**10. Treatment**

Prior to the use of systemic corticosteroids, pemphigus vulgaris was an often fatal disease. Most patients would die within 2–5 years from the onset of the disease. Extensive involvement of the body surface led to the loss of epidermal barrier function and increased fluid loss or secondary bacterial infections. The anti-inflammatory effects of corticosteroids have made them one of the most important drugs in the treatment of autoimmune bullae diseases, and their use has reduced the mortality rate by 60%. Without treatment, PV has a mortality rate ranging from 60 to 90% [28]. However, these agents are not without their side effects, and the mortality of PV remains significant (5–20%), largely due to complications of long-term immunosuppression. However, immunosuppressive agents remain important in the treatment of PV [29].

The first line of treatment is corticosteroids. Recommends starting prednisone treatment at doses of 0.5–1.5 mg/kg/day (mean 1 mg/kg/day, 60 mg/day) for approximately 2 weeks or more. If disease control is not achieved thereafter, the dose is increased to 2 mg/kg/day or reduced to 25% per week unless relapsed [29]. Pulse therapy in the form of 1 gr/day can also be used (with close cardiological monitoring), but it is not recommended due to the high risk of side effects.

The following should be considered when deciding which immunosuppressive drug to use in the patient. First, the patient's medical condition, general health, comorbidities, and the response of PV to corticosteroid therapy. Second, the level of steroid-sparing effect required to maintain clinical remission if the disease is under control. Third, data on remission times, the incidence of relapse, and time to relapse [29].

Adjuvant Therapies; azathioprine (AZA) is a cytotoxic drug used in many autoimmune diseases. It is the oldest and most prescribed immunosuppressive drug used for PV, and contributes to treatment by suppressing lymphocyte proliferation and antibody synthesis. AZA is an effective adjunctive immunosuppressive agent for pemphigus, with clinical remission rates of approximately 50% in retrospective studies [25]. The recommended dose of AZA in PV is 1 to 3 mg/kg/day orally in two divided doses. It should be used for four to six weeks to achieve a full therapeutic effect, which limits its use as monotherapy. In case of unsatisfactory clinical response, it is recommended to continue use for 3 months before replacing with another adjuvant [20]. Due to genetic polymorphisms that affect AZA clearance and activation, testing for thiopurine methyltransferase (TPMT) levels is strongly recommended prior to initiating therapy. In general, adults with pemphigus with high TPMT activity should be treated with a normal dose of AZA (up to 2.5 mg/kg/day), and those with moderate or low TPMT activity at a low maintenance dose (up to 0.5–1.5 mg/kg/day) should be treated with AZA therapy, should not be given to patients without TPMT activity [26]. Blood and liver enzymes should be monitored weekly for the first month of treatment and biweekly after the second month. Intervals can be increased later. Serious side effects include reversible lymphopenia, neutropenia and early pancreatitis. More commonly, gastrointestinal upset and hepatotoxicity, which can be reduced by dose adjustment, have been reported [29].

Mycophenolate mofetil (MMF) has been used as an adjuvant to corticosteroids in patients who do not respond to AZA. Several groups prefer MMF to AZA as first-line adjuvant therapy in PV because of its low hepatotoxicity and comparable efficacy. It is started at a dose of 2–3 g/day divided into two doses in combination with MMF systemic steroid. This combination therapy has been shown to provide clinical

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remission in an average of 9 months. Therapeutic failure should only be considered after 3 months of use at a dose of 3 g/day. Its main side effects are altered bowel habits, neutropenia, lymphopenia and myalgia. Its use is contraindicated in case of hematological dysfunction, acute and chronic infections, pregnancy and malignancy. Because it is teratogenic, contraception should be initiated in women of childbearing age before starting MMF therapy. Complete blood count and liver-kidney function tests should be performed at the start of treatment, every other week for the first 3 months, and monthly after 3 months of treatment. In addition, patients should be followed up for the development of cutaneous neoplasms and lymphoma.

Although not as frequently used as AZA or MMF, it is an alternative to methotrexate (MTX) for immunosuppressive therapy in pemphigus vulgaris. In a retrospective study of 30 PV patients treated with adjuvant methotrexate at a dose of 15 mg per week, it was shown that 84% of patients showed clinical improvement within 6 months and the steroid dose could be reduced in 21 (76.6%) and MTX was effective and safe in the treatment of PV has been reported [30]. Before starting treatment, complete blood count, liver and kidney function tests and urinalysis should be performed. It is then recommended to monitor the blood count and liver function tests once a week for the first month, monthly for the next 2 months, and then every 2–3 months. Major side effects are susceptibility to infections and liver dysfunction. Hepatotoxicity is important during drug use. In some studies, it has been stated that if the patient is not in the risk group for liver disease, liver biopsy may not be performed by monitoring the procollagen III level [29]. Side effects can be alleviated with the administration of 5–10 mg of folic acid after methotrexate treatment.

Cyclosporine is a selective inhibitor of calcineurin and acts by reducing the transcription of cytokines required for T-lymphocyte proliferation. This may suppress the autoimmune response in the pathogenesis of PV [29]. Some authors report that the efficacy of cyclosporine in the treatment of pemphigus is limited compared to AZA or MMF [31]. The standard dose is 2.5–3 mg/kg/day. Cyclosporine requires close monitoring for hypertension and renal toxicity.

Cyclophosphamide, as an alkylating agent, cross-links DNA and suppresses B and T lymphocyte responses, thereby helping PV treatment by reducing antibody production [29]. Cyclophosphamide is administered at a dose of 1–3 mg/kg/day (usually 50–200 mg/day). The most important side effects are hemorrhagic cystitis, infertility and leukopenia. Complete remission was achieved in 17 of 20 patients with PV, and treatment failed in three patients. The treatment was applied for an average of 17 months and the patients were followed for 27 months. The median time to complete remission was reported as 8.5 months. Hematuria was observed in five patients, mild infection in six patients, and transitional cell carcinoma of the bladder 15 years later in one patient. There were no deaths due to cyclophosphamide treatment [32]. In another study, weekly intravenous cyclophosphamide infusion with high-dose corticosteroids safely, effectively and quickly controlled the condition of corticosteroid-insensitive patients with resistant PV, shortened hospital stay and prevented the risk of further complications [33]. Several small case series have evaluated regimens of immunoablative intravenous cyclophosphamide with daily oral therapy (1.1–2.5 mg/kg/day), intermittent high-dose intravenous dexamethasone and cyclophosphamide with 50 mg/day oral cyclophosphamide daily. Although none of them are curative, all methods have been found to be effective in the short term. Significant adverse events, including hematuria, infection and transitional cell carcinoma of the bladder, have been observed with high-dose treatment regimens. In a study using low-dose cyclophosphamide (1.0–1.5 mg/kg/day), no significant difference in the safety profile was observed when compared with other immunosuppressive

agents. With the risk of infertility, cyclophosphamide is not considered a first-line steroid-sparing agent in the treatment of PV [25].

Dapsone inhibits various inflammatory mediators, but its exact mechanism of action in PV is unknown [34]. Steroid-reducing effects have been demonstrated at doses up to 100 mg/day or ≤ 1.5 mg/kg/day [35]. In different studies, Dapsone showed a trend toward efficacy as a steroid-sparing drug in PV, but the results were not statistically significant. It can be used with other immunosuppressants, especially Rituximab. It helps in the prophylaxis of Pneumocystis pneumonia [25]. Serum glucose-6-phosphate-dehydrogenase (G6PDH) activity should be checked before starting treatment.

Plasmapheresis, the process typically involves plasma exchange to remove IgG antibodies from the serum and replace them with albumin, fresh frozen plasma, or donor plasma. Plasmapheresis is sometimes used to treat severe pemphigus or PV unresponsive to a combination of corticosteroids and immunosuppressive agents. Although one controlled study reported ineffectiveness, other studies have shown that both reduces serum autoantibody levels and controls disease activity [25]. For maximum efficacy, patients should receive immunosuppressive agents to avoid the antibody rebound phenomenon that may follow IgG removal, the most commonly used agent for this purpose is Cyclophosphamide [25, 29]. Side effects of plasmapheresis include sepsis, hypotension and depletion of clotting factors.

Immunoadsorption (IA) is an advanced technique used to remove circulating antibodies in patients with severe disease and high IgG titers. Removal of pathogenic antibodies from the circulation has been theorized to promote the migration of anti-Dsg3 antibodies from the skin to the systemic circulation, thereby minimizing autoantibody binding to antigens in the epidermis, thereby preventing the underlying pathogenesis of pemphigus. Cost and availability are major limiting factors for the use of IA [29]. The basic principles of IA are actually similar to plasmapheresis, but when the two are compared, IA does not remove plasma proteins such as albumin and clotting factors. The use of plasmapheresis in pemphigus has been largely abandoned due to the significant incidence of serious adverse events such as sepsis [36].

Pulse Corticosteroid, intravenous, pulsed administration of 250 to 1000 mg of methylprednisolone administered over approximately 3 hours per day for 4 to 5 consecutive days can achieve prolonged remission and reduce the total dose of glucocorticoids needed to control the disease. Although the goal of this therapy is to reduce the incidence of complications from long-term steroid use, it can cause cardiac arrhythmias resulting in sudden death, in addition to all the usual glucocorticoid complications, and its use remains controversial. In addition, a controlled trial showed that adjuvant oral dexamethasone pulse was not superior to standard treatment with prednisolone and AZA for PV. Simply giving lower doses of prednisone in divided doses may produce the same result with fewer side effects [25].

Rituximab; chimeric monoclonal anti-CD 20 antibodies. Rituximab binding to CD20 induces B-cell depletion by, at least, four different mechanisms:


### *Pemphigus Vulgaris DOI: http://dx.doi.org/10.5772/intechopen.104814*


Despite being used in the treatment of pemphigus since the early 2000s, anti-CD20 monoclonal antibodies such as rituximab are still considered third-line agents in the European Academy of Dermatology and Venereal Diseases guidelines published in 2015 [26]. Recently, anti-CD20 antibodies have been recommended as the first choice only for moderate to severe and/or resistant pemphigus. Following administration of rituximab, a rapid and sustained decrease in circulating and tissue B lymphocytes is observed, lasting at least 6 to 12 months. Recent evidence suggests that it also affects T lymphocytes [20]. Rituximab treatment reduced the total corticosteroid dose required for clinical remission, thus reducing side effects secondary to long-term high-dose corticosteroids. A recent retrospective case-control study involving 40 patients showed that patients previously treated with rituximab treated with conventional therapy were able to reduce their monthly prednisone dose by 73% from a median of 658.6 mg/month to 177.2 mg/month [12].

It should be administered IV as a slow infusion (four to 6 hours). There are no standardized protocols for the use of rituximab in autoimmune bullous diseases. There is much debate about the optimal dose of Rituximab in pemphigus. Two main protocols are used: the rheumatoid arthritis protocol, which consists of two 1,000 mg infusions two weeks apart, and the lymphoma protocol, which consists of four 500 mg once-weekly infusions [36]. No differences in percent remission and diseasefree time were observed in either protocol. They can be used alone or in combination with intravenous immunoglobulin, plasmapheresis and immunoadsorption. It can also be applied to patients already taking prednisone and immunosuppressive drugs; dose reduction and suspension of the latter should be accelerated, due to the increased risk of infection [20].

Intravenous Immunoglobulin (IVIg); derived from a pool of donors, IVIg consists of human plasma-derived IgG, sugars, salts and solvents [36]. It is thought that IVIg functions by saturating the neonatal Fc receptor, thereby increasing the catabolism of the patient's serum antibodies containing pathogenic autoantibodies [25]. IVIg is mostly used in patients resistant to corticosteroid and immunosuppressive treatments. 2 gr/kg is applied in each session. In studies, it has been shown that the application of 0.4 g/kg/day for 5 consecutive days is effective in the treatment [20, 36]. It can also be combined with rituximab. Slow 5–5.5 hour infusions can minimize infusion reactions [13]. A major benefit of IVIg is its few side effects. The most common side effects are headache, dyspnea, tachycardia, and abdominal discomfort. The most serious adverse events are aseptic meningitis and cerebrovascular accidents, occurring in <1% of PV patients treated with IVIg [13]. It can be used on pregnant women.

TNF-α inhibitors; TNF-α is one of the cytokines involved in acantholysis. Although the use of Infliximab and Etanercept as a case report appears to be effective in the treatment of PV, there are conflicting results [20].

Topical treatment; PV is largely managed with systemic therapy, but skin and mucosal care are extremely important. For this purpose, topical corticosteroids and, if there is a risk of infection, antibiotic creams are often added to the treatment. It has also been reported that tacrolimus and pimecrolimus, pilocarpine gel 4%, nicotinamide gel 4%, 0.1% sulfadiazine creams are also beneficial [37].

During the treatment period, patients should be followed closely for diabetes, hypertension, heart failure, myopathy, osteoporosis, avascular bone necrosis, glaucoma, cataract due to corticosteroids, infections, especially respiratory tract infections, hepatitis, CMV reactivation or hematological abnormalities (anemia, leukopenia) as a result of immunosuppression.

Future Therapies; CAAR-T Therapy, BTK inhibitor and p38MAPK inhibitor are included.

CAAR-T Therapy; T cells expressing chimeric autoantibody receptors (CAAR-T cells) that target antibody-producing B cells are one of the latest proposed avenues for treating for autoimmune conditions.

Bruton tyrosine kinase (BTK) Inhibitor; Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases [38]. One of the new potential treatments for pemphigus, the BTK inhibitor rilzabrutinib (PRN1088) was recently tested in patients with PV in a phase II trial and controlled 50–56% of lesion activity in patients in a mean of 4 weeks [39]. Thus, inhibition of kinases such as BTK shows promising potential for future treatment of PV.

p38MAPK inhibitor (SB202190); In a murine model of pemphigus, p38MAPK inhibition prevented blister formation. On the other hand, in a study, the formation of blisters in the mucosa could not be prevented by a p38MAPK inhibitor, and they claimed that, unlike the epidermis, the ultrastructural changes of blister formation and desmosomes were independent of p38MAPK in the oral mucosa [40].
