Pemphigus comprehends a group of autoimmune bullous diseases characterized by IgG autoantibodies production against desmogleins.1,2 Both pemphigus vulgaris (PV) and pemphigus foliaceus (PF) clinical forms are prevalent in some Brazilian regions, whose pathogenesis has yet been extensibility studied.3–6 In Southeastern Brazil, HLA susceptibility/protective alleles/haplotypes have been identified, differentiating PV from PF in terms of HLA genetic profile.7

The main pemphigus treatment outcome is to reach clinical remission. The standard pemphigus treatment consists of oral corticosteroid, with/without adjuvant immunosuppressive drugs.1,8 However, several morbidities associated with long-term daily corticosteroid use have been reported.9,10

Rituximab was introduced for the pemphigus treatment in 2001.11 In the last years, it has been considered the first-line option to treat pemphigus in developed countries.1 Nevertheless, in Brazil, Rituximab has been prescribed as an exceptional option, for those cases of unresponsiveness to commoner drugs,12–14 which encouraged us to look for a diverse treatment in order to decrease corticoid side effects when chronically prescribed.9,10

Knowing that autoimmune diseases are efficaciously controlled with pulse therapy regimens,15 besides the fact that we work in infirmaries for dermatological and rheumatological patients in shared clinical management, we introduced pulse therapy with Dexamethasone-Cyclophosphamide (DCP) or exclusive Dexamethasone (DP) in the treatment of pemphigus, based on Pasricha et al. (1998) first report.16

Here, we aimed to compare the outcomes of DCP/DP regimens in a Brazilian cohort of PV and PF patients according to the demographic and clinical data profiles.

The study included 78 pemphigus patients, 37 with PV and 41 with PF. Information about gender, age, disease duration and previous treatments before pulse therapy prescription, and allocation in DCP and DP regimens are described in Table 1. The two groups presented statistical differences in terms of age and duration of disease, being PV patients older than PF, and PF duration disease greater than PV (p < 0.001 for both). The allocation of PV and PF patients in DCP or DP regimens was similar (p = 0.235). Therefore, the results were analyzed comprehending both regimens, named DCP/DP therapy.

Five PV patients were allocated to the pulse regimen as a first option because of the severity of the disease.

Data on pulse therapy outcomes in Phases I‒IV for PV and PF groups are expressed in Table 2.

Over the last decades, pulse therapy has become a safe option to treat pemphigus: it avoids the long-term side effects of oral daily treatment with corticosteroids and/or immunosuppressant drugs.9,10,16–21 The main reported modalities of pulse therapy comprehend DCP and dexamethasone pulse with oral azathioprine, resulting in similar control of the disease, but a higher frequency of relapse in azathioprine regimen.22 In Brazil, a unique report on pulse therapy for pemphigus was achieved from the literature.23

DCP has been prescribed to more than 300 pemphigus patients in India; 190 (84%) of 227 patients who completed the treatment were free of disease (25.3% with follow-up of more than 5 years).18 The comparison of steroid-sparing adjuvants has shown DCP and cyclosporine the best drugs in terms of relapse.19

In the present study, we compared the outcomes of DCP/DP in the two main clinical forms of pemphigus in a Brazilian prevalent region for PV and PF.3 Considering the total sample of PV and PF groups, who completed one cycle of DCP/DP, the frequencies of remission were similar for both (14 [37.8%] of 37 PV, and 14 [34.1%] of 41 PF). If we consider the patients who followed to Phase IV, 14 (82.4%) of 17 PV and 14 (77.8%) of 18 PF presented remission with a median of follow-up of 12-months and 26-months, respectively.

The duration of Phase I determines the duration of complete pulse therapy. The factors that influence the Phase I are important to establish the prognosis of DCP/DP response. In Phase I, 25 (67.7%) of 37 PV, and 23 (56.1%) of PF acquired similar frequencies of remission. Noteworthy, while PF is considered to have a better prognosis than PV, the PF group has taken longer to acquire remission when compared to PV, with a median of 10 and 6 pulses (p = 0.005), and 11 and 5-months, respectively (p = 0.002). Roga, Augustine (2018) described 10-months for PV and 8-months for PF, but PF took more cycles than PV to achieve control.22 Mundakkat, Sridharan (2018) associated the longer duration of the induction phase (Phase I) with oral and skin score severity, and with the duration of illness.24 It is important to point out that DCP/DP, with exception of 5 PF cases, was prescribed to patients who did not present a response to previous treatment.

In fact, the disease duration before pulse therapy prescription was longer in PF compared to PV (median = 69-months and 14 months, respectively; p < 0.001). The PF epidemiological and clinical behavior could explain this finding ‒ PF usually begins at an early age, courses with low severity, allowing for a long period without the use of any aggressive therapeutic agent.3 These facts may justify the great number of pulses to acquire remission in the PF group seen in Phase I. Although the severity of PV is greater than PF, PV patients started pulse therapy earlier following a shorter period of the disease compared to PF, which could justify the faster response and the smaller number of pulses that were necessary to achieve remission in Phase I.22,24

The frequencies of failure in Phase I was similar for PV and PF (13.5% and 14.6%, respectively) (Table 2). The number of pulses considered for failure was greater for PF, compared to PV (median = 25 and 13, respectively). In Phases II and III, few patients relapsed (2 PV and 1 PF). In Phase IV, when the patients do not use any corticoid or immunosuppressor, relapse was seen in 3 (17.6%) of 17 PV and in 4 (22.2%) of 18 PF patients. Searching for factors that could be influencing the outcomes of remission off-therapy in Phase IV, and failure in Phase I (Table 3), the number of pulses in Phase I was greater in the failure subgroup in both PV and PF. In terms of age, the youngest PV patients presented more frequency of failure compared to those in remission off-therapy (median = 36-y-old and 50.5-y-old, respectively). Incomplete or irregular treatment and/or single-medication pulse therapy could lead to relapse or therapeutic failure. For Pasricha et al., successful pulse therapy depends on the strict protocol and rigorous patient follow-up.18 Youngest PV patients were treated with a DP regimen, which could justify the highest frequency of failure.

PV and PF patients did not differ in terms of abandonment or clinical intercurrences. Abandonment occurred in 7 (18.9%) of 37 PV, and in 5 (12.2%) of 41 PF. Clinical intercurrences were noted in 3 (8.1%) of 37 PV, and in 5 (12.2%) of 41 PF patients. Considering dropout off-treatment, 27% of PV and 24.4% of PF did not finalize the treatment. Mahajan et al. (2022) reported a 41.5% dropout rate in pemphigus patients treated with DCP.21 We were able to identify not only difficult transportation from other cities to the reference center and personal and family problems as the main reasons for dropout but also abandonment without registered justification in the medical charts. Maintaining patients’ adherence to pulse therapy is certainly a challenge for physicians working with this therapeutic regimen. For the patients ongoing this treatment modality, we started scheduling weekly appointments with them before the attendance, which could explain the best adherence to treatment.25

Finally, pulse therapy is not free of side effects, being asthenia, fatigue, myalgia, arthralgia, flushing, palpitations, insomnia, headache, anorexia, and nausea and vomiting the most commonly described (see Ref.26 to review pulse therapy modalities).21,26 Most of the patients tolerated pulse therapy well and presented with minor side effects. Notwithstanding, there was one case of prostatic adenocarcinoma, diagnosed seven months after pulse therapy was suspended. This 60-year-old patient had used CYP for 4.5 years with a cumulative dose of 20 g. Serious side effects reported for this drug, like lymphoproliferative diseases, hemorrhagic cystitis, and bladder cancer may occur after 30‒100 g of CYP cumulative dose.27 Furthermore, there are no reports to date relating CYP and prostatic cancer. Hence, we cannot directly attribute this case of prostatic cancer to DCP. Anyway, physicians should monitor the emergence of this kind of event. Although deaths during pulse therapy have been described, in this study no death was registered.26

Before the corticosteroids era, pemphigus lethality could reach 70%. Following the introduction of corticosteroids and adjuvant therapy, it dropped to less than 10%.28 Since its introduction in 1982 by Pasricha et al., DCP has been revolutionizing the pemphigus treatment. This modality provides not only the control but also the remission of pemphigus, with less associated severe side effects.16,19,21,24,29

In developing countries, while we do not have Rituximab as a first-line sparing agent for the pemphigus treatment, DCP/DP should be considered as a safe modality to treat pemphigus.30 Since the present study has shown an association of higher failure with disease duration before pulse therapy, we recommend starting the pulse therapy promptly in mild-severe PV and PF disease.

The present results provide a better understanding of pulse therapy and may be useful for further studies aiming to clarify the association of the genetic profile of pemphigus patients with the DCP/DP treatment.

PV and PF groups presented similar frequencies of DCP/DP outcomes: remission, failure, relapse and drop-out. Compared to PV, PF patients required a higher number of pulses to achieve remission during Phase I, which could be related to a longer disease duration before pulse therapy prescription.

This study was partially funded by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) (#2010-51729-2) and FAEPA (Fundação de Apoio ao Ensino, Assistência e Pesquisa).

Ludmilla Figueiredo Vale Fontenelle: Data collection, analysis, and interpretation; statistical analysis; writing of the manuscript; effective participation in the research guidance; critical review of the literature; final approval of the final version of the manuscript.

Roberto Bueno-Filho: Analysis and interpretation; critical review of important intellectual content; final approval of the final version of the manuscript.

Sebastián Vernal: Analysis and interpretation; critical review of important intellectual content; final approval of the final version of the manuscript.

Renata Delfino: Data collection, analysis, and interpretation; final approval of the final version of the manuscript.

Giovanna Stefanne Lópes Barbosa: Analysis and interpretation; critical review of important intellectual content; final approval of the final version of the manuscript.

Eduardo Antonio Donadi: Analysis and interpretation; critical review of important intellectual content; final approval of the final version of the manuscript.

Ana Maria Roselino: Study concept and design; critical review of important intellectual content; effective participation in the research guidance; critical review of the literature; final approval of the final version of the manuscript.

None declared.