoints.)
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