Initial management of pemphigus vulgaris and pemphigus foliaceus

INTRODUCTION — The term "pemphigus" describes a group of autoimmune, mucocutaneous, blistering disorders characterized by acantholysis (loss of keratinocyte-to-keratinocyte adhesion) in the epithelium of mucous membranes or skin. Pemphigus vulgaris (picture 1A-D) and pemphigus foliaceus (picture 2A-B) are the two most common forms of pemphigus. Significant morbidity and mortality can occur as a result of complications of these diseases and their treatments.

Systemic glucocorticoids and rituximab are the mainstays of therapy for pemphigus vulgaris and pemphigus foliaceus and are usually highly effective for obtaining control of disease (algorithm 1). Other immunomodulatory agents, such as azathioprine and mycophenolate mofetil, are commonly prescribed in conjunction with systemic glucocorticoids in an attempt to minimize the risk for adverse effects of long-term, high-dose glucocorticoid therapy. Interventions such as intravenous immune globulin (IVIG), immunoadsorption, and cyclophosphamide are typically reserved for patients with refractory disease. (See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

The initial management of pemphigus vulgaris and pemphigus foliaceus will be reviewed here. The management of refractory pemphigus vulgaris and pemphigus foliaceus, the pathogenesis and diagnosis of pemphigus, and the diagnosis and management of paraneoplastic pemphigus and fogo selvagem (endemic pemphigus foliaceus) are reviewed separately.

●(See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

●(See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

●(See "Paraneoplastic pemphigus".)

●(See "Fogo selvagem (Brazilian endemic pemphigus foliaceus)".)

RATIONALE FOR TREATMENT — Although pemphigus vulgaris typically presents as a more severe disorder than pemphigus foliaceus due to the frequent presence of both mucosal and cutaneous involvement, both disorders can lead to significant morbidity:

●Oral mucosal involvement, which occurs in almost all patients with pemphigus vulgaris, is usually accompanied by severe pain and may lead to poor alimentation, resulting in weight loss and malnutrition (picture 1A, 1E-F).

●The widespread loss of the epidermal barrier in pemphigus vulgaris and pemphigus foliaceus may lead to protein loss, fluid loss, electrolyte imbalances, dietary insufficiencies, increased catabolism, and increased risk for local and systemic infections (picture 1B-D, 1G). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Clinical features'.)

The complications of pemphigus vulgaris can be life threatening. It is estimated that prior to the use of systemic immunosuppressants, more than 70 percent to nearly 100 percent of patients died within one to five years [1-3]. Pemphigus foliaceus, which is characterized by shallow blisters and involvement limited to the skin, is considered to have a better prognosis than pemphigus vulgaris (picture 2A-C) [3]. However, progression of pemphigus foliaceus may lead to extensive involvement and similar complications.

APPROACH TO TREATMENT — The initial goal of treatment in pemphigus is to induce complete remission while minimizing treatment-related adverse effects. Long-term remission after the discontinuation of therapy is the ultimate goal for patient management, although it may take some time to achieve:

●Whom and when to treat – Given the potential for severe morbidity and mortality from pemphigus vulgaris and pemphigus foliaceus, treatment is always indicated at the time of disease onset, even for patients who initially present with mild disease.

●Precautions – Treatment must be approached carefully because the therapeutic regimens for pemphigus are not benign. Most of the estimated 5 to 10 percent mortality rate from pemphigus vulgaris is considered to result from complications from treatment [4-7]. Infections, ranging from minor skin infections to life-threatening, opportunistic infections, are common complications of the immunosuppressive regimens typically used for pemphigus therapy [8,9].

●General approach – The paucity of large, high-quality, prospective trials that compare treatments for pemphigus and the variability in study protocols, outcome measures, and results have made definitive conclusions on the best approach to treatment difficult [10]. Adherence to the definitions for patient assessment outlined by a 2008 consensus of experts may facilitate systematic interpretation of published literature in the future [11].

In general, a similar therapeutic approach is taken for pemphigus vulgaris and pemphigus foliaceus (algorithm 1). Many studies that have evaluated therapies for pemphigus have combined patients with these disorders [12]:

•Attaining disease control – The first priority for patient management is to attain rapid disease control. This is typically achieved through the administration of systemic glucocorticoids or a combination of systemic glucocorticoids and rituximab [13-15]. (See 'Selection of primary therapy' below and 'Rituximab and systemic glucocorticoids' below.)

•Incorporating adjuvant immunosuppressive therapy – Although systemic glucocorticoid therapy is effective, the high doses and long treatment periods that are needed to maintain the clinical response may lead to serious or life-threatening side effects [4]. Thus, for patients who are not receiving rituximab, adjuvant immunosuppressants (mycophenolate mofetil or azathioprine) are typically prescribed at the start of systemic glucocorticoid therapy or shortly thereafter, with the goal of reducing dependence on systemic glucocorticoid therapy. (See 'Systemic glucocorticoids and adjuvant immunosuppressive therapy' below and 'Adjuvant conventional immunosuppressive therapies' below.)

Additional adjuvant therapies typically reserved for refractory pemphigus are reviewed separately. (See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

•Tapering and cessation of therapy following achievement of disease control – Following achievement of disease control, therapy is reduced slowly to the lowest dose that is necessary to prevent the appearance of new lesions. For patients on systemic glucocorticoids and adjuvant immunomodulatory therapy, the systemic glucocorticoid is typically tapered and discontinued prior to the tapering of adjuvant therapy. (See 'Assessing the response to therapy' below and 'After achievement of disease control' below.)

•Symptom management – Measures aimed at managing oral pain and cutaneous wounds are additional, important aspects of the management of pemphigus [1]. Such measures may help to improve patient quality of life and prevent and manage secondary infection. (See 'Supportive care' below.)

ASSESSING THE RESPONSE TO THERAPY — Patients with pemphigus should be followed closely to evaluate disease activity and the response to treatment, as well as to assess for adverse effects of therapy. Because pemphigus is a dynamic disease, management often requires frequent adjustments of therapy [1].

The response to treatment is primarily assessed through clinical observation. Features that indicate control of disease activity include:

●Cessation of new blister formation

●Established lesions begin to heal

●Absent Nikolsky sign (picture 3)

Complete remission (on or off therapy) is considered the absence of new or established lesions. Complete remission off therapy is considered the absence of new and/or established lesions for at least two months after stopping systemic therapy [14].

Enzyme-linked immunosorbent assay (ELISA) titers for desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) autoantibodies may be helpful as an adjunct to clinical assessment, since titers may correlate with disease activity [16-20]. However, the correlation is not perfect, and ELISA results must be interpreted carefully. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Enzyme-linked immunosorbent assay'.)

INITIAL THERAPY — Systemic glucocorticoids play a central role in the treatment of pemphigus due to the high efficacy of these agents for achieving rapid control of the disease (algorithm 1) [13,21]. The major approaches to initial treatment are:

●Rituximab and systemic glucocorticoid therapy

●Systemic glucocorticoid therapy with the concurrent or subsequent addition of an adjuvant therapy (typically mycophenolate mofetil or azathioprine)

Systemic glucocorticoid monotherapy is an alternative approach that can be effective for some patients. However, due to the potential serious adverse effects of long-term treatment with high doses of systemic glucocorticoids, combination therapy with rituximab or adjuvant conventional immunosuppressive therapy is generally preferred, particularly for patients with increased risk for complications of prolonged (>4 months) glucocorticoid therapy [14]. In addition, in patients with moderate to severe pemphigus, the combination of rituximab and prednisone appears to be more effective than prednisone monotherapy [15]. (See 'Selection of primary therapy' below and 'Rituximab and systemic glucocorticoids' below and 'Systemic glucocorticoids and adjuvant immunosuppressive therapy' below.)

Selection of primary therapy — Combination therapy with rituximab and prednisone is our preferred initial approach to pemphigus (algorithm 1). When rituximab therapy is not feasible, we treat with prednisone and adjuvant mycophenolate mofetil or azathioprine. The high cost of rituximab can limit the use of rituximab in some settings.

Our approach is based upon the following considerations:

●Rituximab plus prednisone versus prednisone alone – Rituximab plus prednisone is preferred over prednisone monotherapy based upon a randomized trial that supports a greater likelihood of achieving complete remission off therapy and a lower likelihood of severe adverse events in patients with moderate to severe pemphigus [15]. (See 'Rituximab and systemic glucocorticoids' below.)

●Rituximab plus prednisone versus prednisone plus mycophenolate mofetil or azathioprine – Rituximab plus prednisone is preferred over prednisone plus mycophenolate mofetil based upon a randomized trial that supports a higher likelihood of achieving sustained complete remission, lower dependence on oral glucocorticoids, and reduced disease flares in patients with moderate to severe pemphigus [22]. Of note, serious adverse events occurred in a slightly higher proportion of patients treated with rituximab [22]. (See 'Rituximab and systemic glucocorticoids' below.)

Rituximab has not been directly compared with azathioprine. However, a network meta-analysis suggests a greater likelihood of disease remission and lower cumulative glucocorticoid doses with rituximab therapy [23].

●Prednisone plus mycophenolate mofetil versus prednisone plus azathioprine versus prednisone alone – Mycophenolate mofetil and azathioprine are employed as glucocorticoid-sparing therapies. Clinician familiarity and comfort with use of mycophenolate mofetil and azathioprine and consideration of drug adverse effect profiles typically guide selection between these drugs. The broader serious adverse effect profile and greater complexity of dosing of azathioprine prompt us to choose mycophenolate mofetil over azathioprine in most cases.

However, in a network meta-analysis that compared adjuvant therapies for pemphigus, azathioprine yielded lower cumulative glucocorticoid doses compared with mycophenolate mofetil, suggesting a greater glucocorticoid-sparing effect for azathioprine [23]. Glucocorticoid-sparing effects of mycophenolate mofetil were unconfirmed. In regards to remission, the network meta-analysis did not identify statistically significant differences in achievement of disease remission between mycophenolate mofetil and azathioprine or between adjuvant therapy with these agents and prednisone monotherapy [23]. (See 'Adjuvant conventional immunosuppressive therapies' below.)

Alternative approaches have also been proposed [24]. In addition to the option of initial therapy with rituximab and/or prednisone for pemphigus of any severity, the 2020 European S2K guidelines describe oral dapsone plus topical corticosteroid and topical corticosteroid monotherapy as options for the initial treatment of mild pemphigus foliaceus (pemphigus foliaceus involving <5 percent of the total body surface area) [24]. However, superiority of this approach has not been proven, and dapsone treatment may be insufficient in a significant proportion of patients [25].

Rituximab and systemic glucocorticoids

Administration — Rituximab is given via intravenous infusion. Systemic glucocorticoids are typically given orally. For practical reasons related to obtaining and administering rituximab, glucocorticoid therapy often begins before rituximab therapy. Initial signs of clinical improvement related to systemic glucocorticoid therapy usually become evident within two to three weeks. Effects of rituximab may not appear for 8 to 12 weeks (see 'Systemic glucocorticoids' below):

●Rituximab – The therapeutic regimen for rituximab involves two initial infusions followed by periodic maintenance doses, as needed. Typical initial dosing is as follows:

•Two 1000 mg intravenous infusions separated by two weeks [26]

Intravenous methylprednisolone (100 mg) or an equivalent glucocorticoid should be given 30 minutes prior to each rituximab infusion.

●Systemic glucocorticoids – Systemic glucocorticoid therapy typically consists of oral prednisone (or prednisolone). Initial doses range from 0.5 to 1.5 mg/kg per day [14]. Our typical initial prednisone regimen is based upon disease severity:

•Mild pemphigus – 0.5 mg/kg per day

•Moderate to severe pemphigus – 1 mg/kg per day

Clinical characteristics supportive of mild pemphigus include <5 percent total body surface area involvement, no oral lesions, or limited oral lesions that do not impair food intake or require analgesics [24]. Clinical characteristics supportive of moderate to severe pemphigus include involvement of multiple mucosal sites, severe oral lesions or dysphasia with weight loss, significant pain, or ≥5 percent total body surface area involvement [24].

Efficacy — Combination therapy with rituximab and prednisone is an effective initial treatment [15,23]. The most robust data regarding use of rituximab as an initial treatment for pemphigus come from a prospective, open-label, randomized trial:

●In a trial, 90 patients with newly diagnosed, moderate to severe pemphigus vulgaris or pemphigus foliaceus were randomly assigned to either intravenous rituximab (1000 mg on days 1 and 14, then 500 mg at months 12 and 18) plus oral prednisone (0.5 mg/kg per day for moderate disease and 1 mg/kg per day for severe disease) tapered over three to six months or prednisone alone (1 mg/kg per day for moderate disease and 1.5 mg/kg per day for severe disease) tapered over 12 to 18 months [15]. At month 24, 41 of 46 patients (89 percent) in the rituximab plus prednisone group were in complete remission off therapy compared with 15 of 44 patients (34 percent) in the prednisone only group (absolute difference 55 percentage points, 95% CI 38-72). In addition, the rituximab plus prednisone group had a shorter median delay to achieve complete remission off therapy (277 versus 677 days) and less frequent severe adverse events compared with the prednisone only group.

In addition, a randomized trial that compared rituximab with mycophenolate mofetil (both given in conjunction with systemic glucocorticoids) supports greater benefit of rituximab [22]. (See 'Mycophenolate mofetil' below.)

The results of a population-based, retrospective cohort study suggest that rituximab therapy for pemphigus may also be associated with reduced risk for certain long-term cardiovascular and metabolic adverse events when compared with conventional immunosuppressant therapy [27]. The study utilized a computerized database to compare a total of 1602 patients with pemphigus and either a history of rituximab therapy or a history of azathioprine or mycophenolate mofetil therapy. Patients treated with rituximab had lower risk for myocardial infarction (risk ratio [RR] 0.45, 95% CI 0.24-0.85), stroke (RR 0.42, 95% CI 0.26-0.69), peripheral vascular disease (RR 0.47, 95% CI 0.28-0.79), hypertension (RR 0.48, 95% CI 0.38-0.63), hyperlipidemia (RR 0.45, 95% CI 0.32-0.64), type 2 diabetes (RR 0.63, 95% CI 0.51-0.77), obesity (RR 0.49, 95% CI 0.34-0.72), and osteoporosis (RR 0.46, 95% CI 0.30-0.71). Proposed rationales for reduced risk included reduced systemic glucocorticoid exposure (not specifically assessed in this study) and a potential inhibitory effect of rituximab on atherosclerotic and cardiovascular disease. A statistically significant difference in all-cause mortality was not detected.

Successful use of rituximab as a single initial agent is also described in case reports and retrospective studies [28-31]. Randomized trials are needed to clarify the efficacy and safety of this approach to treatment.

Adverse effects — Major risks of rituximab include infusion reactions and infections. The adverse effects of rituximab and systemic glucocorticoids are reviewed in greater detail separately. Of note, progressive multifocal leukoencephalopathy has been reported in patients treated with rituximab for other indications [32,33]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Adverse effects'.)

Systemic glucocorticoids and adjuvant immunosuppressive therapy — Treatment with a systemic glucocorticoid and an adjuvant immunomodulatory agent is an alternative to rituximab and systemic glucocorticoid therapy (algorithm 1). Systemic glucocorticoid therapy is typically started immediately. Adjuvant conventional immunosuppressive drugs (typically mycophenolate mofetil or azathioprine) are typically prescribed concurrently or shortly after the start of glucocorticoid therapy. (See 'Adjuvant conventional immunosuppressive therapies' below.)

Systemic glucocorticoids

Administration — Oral prednisone (or prednisolone) is the typical mode of glucocorticoid administration for pemphigus [14]. In most patients, systemic glucocorticoid therapy leads to cessation of blistering within two to three weeks and full disease control within six to eight weeks [34].

The initial dose for prednisone or prednisolone is generally 0.5 to 1.5 mg/kg per day [14]. Our typical regimen is [24]:

●Mild pemphigus – 0.5 to 1 mg/kg per day

●Moderate to severe pemphigus – 1 to 1.5 mg/kg per day

Clinical characteristics supportive of mild pemphigus include <5 percent total body surface area involvement, no oral lesions, or limited oral lesions that do not impair food intake or require analgesics [24]. Clinical characteristics supportive of moderate to severe pemphigus include involvement of multiple mucosal sites, severe oral lesions or dysphasia with weight loss, significant pain, or ≥5 percent total body surface area involvement [24].

Intravenous pulsed glucocorticoids have also been utilized for the treatment of pemphigus vulgaris but are not proven to be superior to oral therapy and are typically reserved for refractory disease [14]. Treatment regimens have varied widely, and data comparing regimens that incorporate intravenous or oral pulsed glucocorticoids with regimens that do not include pulsed glucocorticoids are limited to a few small studies that have [35,36] or have not [37] demonstrated benefits over various nonpulsed regimens.

Efficacy — Support for the use of systemic glucocorticoids as a primary treatment for pemphigus stems from randomized trials and other studies that have documented improvement in pemphigus with glucocorticoid monotherapy in the majority of patients and from extensive clinical experience with this treatment [38-41]. As an example, in a randomized, open-label trial in which 30 patients with pemphigus vulgaris were treated with prednisolone alone (2 mg/kg per day), 23 of these patients (77 percent) responded to treatment, and the average time to cessation of blistering was 18 days [38].

The dramatic fall in mortality from pemphigus observed after the introduction of systemic glucocorticoid therapy also supports the value of systemic glucocorticoid therapy for this indication. (See 'Rationale for treatment' above.)

Adverse effects — Adverse effects, such as hypertension, hyperlipidemia, diabetes mellitus, osteoporosis, increased susceptibility to infections, gastrointestinal ulcers, and aseptic bone necrosis, may cause significant morbidity and mortality among patients who receive prolonged systemic glucocorticoid therapy. Frequent patient follow-up and the implementation of appropriate preventive and therapeutic measures for glucocorticoid-related adverse effects are essential. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Adjuvant conventional immunosuppressive therapies — The major rationale for adjuvant immunosuppressive therapy is a glucocorticoid-sparing effect rather than a direct disease-modifying effect [42]. Azathioprine and mycophenolate mofetil are the principal adjuvant immunosuppressive agents for the initial management of pemphigus. Although there is more evidence to support a glucocorticoid-sparing effect of azathioprine, the more favorable side effect profile and ease of administration of mycophenolate mofetil contributes to the frequent use of mycophenolate mofetil. (See 'Azathioprine' below and 'Mycophenolate mofetil' below.)

Azathioprine

●Administration – The level of activity of thiopurine methyltransferase (TPMT), an enzyme involved in the degradation of azathioprine to inactive metabolites, influences dosing of azathioprine. Reduced TPMT activity is associated with an increased risk for azathioprine-induced myelosuppression [43,44]. TPMT activity may be assessed through testing for the level of enzyme activity or genotyping (see "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Introduction'):

•Reduced dosing is advised for patients with intermediate or low TPMT activity. Azathioprine therapy is not recommended for patients with absent TPMT activity [14,24]. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)

Typical dosing is as follows:

-High TPMT activity – Up to 2.5 mg/kg (ideal body weight) per day.

We typically begin treatment with 1 mg/kg (ideal body weight) per day of azathioprine. We increase the dose by increments of 0.5 mg/kg to reach a maintenance dose of 2.5 mg/kg per day within two to three weeks, provided serious toxicity is not detected.

-Intermediate or low TPMT activity – Lower initial doses and maintenance doses (maintenance dose up to 0.5 to 1.5 mg/kg per day [ideal body weight] depending on level of enzyme activity).

•TPMT testing is particularly important in populations with an elevated risk for TPMT polymorphisms [14]. An initial dose of 50 mg per day with close monitoring for adverse effects has been suggested when TPMT testing is not performed in low-risk populations [14]. The dose may be gradually titrated upwards, as tolerated, up to 2.5 mg/kg per day.

●Efficacy – Randomized trials that evaluated the glucocorticoid-sparing effects of azathioprine have found conflicting results. A network meta-analysis of randomized trials comparing glucocorticoid-sparing adjuvants in patients with pemphigus supports the ability of azathioprine to reduce cumulative glucocorticoid doses compared with glucocorticoid monotherapy (cumulative glucocorticoid dose mean difference -3023 mg, 95% CI -4701 to -1364 mg) [23].

Examples of individual trials comparing systemic glucocorticoids and azathioprine with systemic glucocorticoids alone include:

•A randomized, open-label trial of 120 patients with pemphigus vulgaris that compared four treatment regimens in which prednisolone (2 mg/kg per day up to a maximum of 120 mg per day followed by a taper) was given alone or in conjunction with another immunosuppressive agent supported the glucocorticoid-sparing effects of azathioprine (2.5 mg/kg per day for two months then 50 mg per day) [38]. After one year, patients who received combination therapy with prednisolone and azathioprine had a significantly lower mean total dose of prednisolone than patients treated with prednisolone alone (7712 versus 11,631 mg). However, clinical outcomes were similar in the two groups. After one year, complete remission was attained by 77 percent of patients in the prednisolone-only group and 80 percent of patients who received combination therapy.

•In a 12-month, randomized trial in which 56 patients with a new diagnosis of pemphigus vulgaris were treated with prednisolone (2 mg/kg per day up to 120 mg per day followed by a taper) plus azathioprine (2.5 mg/kg per day) or prednisolone in a similar regimen plus a placebo pill, patients in both groups achieved statistically significant clinical improvement. A nonsignificant trend towards a lower mean disease activity score was detected in the combination therapy group at each monthly assessment during the last six months of the trial [39]. This difference achieved statistical significance when data from the last three months of therapy were jointly assessed. In contrast to the trial above, a significant difference in the mean total dose of prednisolone was not detected.

A 2011 systematic review and meta-analysis of randomized trials published prior to 2009 supports superior glucocorticoid-sparing effects of azathioprine compared with mycophenolate mofetil based upon the meta-analysis of two randomized trials (one of which did not find a statistically significant difference in glucocorticoid-sparing effects) [10]. A subsequent network meta-analysis also supports this finding (cumulative glucocorticoid dose mean difference -2302 mg, 95% CI -3640 to -964 mg) [23].

●Adverse effects – Due to a risk for myelosuppression, close laboratory monitoring is necessary for patients treated with azathioprine. We monitor a complete blood count with differential, renal function tests, and liver function tests at baseline, every two weeks for the first three months, and periodically (every two to three months) thereafter.

In addition to myelosuppression, malignancy, gastrointestinal disorders, and infections are potential adverse effects of azathioprine therapy. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)

Mycophenolate mofetil

●Administration – Doses of 2 g per day (taken as 1 g twice daily) are typically used when mycophenolate mofetil is added to systemic glucocorticoid therapy in adults. Enteric-coated mycophenolate sodium is an alternative form of mycophenolate that is given to adults in a dose of 720 mg twice daily.

●Efficacy – A beneficial effect of adjuvant mycophenolate mofetil on the likelihood that patients will respond to glucocorticoid treatment has not been demonstrated in randomized trials [38,40,41]. One trial found that adjuvant mycophenolate mofetil was associated with a longer duration of clinical remission [40].

A few randomized trials have evaluated the effects of adjuvant treatment with mycophenolate mofetil on glucocorticoid requirements and patient outcomes, with conflicting results. Although two randomized trials found a statistically significant reduction in glucocorticoid consumption in patients who received adjuvant mycophenolate mofetil compared with patients treated with a glucocorticoid alone [38,40], another randomized trial failed to find a significant glucocorticoid-sparing effect [41]. A network meta-analysis of randomized trials did not confirm a glucocorticoid-sparing effect [23].

Mycophenolate has been compared with other therapies. A meta-analysis of two randomized trials that compared the glucocorticoid-sparing effects of azathioprine and mycophenolate mofetil found that mycophenolate mofetil appeared to have inferior glucocorticoid-sparing effects [10]. (See 'Azathioprine' above.)

Compared with rituximab, mycophenolate mofetil appears to be less effective and to have inferior glucocorticoid-sparing effects but may have a slightly lower risk for severe adverse effects [22]:

•In a trial, 135 patients with moderate to severe pemphigus vulgaris were randomly assigned to receive either intravenous rituximab (1000 mg on days 1, 15, 168, and 182) or mycophenolate mofetil (1 g per day increased to 2 g per day by week 2) [22]. All patients also received an oral glucocorticoid (1 to 1.5 mg/kg per day) with the goal of discontinuation of the glucocorticoid by week 24. The 125 patients who received at least one dose of trial medication were included in the efficacy analysis. At week 52, 40 percent of patients (25 of 62) in the rituximab group achieved sustained complete remission compared with 10 percent of patients (6 of 63) in the mycophenolate mofetil group. In addition, patients in the rituximab group had a lower mean cumulative dose of oral glucocorticoids (3545 versus 5140 mg) and fewer disease flares (6 versus 44 disease flares). Serious adverse events occurred in 15 of 67 patients (22 percent) in the rituximab group compared with 10 of 68 patients (15 percent) in the mycophenolate mofetil group.

●Adverse effects – The most common side effects of mycophenolate mofetil are gastrointestinal complaints. Enteric-coated mycophenolate sodium may have some benefit for patient tolerance while maintaining the immunosuppressive effects [45].

Pancytopenia is another important side effect of mycophenolate. A complete blood count with differential can be obtained at baseline and every two weeks during the first two to three months of therapy, then once monthly within the first year, and every three months thereafter [46].

Renal function tests and liver function tests can be obtained at baseline, after one month, and periodically thereafter. Side effects of mycophenolate mofetil are reviewed in greater detail separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Adverse effects'.)

AFTER ACHIEVEMENT OF DISEASE CONTROL — Once disease activity has been under control (cessation of new blister formation and established lesions beginning to heal) for a minimum of two weeks and approximately 80 percent of lesions have healed, glucocorticoid tapering should begin, with the goal of reaching the lowest dose needed to keep the disease under control (algorithm 1) [14]. The ultimate goal is to withdraw all treatment. Tapering of adjuvant conventional immunosuppressive therapies can begin after the cessation of systemic glucocorticoids (see 'Assessing the response to therapy' above and 'Adjuvant conventional immunosuppressive therapies' above):

●Tapering of systemic glucocorticoids – The optimal method of tapering glucocorticoids in patients with pemphigus has not been determined. Thus, approaches to glucocorticoid tapering vary [11,24]. Our approach for a 70 kg adult is as follows:

•Once no new lesions have formed for seven days, we reduce prednisone from 1 mg/kg per day to 0.75 mg/kg per day.

•If at least seven days have elapsed since the first dose reduction and no new lesions have formed, we reduce the dose of prednisone to 0.5 mg/kg per day.

•If at least 14 days have elapsed since the reduction to 0.5 mg/kg per day and no new lesions have formed for at least one week, we reduce the dose of prednisone to 30 mg per day.

•Thereafter, we continue dose reductions in a stepwise manner with at least 14 days between each reduction and continue the requirement that no new lesions form within seven days prior to the next reduction. Our dose reduction series is as follows: 30, 25, 20, 15, 10, 7.5, 5, 2.5, and 0 mg per day.

Other experts have suggested tapering prednisone by 25 percent every two weeks until a dose of 20 mg per day, then decreasing by 2.5 mg per week until a dose of 10 mg per day, and decreasing by 1 mg per day thereafter [11].

●Tapering of adjunctive therapy – The best approach to tapering adjuvant therapy is unclear. We continue adjuvant therapy with azathioprine or mycophenolate until at least three months after prednisone has been completely and successfully discontinued. Then, we begin to reduce the dose of the adjuvant medication. We reduce azathioprine by 50 mg every eight weeks, mycophenolate mofetil by 500 mg every eight weeks, or mycophenolate sodium by 360 mg every eight weeks until treatment cessation. Some clinicians continue full-dose adjuvant therapy for a longer period.

●Rituximab maintenance dosing – Repetition of rituximab therapy has been proposed as a method to maintain remission. However, the indications, efficacy, and most appropriate regimen for this approach remain unclear. The US Food and Drug Administration (FDA) package insert supports 500 mg given at month 12 and every 6 months thereafter or based on clinical evaluation. The 2020 European S2K guidelines suggest that patients in clinical remission who initially presented with severe pemphigus and/or had high levels of anti-desmoglein (Dsg) antibodies three months after administration of rituximab are potential candidates for a 500 or 1000 mg infusion of rituximab at month 6 [24]. In a randomized trial that compared rituximab and prednisone with mycophenolate mofetil and prednisone, patients in the rituximab group were routinely given a repeat course of rituximab (two 1000 mg doses separated by two weeks) at month 6 [22].

MANAGEMENT OF RELAPSES — Relapses of pemphigus may be defined as the appearance of three or more new lesions in a month that do not heal spontaneously within one week or by the extension of established lesions in a patient who has achieved disease control [14]:

●Patients who received rituximab as initial treatment – Relapses that occur during tapering of prednisone, but more than four to six months after the last dose of rituximab, may be treated with a repeat 2 g cycle of rituximab (algorithm 1) [24]. In addition, the dose of prednisone can be increased to regain faster disease control (eg, to the second-to-last prednisone dose that controlled disease).

Relapses that occur during prednisone tapering, but prior to four to six months after the last dose of rituximab, can be managed with a return to the second-to-last dose of prednisone, with the goal of regaining disease control within two weeks [14]. If disease control is not achieved within two weeks, prednisone can be increased to the initial dose.

Upon achievement of stable disease control for at least two weeks, tapering of prednisone can be reattempted. An immunosuppressant (eg, mycophenolate mofetil or azathioprine) may be added for patients in whom successful tapering of prednisone is difficult.

Relapses that occur after cessation of prednisone are managed on a case-by-case basis, with a return to initial treatment regimens or modulation of therapy based upon severity. (See 'Initial therapy' above.)

Patients who do not improve with this approach or experience recurrent relapses may benefit from therapies for refractory pemphigus. (See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

●Patients who did not receive rituximab as initial treatment – If relapse occurs during prednisone tapering and rituximab therapy is feasible, patients can be treated with a standard 2 g cycle of rituximab (algorithm 1) [24].

If rituximab therapy is not feasible and relapse occurs during prednisone tapering, the prednisone dose should be increased to the second-to-last dose prior to relapse until control of disease is achieved within two weeks [14]. If patients do not achieve disease control with this intervention, changing to a different oral immunosuppressant should be attempted (eg, from mycophenolate mofetil to azathioprine or vice versa) [14]. An oral immunosuppressant should be added for patients receiving systemic glucocorticoid monotherapy [14].

Upon achievement of stable disease control for at least two weeks, tapering of prednisone can be reattempted.

Patients who are refractory to this approach or experience recurrent relapses may benefit from rituximab or other therapies for refractory disease. (See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

FAILURE TO ACHIEVE DISEASE CONTROL — Patients for whom initial therapy does not result in disease control within one month require escalation of therapy (algorithm 1). Options include [24]:

●Increase dose of prednisone up to 1.5 mg/kg per day

●Add rituximab (if not already received)

●Add azathioprine or mycophenolate mofetil (if rituximab is not feasible and patient is not already on one of these therapies)

When these measures are insufficient, patients may benefit from therapies reserved for refractory disease. The management of pemphigus vulgaris and pemphigus foliaceus that are refractory to initial therapy is reviewed separately. (See "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

OTHER ADJUVANT THERAPIES — Although azathioprine and mycophenolate mofetil are the mainstays of adjuvant therapy for pemphigus, other therapies are occasionally utilized. Efficacy data for these interventions are limited.

Dapsone — Based upon reports of efficacy in some patients and the favorable status of dapsone as a nonimmunosuppressive therapy [25,47-53], some clinicians choose to use dapsone as an adjuvant therapy in patients with pemphigus, particularly for patients with pemphigus foliaceus or IgA pemphigus:

●Administration – Target doses for dapsone for pemphigus range from 50 to 200 mg per day. Treatment is usually initiated at a low dose (eg, 25 or 50 mg per day in adults) and titrated upward as tolerated. The maximum dose is considered 1.5 mg/kg or 250 mg per day.

●Efficacy – A 2009 review of case reports and case series identified 37 patients with pemphigus vulgaris and 18 patients with pemphigus foliaceus who were treated with dapsone (50 to 300 mg per day) with or without prednisone or other immunosuppressive therapies [47]. Responses to dapsone were documented in 86 percent of the patients with pemphigus vulgaris and 78 percent of the patients with pemphigus foliaceus. The responders included 6 of 6 patients with pemphigus vulgaris and 9 of 14 patients with pemphigus foliaceus who received dapsone as monotherapy.

A subsequent, small, randomized trial that evaluated the efficacy of adjuvant dapsone (150 to 200 mg per day) for facilitating the tapering of systemic glucocorticoids in patients with pemphigus vulgaris that was well controlled with a systemic glucocorticoid (with or without an adjuvant immunosuppressant), but refractory to glucocorticoid tapering, failed to find a statistically significant effect [48]. A reduction in the dose of prednisone to less than 7.5 mg per day was achieved within one year in 5 of 9 patients (56 percent) treated with adjuvant dapsone and 3 of 10 patients (30 percent) who received a placebo pill instead of dapsone as adjuvant therapy.

Monotherapy with relatively high doses of dapsone (200 to 300 mg per day) appeared to be effective as an initial treatment for pemphigus foliaceus in a small series [25]. Five of the nine patients had at least a 50 percent reduction in the extent of the disease within 15 days. However, four patients failed to respond to dapsone treatment, three patients required discontinuation of therapy, one patient ceased treatment due to toxic hepatitis and hemolytic anemia, and two patients ceased treatment due to methemoglobinemia. Additional studies are necessary to determine the role of dapsone in the treatment of pemphigus.

●Adverse effects – Hemolysis is an expected side effect of dapsone that occurs, to some degree, in all treated patients. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency have an elevated risk for severe hemolytic anemia related to dapsone therapy. Thus, we evaluate patients for G6PD deficiency prior to the initiation of dapsone. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Additional adverse effects of dapsone include methemoglobinemia, agranulocytosis, hypersensitivity, and motor neuropathy. Close hematologic monitoring for hemolysis and agranulocytosis is essential during treatment.

Other agents — Other drugs that have been used as adjuvants to systemic glucocorticoids for pemphigus are methotrexate, cyclosporine, and combination therapy with a tetracycline derivative and nicotinamide:

●Methotrexate – No randomized trials have evaluated the efficacy of methotrexate as an adjuvant therapy. Support for this drug is derived from uncontrolled studies and case series [54-56]. Typical dosing is 10 to 25 mg per week.

In a retrospective study of 23 patients with pemphigus vulgaris for whom methotrexate (up to 15 to 25 mg per week) was added to systemic glucocorticoid therapy, 21 patients (91 percent) had improvement in blistering after the addition of methotrexate, and 16 patients (70 percent) were eventually able to discontinue prednisone completely (mean time to discontinuation of prednisone therapy 18 months) [56]. In a separate case series, six of nine patients treated with adjuvant methotrexate (10 to 17.5 mg per week) for pemphigus vulgaris were able to discontinue prednisone within six months [57].

●Cyclosporine – Although efficacy of cyclosporine was reported in case series of patients with pemphigus [58,59], two randomized trials did not demonstrate an advantage of cyclosporine therapy [60,61]. Dosing for cyclosporine is 2.5 to 5 mg/kg per day.

●Tetracyclines and nicotinamide – Limited data from retrospective studies suggest that combination therapy with a tetracycline derivative (eg, tetracycline, doxycycline, or minocycline) and nicotinamide (also known as niacinamide), a well-tolerated regimen often used for bullous pemphigoid, may be a useful adjuvant to systemic glucocorticoid therapy for pemphigus [62,63].

The typical adult dose for tetracycline is 500 mg four times daily. Doxycycline and minocycline are given as 100 mg twice daily, and nicotinamide is usually given as 500 mg three times per day. Of note, a small, uncontrolled, prospective study found poor treatment results when tetracycline and nicotinamide were given as the primary therapeutic regimen for pemphigus rather than as a glucocorticoid-sparing therapy [64].

Successful treatment of pemphigus vegetans (a rare variant of pemphigus vulgaris) with only minocycline and nicotinamide is documented in a case report [65].

SUPPORTIVE CARE

Skin care — Local skin care measures may help to improve patient comfort and reduce the risk for infection:

●Blister and wound care – Clinicians or patients should puncture and drain large blisters in a sterile manner. The epithelial roof of the blister should be left intact after draining to serve as wound covering and to reduce the risk for infection.

Wound areas should be kept clean to reduce the risk for infection. Erosions may be covered with antibiotic ointment or a bland emollient (eg, petrolatum), with or without a nonadhesive wound dressing.

●Persistent lesions – In our experience, twice-daily application of a high-potency topical corticosteroid (eg, clobetasol propionate ointment or gel) directly to erosions can be a useful adjunct to systemic therapy for persistent, active, hard-to-treat pemphigus lesions [1]. Intralesional injection of triamcinolone acetonide (20 mg/mL) may also help to heal persistent lesions [1].

●Recognition and prevention of secondary infection – Patients should be informed about the warning signs of infection (eg, purulence, crusting, worsening pain, fever) to facilitate prompt diagnosis and early treatment.

The possibility of secondary infection (particularly herpes simplex virus infection) should be considered for lesions that fail to respond as expected to therapy, and infection should be treated appropriately if detected [1,66,67]. Due to the inhibitory effects of herpes simplex virus infection on healing of skin lesions in patients with pemphigus, we often initiate prophylactic antiviral therapy after an episode of pemphigus complicated by herpes simplex infection. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Diagnosis'.)

Management of oral symptoms — Oral mucosal involvement in pemphigus vulgaris causes discomfort, which may be severe.

In addition to treatment of the disease process with systemic therapy, we have found the following measures useful for reducing symptoms during active disease:

●General measures:

•Avoidance of spicy, sharp, abrasive, or very hot foods.

•Application of topical anesthetics as needed (eg, viscous lidocaine 2% solution, lidocaine 2% gel).

•Oral hygiene (teeth should be brushed twice daily with a soft-bristle brush with a bland toothpaste and flossed daily; additionally, professional dental cleanings may be of use).

●Topical anti-inflammatory therapies – In our experience, topical corticosteroids help to improve oral symptoms of pemphigus in some patients. We often utilize a medium- or high-potency topical corticosteroid (eg, triamcinolone 0.1% in dental paste or fluocinonide 0.05% gel applied with gauze occlusion) or a corticosteroid mouthwash (eg, 5 mL of dexamethasone 0.5 mg/5 mL solution as a mouth rinse) two to three times per day. We have also found topical tacrolimus 0.1% ointment useful. Patients may find topical anesthetics (eg, viscous lidocaine) helpful for managing symptoms.

●Prevention and treatment of Candida infections – Candida infection is a common occurrence in patients with mucosal pemphigus vulgaris who are treated with systemic glucocorticoids. We prescribe oral nystatin swish and swallow (or swish and spit) or clotrimazole lozenges as prophylaxis for patients receiving systemic glucocorticoids or monitor patients closely for the development of oropharyngeal candidal infection and treat if infection develops. (See "Oropharyngeal candidiasis in adults".)

Patient support — The International Pemphigus and Pemphigoid Foundation provides resources for patient support.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pemphigus".)

SUMMARY AND RECOMMENDATIONS

●Disease overview – Pemphigus is defined as a group of autoimmune, blistering disorders that result in intraepithelial blistering in mucous membranes and/or skin (picture 1A-D, 2A-B). Pemphigus vulgaris and pemphigus foliaceus are the most common subtypes of pemphigus. (See 'Rationale for treatment' above and 'Approach to treatment' above.)

●Goals of treatment – Pemphigus is a potentially life-threatening disorder for which treatment is always indicated. The initial goal of treatment is to induce complete remission while minimizing treatment-related adverse effects. Long-term remission after the discontinuation of therapy is the ultimate goal. The response to treatment is primarily assessed through clinical evaluation. (See 'Approach to treatment' above and 'Assessing the response to therapy' above.)

●General approach – Initial treatment of pemphigus vulgaris and pemphigus foliaceus generally consists of systemic glucocorticoids in conjunction with other immunomodulatory therapies, such as rituximab, azathioprine, and mycophenolate mofetil (algorithm 1). Systemic glucocorticoid therapy is useful for achieving rapid disease control. Improved efficacy and/or glucocorticoid-sparing effects are the primary reasons for combination therapy (see 'Approach to treatment' above and 'Initial therapy' above):

•For patients with pemphigus vulgaris or pemphigus foliaceus, we suggest initial treatment with a combination of prednisone and rituximab rather than prednisone alone or prednisone in conjunction with mycophenolate mofetil (algorithm 1) (Grade 2B). Randomized trials support greater efficacy of combination therapy with prednisone and rituximab in moderate to severe pemphigus. Indirect evidence suggests that azathioprine is less effective than rituximab. (See 'Selection of primary therapy' above and 'Rituximab and systemic glucocorticoids' above.)

When rituximab therapy is not feasible, an alternative initial approach is prednisone and adjuvant azathioprine or mycophenolate mofetil (algorithm 1). Selection between azathioprine and mycophenolate mofetil is often based upon clinician comfort with these drugs and consideration of risk for drug-related adverse effects. Although there is more evidence to support a glucocorticoid-sparing effect of azathioprine, the more favorable side effect profile and ease of administration of mycophenolate mofetil contributes to our frequent use of mycophenolate mofetil. (See 'Systemic glucocorticoids and adjuvant immunosuppressive therapy' above.)

●After achievement of disease control – Once disease activity is under control (cessation of new blister formation and established lesions beginning to heal) for at least two weeks and 80 percent of established lesions have healed, tapering of prednisone can begin. Tapering of adjuvant immunosuppressive therapies can begin after successful cessation of prednisone. (See 'After achievement of disease control' above.)

●Relapsing or refractory disease – Relapses after achievement of disease control are managed with the resumption of previously effective doses of prednisone and/or the addition of rituximab or conventional immunosuppressive therapy (algorithm 1). Patients who do not respond to this approach or experience frequent relapses may benefit from therapies for refractory disease. Patients who fail to respond to preferred initial therapies may also benefit from therapies for refractory disease. (See 'Management of relapses' above and "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)

The possibility of secondary infection (eg, herpes simplex virus infection) should also be considered when individual lesions fail to respond to therapy. (See 'Skin care' above.)

●Supportive care – Cutaneous and mucosal involvement in pemphigus may result in significant pain, functional impairment, and negative effects on quality of life. Skin and wound care measures, interventions to improve oral symptoms, and patient support groups can be beneficial. (See 'Supportive care' above.)