INTRODUCTION — Pemphigus vulgaris and pemphigus foliaceus are autoimmune blistering diseases that may result in significant morbidity and death. Traditional first-line treatment for pemphigus consists of systemic immunosuppression with systemic glucocorticoids with or without adjuvant immunosuppressive medications [1-3]. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus" and "Initial management of pemphigus vulgaris and pemphigus foliaceus".)
Patients who do not respond to traditional first-line therapies may benefit from additional interventions. Treatment regimens that include rituximab, intravenous immune globulin (IVIG), immunoadsorption, plasmapheresis, and cyclophosphamide may lead to clinical improvement in these patients.
The treatment of pemphigus vulgaris and pemphigus foliaceus refractory to initial therapies will be reviewed here. The initial management of pemphigus vulgaris and pemphigus foliaceus, and the management of paraneoplastic pemphigus are reviewed separately. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus" and "Paraneoplastic pemphigus", section on 'Treatment'.)
DEFINITION — The traditional initial approach to the treatment of pemphigus vulgaris and pemphigus foliaceus consists of systemic glucocorticoid therapy, which is often given in conjunction with an adjuvant nonsteroidal immunosuppressant, such as azathioprine or mycophenolate mofetil. The term refractory pemphigus is generally used to refer to pemphigus that fails to respond sufficiently to optimal administration of these agents. The initial management of pemphigus is reviewed in detail separately. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus".)
Various definitions for refractory pemphigus have been utilized in the medical literature. In 2008, a panel of experts proposed standardized definitions for the assessment of therapeutic responses in pemphigus for use in clinical studies, including definitions of treatment failure from certain therapies [4]. The consistent use of these guidelines in clinical studies may facilitate systematic interpretation of the literature in the future and may provide further clarification on therapeutic efficacy.
OVERVIEW — Pemphigus is a chronic disorder that usually requires treatment for a period of years. A retrospective study of 40 patients with pemphigus vulgaris who were seen in an academic medical center between 1983 and 1993 and followed for an average of 7.7 years found that long-lasting complete remission (ie, complete clinical remission off systemic therapy for at least six months) was achieved in 25 percent after 2 years, 50 percent after 5 years, and 75 percent after 10 years [5].
Although the majority of patients with pemphigus vulgaris or pemphigus foliaceus (around 60 to 80 percent) can achieve at least initial improvement with traditional first-line therapies [6-8], other patients fail to respond or experience frequent relapses while on these therapies. Our first steps for patients who fail initial therapy are to optimize the dose of the systemic glucocorticoid (up to a maximum of an equivalent of 1.5 to 2 mg/kg per day of prednisone) and adjuvant agent, or to change the adjuvant therapy to a different first-line agent (eg, change from azathioprine to mycophenolate mofetil or vice versa). If an adequate response still cannot be obtained, we proceed with the initiation of other therapies.
The major therapeutic options for refractory disease include interventions that directly target the antibody-mediated pathogenesis of pemphigus (rituximab, intravenous immune globulin [IVIG], immunoadsorption, and plasmapheresis) and cyclophosphamide, a drug that may be used as an alternative adjuvant immunosuppressant. Concern for the high cost of rituximab, IVIG, immunoadsorption, and plasmapheresis and the unfavorable adverse effect profile of cyclophosphamide (eg, sterility, cytopenia, hemorrhagic cystitis) contribute to the preferred use of these agents for refractory pemphigus, rather than for new-onset disease.
In addition to patients who fail to respond to first-line regimens, other patients with pemphigus may benefit from the therapies utilized for refractory disease. Patients with contraindications to initial therapies or who are unable to tolerate initial treatments may also benefit from treatments used for refractory disease.
TREATMENT OPTIONS
Treatment selection — The paucity of high-quality studies on the treatment of refractory pemphigus impedes both conclusions on the relative efficacies of interventions as well as the formation of definitive guidelines on the best approach to the treatment [9]. Thus, therapeutic choice remains heavily influenced by consideration of patient tolerability for specific treatments and treatment availability. In particular, treatment-specific contraindications should be considered.
Examples of clinical scenarios that have influenced the choice of therapy for our patients include:
●Preference to avoid cyclophosphamide in a patient of child-bearing potential due to the risk of cyclophosphamide-induced premature gonadal failure
●Preference to avoid extracorporeal therapies such as immunoadsorption and plasmapheresis in older patients with severe heart disease
●Preference for use of a rapid-acting therapy (eg, immunoadsorption) in patients with severe manifestations of the disease
Treatment availability is a major factor in treatment selection that is based on both the ability to obtain a treatment and access to appropriate equipment and expertise to administer it safely. For example, although the use of cyclophosphamide for refractory pemphigus has decreased in clinical settings where patients have access to other less toxic treatment options, the relatively higher cost and more limited availability of rituximab, intravenous immune globulin (IVIG), immunoadsorption, and plasmapheresis contributes to the continued use of cyclophosphamide in certain clinical settings. Whenever possible, the therapies utilized for refractory pemphigus should be administered by clinicians experienced in the use and adverse effects of these treatments. Referral to specialized treatment centers can be useful for additional access to treatments.
We manage most patients with refractory pemphigus with the addition of one of the therapeutic options for refractory pemphigus to baseline immunosuppressive regimen that consists of systemic glucocorticoids with or without a first-line adjuvant medication. Although combination therapy with immunoadsorption and rituximab has been utilized by ourselves and other clinicians for patients with severe, refractory disease (extensive involvement or involvement of mucosal sites that may result in significant morbidity [conjunctiva, pharynx, larynx, or esophagus]), additional studies are necessary to confirm whether this approach is ideal. (See 'Combination therapy' below.)
Rituximab — Based upon the rationale that pemphigus is primarily an autoantibody-driven autoimmune disorder, therapies that deplete autoreactive B cell clones have been investigated for the treatment of pemphigus [10,11]. Rituximab, a monoclonal antibody directed against the CD20 antigen on B lymphocytes, has demonstrated efficacy for pemphigus vulgaris and pemphigus foliaceus [12-15]. The immunologic effects of rituximab that contribute to its benefit in pemphigus may be complex; long-lasting B cell depletion following rituximab treatment may be one significant factor [16-18]. Additional findings during rituximab therapy that may be involved in the treatment effect include a preferential decline in autoantibodies compared with pathogen-specific antibodies (potentially due to a different effect of rituximab on autoreactive and pathogen-specific plasma cells) and a decline in autoreactive CD4+ T cells (a possible indirect effect of B cell depletion) [16,17].
Efficacy and administration — In accordance with the emergence of rituximab therapy for pemphigus from patients with lymphoma [19,20], dosing for rituximab in pemphigus initially reflected a regimen commonly used for lymphoma (375 mg/m2 once weekly for four weeks) [21]. Since then, other dose regimens for rituximab have been evaluated in clinical studies [22-25]. Most often, a dose regimen similar to that used in the treatment of rheumatologic disease (two 1000 mg infusions separated by two weeks) is given. Lower dose regimens (eg, two 500 mg doses of rituximab separated by two weeks) may be associated with reduced duration of remission. (See 'Standard dosing' below and 'Lymphoma dosing' below and 'Other protocols' below.)
Standard dosing — Rituximab appears to be effective for refractory pemphigus when administered in a regimen similar to the regimen used for rheumatoid arthritis (two 1000 mg infusions separated by two weeks) [22-24,26]. Advantages of this dose over lymphoma dosing include the requirement for fewer infusion sessions and the often lower total dose of rituximab required for treatment.
The suggested dosing is two 1000 mg intravenous infusions separated by two weeks given in combination with a tapering course of systemic glucocorticoids [27]. Maintenance therapy may consist of 500 mg given at month 12 and every 6 months thereafter or based on clinical evaluation. Relapses may be treated with a 1000 mg dose, and based upon the clinical evaluation, the systemic glucocorticoid may be resumed (if discontinued) or the glucocorticoid dose increased. Intravenous methylprednisolone (100 mg) or an equivalent glucocorticoid should be given 30 minutes prior to each rituximab infusion.
Rituximab has also demonstrated efficacy for the initial treatment for pemphigus when given in combination with prednisone [15]. Use of rituximab in newly diagnosed pemphigus is reviewed separately [15]. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Rituximab and systemic glucocorticoids'.)
One of the largest prospective studies to evaluate the treatment of refractory pemphigus with this protocol is a study of 42 patients with severe refractory pemphigus vulgaris (n = 37) or pemphigus foliaceus (n = 5) in which patients were treated with rituximab and prednisone (0.5 mg/kg per day followed by a taper to discontinuation) [28]. After six months, complete remission (defined as an absence of new or established lesions) occurred in 36 patients (86 percent), including 29 patients who had complete remissions for at least two months after treatment was stopped and seven patients who required minimal therapy (≤10 mg per day of prednisone for at least two months).
The median time to complete remission was 70 days (range 30 to 150 days). The seven patients who required minimal therapy were able to discontinue treatment within three additional months. An additional 500 mg dose of rituximab led to complete remissions in the six patients who had partial remissions and to reinstitution of complete remission in 20 patients who relapsed. The median time to relapse was 16 months (range 6 to 41 months). Additional doses of rituximab also appeared to be of benefit for patients who relapsed or failed to achieve remission after a single cycle of rituximab in a retrospective study of 92 patients with pemphigus vulgaris or pemphigus foliaceus [26].
Lymphoma dosing — Uncontrolled studies and case series support a beneficial effect of rituximab given in a dose of 375 mg/m2 in various regimens [11]. The benefit of a single cycle of rituximab (375 mg/m2 once weekly for four weeks) was illustrated in an open, multicenter study of 14 patients with pemphigus and 7 patients with pemphigus foliaceus. The patients had disease that was refractory to systemic glucocorticoids, had experienced multiple relapses during glucocorticoid tapering, or were unable to receive systemic glucocorticoids due to contraindications to glucocorticoid therapy [29]. The treatment protocol consisted of rituximab and a systemic glucocorticoid that was tapered as tolerated. Five patients did not receive a systemic glucocorticoid due to contraindications for glucocorticoid therapy.
Of the 21 patients, 18 (86 percent) achieved complete remission (defined as epithelialization of all lesions) within three months. The median time to complete remission for cutaneous pemphigus vulgaris, mucosal pemphigus vulgaris, and pemphigus foliaceus were 30, 90, and 60 days, respectively. Two additional patients achieved complete remission within six months and one year. Although nine of the patients who achieved complete remission relapsed during the course of the study within a mean of 19 months, seven of these patients were successfully managed with topical or systemic glucocorticoids, and the remaining two responded to a second course of rituximab.
The number of treatments administered with this dose of rituximab may influence patient outcomes. A retrospective analysis of 27 patients found that three or more infusions of rituximab (375 mg/m2 once weekly) was associated with better patient outcomes than fewer treatments [30].
Additional doses of rituximab after completion of an initial treatment cycle are typically reserved for patients who relapse or do not respond adequately to therapy. The findings of a nonrandomized prospective study of 17 patients treated for pemphigus with 375 mg/m2 of rituximab once weekly for four weeks suggest that a prophylactic infusion of rituximab six months after treatment may not be of benefit [31].
Other protocols — Rituximab administered in a lower dose than described above may be effective for pemphigus [25,32] though further study is necessary to clarify whether long-term outcomes are less favorable when compared with outcomes from higher dose regimens [25,32,33]. The comparative efficacy of low-dose rituximab (two 500 mg doses of rituximab separated by two weeks) and standard rheumatologic dosing of rituximab (two 1000 mg infusions separated by two weeks) was evaluated in a 48-week randomized trial with 22 patients with pemphigus vulgaris or pemphigus foliaceus [32]. The study population included both patients who had failed other therapies and patients who received rituximab as initial treatment. Most patients received systemic glucocorticoids in addition to rituximab and adjuvant immunosuppressants (primarily azathioprine) were added for patients with incomplete responses to treatment.
All 11 patients in the low-dose rituximab group and 10 of 11 patients in the standard rheumatologic dosing group achieved complete remission. Although the trial did not find statistically significant differences in the primary endpoints (time to disease control, time to end of consolidation phase, time to partial remission, or time to complete remission) between the two groups, there was a nonstatistically significant trend towards greater risk for relapse among patients treated with low-dose rituximab than among patients given the rheumatologic dose regimen (64 versus 36 percent relapsed, respectively). In addition, patients in the low-dose rituximab group had a significantly higher cumulative dose of azathioprine, and a statistically significant decline in enzyme-linked immunosorbent assay (ELISA) indices of desmoglein 1 and desmoglein 3 was evident only in the rheumatologic dose group.
Limited data suggest that intralesional injection of rituximab may be an effective treatment modality for oral pemphigus. In an open study, all of three patients given intralesional rituximab (5 mg/cm2 on days 1 and 15) for refractory oral pemphigus vulgaris had marked improvement [34]. One patient achieved clinical remission of oral lesions at week 12 and the remaining two patients achieved clinical remission at week 16. Adverse effects were limited to pain from injection in one patient. Of note, marked reductions in peripheral blood CD19+ B cell counts were noted in all patients two weeks after the initial treatment session. Patients were followed for up to six months; one patient relapsed five months after the start of therapy. Further study is necessary to confirm the efficacy of this therapy.
Children — Pemphigus is rare in children and data on rituximab therapy for pemphigus in this population are limited [35,36]. The findings of a retrospective study of 10 children (<18 years of age) who had severe or resistant pemphigus or who were unable to tolerate other treatments support a beneficial effect of rituximab in children. The study evaluated outcomes after treatment with rituximab (either two 500 mg doses of rituximab separated by 15 days or two 375 mg/m2 doses of rituximab separated by 15 days) [35]. All 10 children improved after rituximab therapy, including 7 children who achieved complete remission off all therapy after a single infusion cycle. The mean time to complete remission was 21 weeks. Six children experienced relapses, with a mean time to relapse of 13 months. Two of the children who relapsed were subsequently given rituximab and both achieved good results. Further study is needed to confirm the safety and efficacy of rituximab for pemphigus in children.
Combination therapy — Rituximab has been combined with IVIG or immunoadsorption in attempts to take advantage of the fast onset of action of these therapies [37-41]. Although rapid and long-lasting remissions have been reported in uncontrolled studies of patients with refractory pemphigus who were treated with combination therapy [37-41], the efficacy of rituximab given with and without these therapies has not been directly compared. Examples of studies that have evaluated combination therapy are provided:
●In an uncontrolled study of 11 patients with refractory pemphigus vulgaris, combination therapy with rituximab and IVIG was associated with rapid resolution of lesions and sustained clinical remissions in nine patients [37]. The remaining two patients relapsed after initial therapy, but achieved sustained remissions following one or two additional courses of rituximab. Among the 10 patients available for a 10-year follow-up study (follow-up range of 111 to 136 months), all remained in remission without recurrence of disease. [41]. Pemphigus IgG autoantibodies remained undetectable in serum during the 10-year follow-up period.
●In a series of 23 patients with severe pemphigus treated with immunoadsorption, rituximab, pulsed dexamethasone, and azathioprine or mycophenolate mofetil, improvement in pemphigus was noted within a few weeks and 19 patients (83 percent) achieved long-term complete remissions [38].
●In a retrospective study of 10 patients with refractory pemphigus vulgaris, eight patients achieved complete remission within six months after the addition of immunoadsorption and rituximab to systemic glucocorticoids and/or glucocorticoid sparing agents [39].
●In an uncontrolled study of seven patients with severe or refractory pemphigus treated with immunoadsorption, rituximab, and conventional immunosuppressants with or without IVIG, all patients had improvement in clinical manifestations within four weeks and three patients achieved long-term remissions [40].
Adverse effects — Although serious infections have been reported in patients treated with rituximab for pemphigus, the effect of rituximab on risk for infections is unclear because of the concomitant use of other immunosuppressive drugs [11]. A 2009 review of 136 patients treated with rituximab for pemphigus found that severe infections were reported in about 10 percent of patients and fatal infectious events occurred in 3 percent of patients [11]. Of note, progressive multifocal leukoencephalopathy has been reported in patients treated with rituximab for other indications [42,43]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Hypogammaglobulinemia and infection'.)
Infusion reactions are a common side effect of rituximab therapy. Deep venous thrombosis, pulmonary embolism, long-term hypogammaglobulinemia, and neutropenia have also been reported in patients treated with rituximab for pemphigus [11]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Other adverse effects'.)
Intravenous immune globulin (IVIG) — Intravenous immune globulin (IVIG) appears to be effective for refractory pemphigus. However, the mechanism through which IVIG improves pemphigus is not fully understood. Some authors have proposed that the infusion of IVIG may contribute to a reduction in circulating pemphigus autoantibodies by stimulating an increase in catabolism of immunoglobulins [44].
Efficacy and administration — The highest quality evidence for a beneficial therapeutic effect of IVIG in pemphigus is provided by an 85-day multicenter, randomized trial in 61 adults with glucocorticoid-resistant pemphigus (defined as a failure to respond to the equivalent of 20 mg per day or more of prednisolone) [45]. Patients in the trial were treated with 400 mg/kg of IVIG per day for five days, 200 mg/kg of IVIG per day for five days, or a placebo infusion for five days. The primary endpoint in the trial was the duration of time that patients could be maintained on the treatment protocol before symptoms required additional treatment (ie, time to escape protocol).
The trial found that the time to escape protocol was significantly longer for patients in the 400 mg IVIG group compared with the patients in the placebo group [45], supporting a beneficial effect of the 400 mg dose of IVIG. The difference in the time to escape protocol for the 200 mg IVIG group and the placebo group was not statistically significant. Furthermore, a significant decrease in a pemphigus activity score was detected at all study observation points for patients in the 400 mg IVIG group and at all study observation points after day 15 in the 200 mg IVIG group. The pemphigus activity score did not decrease significantly at any time point in the placebo group.
Several uncontrolled studies and case series provide additional support for the use of IVIG for refractory pemphigus [44,46-50]. In most of the series, patients received IVIG at a dose of 2 g/kg/cycle consisting of two to four consecutive treatment days, and IVIG cycles were repeated in four-week to six-week intervals. In some studies, clinical improvement following IVIG has been found to correlate with decreasing titers of desmoglein-specific IgG autoantibodies [44,50]. Additionally, a glucocorticoid-sparing effect of adjuvant IVIG was suggested by a small retrospective study that found significant reductions in glucocorticoid requirements following treatment with adjuvant IVIG. [49].
Adverse effects — In general, IVIG therapy is well tolerated. Side effects are usually mild to moderate adverse events such as headache, back pain, increased blood pressure, and abdominal discomfort [45]. Aseptic meningitis is a serious side effect of IVIG therapy that requires immediate termination of treatment. Anaphylaxis is a potential risk of IVIG treatment in patients with IgA deficiency. (See "Intravenous immune globulin: Adverse effects".)
Immunoadsorption — Immunoadsorption is a therapeutic option for pemphigus that functions through the removal of circulating autoantibodies. In contrast to plasmapheresis, which nonselectively removes plasma proteins from circulation, immunoadsorption removes circulating IgG with a very high specificity [51]. The high cost of immunoadsorption limits use of this therapy. In addition, immunoadsorption for pemphigus is not available in some countries, including the United States.
Efficacy and administration — Several apheresis systems for immunoadsorption have been successfully applied in pemphigus. The most effective columns include regenerative adsorber such as protein A or synthetic ligands (eg, PGAM146, Globaffin) that have a high affinity to the Fc-portion of human IgG [52-55].
The efficacy of immunoadsorption for removing pemphigus autoantibodies is influenced by the adsorber utilized and treatment protocol. In one study in which protein A adsorber was utilized, levels of antibodies against desmogleins 1 and 3 were reduced by an average of 76 percent one month after the start of immunoadsorption treatment [52]. Immunoadsorption is typically administered as an adjuvant to immunosuppressive therapies in short three to four day cycles that are repeated every three to four weeks [52-54,56].
Data on the clinical efficacy of immunoadsorption in pemphigus are primarily limited to small uncontrolled studies and case series [52-55]. The initial response to treatment can be rapid, occurring within a few weeks. Long-term improvement after immunoadsorption has been reported in several case series [52,54]. In our experience, patients with extensive skin involvement seem to benefit most from the addition of adjuvant immunoabsorption to immunosuppressive therapy.
Adverse effects — Most patients appear to tolerate immunoadsorption well. Infrequently reported adverse effects that may be directly related to immunoadsorption therapy include hypotension, bradycardia, anaphylaxis, and sepsis from a central catheter [56].
Plasmapheresis — Compared with immunoadsorption, which specifically removes circulating IgG, plasmapheresis (also known as plasma exchange) nonselectively removes plasma proteins from circulation. Plasmapheresis is a more widely available therapy.
Data are limited on the efficacy of plasmapheresis in pemphigus. Although small uncontrolled studies and case reports have associated improvement in pemphigus with plasmapheresis [57-62], a randomized trial of 40 patients in which treatment with prednisolone alone was compared with prednisolone plus plasmapheresis found no significant difference in efficacy [63].
Cyclophosphamide — Treatment regimens that include cyclophosphamide may be useful for inducing remission in pemphigus and reducing dependence on systemic glucocorticoids [6]. The beneficial effect of cyclophosphamide in pemphigus is likely related to the drug's suppressive effect on B lymphocytes and the ensuing reduction in autoantibody production [64]. The adverse effect profile of cyclophosphamide contributes to restriction of its use primarily for refractory disease [65]. (See 'Adverse effects' below.)
Efficacy and administration — Similar to azathioprine and mycophenolate mofetil, cyclophosphamide is usually prescribed as an adjuvant to systemic glucocorticoid therapy. Treatment regimens utilized for cyclophosphamide have varied. Several series have documented high rates of successful treatment of pemphigus with a pulsed regimen of dexamethasone and cyclophosphamide (monthly infusion of dexamethasone [100 mg for three days] and cyclophosphamide [500 mg for one day] plus daily 50 mg doses of oral cyclophosphamide in between pulsed therapy) [66-68]. However, less consistently favorable results with this regimen have also been reported [69].
A glucocorticoid-sparing effect of adjuvant cyclophosphamide given in a different regimen was demonstrated in a one-year randomized trial (n = 120) that compared the efficacy of four different regimens for newly diagnosed pemphigus [6]. Although the rate of clinical response was similar among patients treated with both prednisolone (2 mg/kg per day followed by a taper) and cyclophosphamide (one 1000 mg intravenous dose per month for six months and every other month thereafter) and patients treated with prednisolone alone (73 and 77 percent, respectively), the cyclophosphamide group had a lower mean total dose of prednisolone (8276 mg versus 11,631 mg). Further, the glucocorticoid-sparing effects of cyclophosphamide were similar to the glucocorticoid-sparing effects of adjuvant azathioprine and mycophenolate mofetil.
The effects of treatment regimens with cyclophosphamide specifically on patients with refractory pemphigus have been evaluated in uncontrolled studies that have demonstrated favorable results in some patients [65,70]. Examples include:
●In a prospective uncontrolled study, 23 patients with pemphigus (20 pemphigus vulgaris, 3 pemphigus foliaceus) who had disease refractory to prednisone plus azathioprine and/or mycophenolate mofetil, who could not tolerate other therapies, or who had rapidly progressive extensive disease were treated with oral cyclophosphamide (2 to 2.5 mg/kg of ideal body weight per day) and prednisone (1 mg/kg of ideal body weight per day followed by a taper after two to three months) [70]. Of note, nine patients with severe disease also received plasma exchange during the first two weeks of treatment.
Complete remission (defined as the absence of lesions for at least four weeks while on treatment with cyclophosphamide and less than 0.15 mg/kg per day of prednisone) was achieved by 17 of 20 patients with pemphigus vulgaris (85 percent) and two of three patients with pemphigus foliaceus. Three patients with pemphigus vulgaris failed to respond to treatment and one patient with pemphigus foliaceus had a partial response. The median time to remission was 8.5 months for patients who did not receive plasma exchange and 8 months for those who received the additional treatment. Six of 12 patients who achieved complete remissions and subsequently discontinued treatment with cyclophosphamide relapsed within a median time of six months.
●In a retrospective study, 21 patients with pemphigus refractory to prednisolone plus azathioprine or methotrexate (18 pemphigus vulgaris, 2 pemphigus foliaceus, 1 paraneoplastic pemphigus) were treated with 4 to 22 pulses of intravenous methylprednisolone (1 g per day for three consecutive days) together with 500 mg of intravenous cyclophosphamide on the second day of treatment [65]. Between the monthly pulse treatments, patients were given oral cyclophosphamide (50 mg per day) and prednisolone. Continuation of adjuvant therapy with other immunosuppressives (mycophenolate mofetil and/or methotrexate) was allowed.
The study found a statistically significant reduction in skin and oral disease scores after treatment. Seven patients (33 percent) achieved an excellent response (defined as quiescent disease), and a lesser degree of response was observed in an additional 13 patients. The median number of pulses given to patients who achieved an excellent response was 12 (range 6 to 19). In addition, four patients with excellent responses achieved clinical remissions (defined as complete resolution of blisters and erosions for at least six months) that lasted for six months to six years. One of these patients was able to completely discontinue treatment while the other three remained on mycophenolate mofetil and low-dose prednisolone.
A few case reports have documented the successful use of immunoablative high-dose cyclophosphamide for severe, refractory pemphigus [71,72]. However, treatment is not uniformly effective, and a disease flare within weeks after treatment has been reported in a patient [71].
Adverse effects — Adverse effects of this cytotoxic drug include myelosuppression, systemic infections, urine bladder toxicity, increased malignancies, and premature gonadal failure. Patients receiving cyclophosphamide should be closely monitored for adverse effects of treatment. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.)
OTHER THERAPIES FOR PEMPHIGUS — In addition to the major therapeutic options for the initial treatment of pemphigus vulgaris and pemphigus foliaceus and the management of refractory disease, multiple other interventions have been reported to be of benefit in small numbers of patients. Examples include topical pimecrolimus [73], topical tacrolimus [74], sulfasalazine with pentoxifylline, gold [75], tetracyclines with or without nicotinamide [76], chlorambucil, mizoribine [77], and subcutaneous veltuzumab [78].
Although case reports have suggested benefit of the biologic TNF-alpha inhibitors infliximab and etanercept in the treatment of pemphigus [79-83], a small randomized trial that compared combination therapy with infliximab and prednisone to treatment with prednisone alone in 20 patients with pemphigus vulgaris found only nonstatistically significant trends towards better results with the addition of infliximab therapy [84]. The small size of the trial was a limiting factor; larger trials might clarify the effects of infliximab therapy.
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
●Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening disorders. Traditional first-line treatment for these diseases consists of a systemic glucocorticoid with or without an adjuvant immunosuppressant, such as azathioprine or mycophenolate mofetil. (See 'Overview' above and "Initial management of pemphigus vulgaris and pemphigus foliaceus".)
●Patients who do not respond sufficiently to traditional first-line treatment may benefit from other interventions, such as rituximab, intravenous immune globulin (IVIG), immunoadsorption, plasmapheresis, or cyclophosphamide. Rituximab can also be beneficial as an initial treatment. (See 'Treatment options' above and "Initial management of pemphigus vulgaris and pemphigus foliaceus", section on 'Rituximab and systemic glucocorticoids'.)
●Due to a lack of high-quality comparative trials, data are insufficient for definitive conclusions on the relative efficacies of therapies for refractory pemphigus. Factors such as patient tolerance for specific treatments and treatment availability influence treatment selection. (See 'Treatment options' above.)
