Management of Pemphigus Vulgaris.

INTRODUCTION: Pemphigus vulgaris (PV) is a chronic, autoimmune, vesiculobullous disease. As a result of the relative rarity of PV, published randomized controlled trials (RCTs) are limited, which makes it difficult to evaluate the efficacy of different treatment regimens in this disease. This also precludes conduct of a meta-analysis.
METHODS: English-language publications describing treatment outcomes of patients with PV were identified by searches of electronic databases through May 2015, and additionally by review of the bibliography of these publications. A total of 89 papers, which included 21 case reports, 47 case series, 8 RCTs, and 13 observational studies, were identified. The findings from these publications, including information on disease course and prognosis, medications used, treatment responses, and side effects, are summarized in the tables and text of this review.
RESULTS: Prior to availability of corticosteroid therapy, PV had a high fatality rate. Early publications from the 1970s reported high-dose, prolonged corticosteroid use and significant associated side effects. Later reports described use of corticosteroids along with steroid-sparing adjuvants, which allows a reduction in the total dose of corticosteroids and a reduction in observed mortality and morbidity. For the majority of patients in these reports, a long-term course on medications lasting about 5-10 years was observed; however, subgroups of patients requiring shorter courses or needing longer-term therapy have also been described. Early diagnosis of PV and early initiation of treatment were prognostic factors. In recent publications, commonly used initial regimens include corticosteroids in combination with mycophenolate or azathioprine; whereas, for patients with inadequate response to these regimens, adjuvants such as intravenous immunoglobulin (IVIg) or rituximab are used.
CONCLUSION: The review findings emphasize the importance of early diagnosis, early initiation of treatment, and use of steroid-sparing adjuvants to allow a reduced total dose and duration on corticosteroids. Also highlighted is the need for more RCTs.

Introduction

Pemphigus vulgaris (PV) is a chronic, autoimmune, mucocutaneous, vesiculobullous disease [1].

The word pemphigus comes from the Greek word pemphix, which means blister [2]. It is a rare disease with estimated worldwide annual incidence of 0.1–0.5 per 100,000 [3]. It occurs in all racial and ethnic groups with the highest incidence seen in Ashkenazi Jews [4]. Occurrence is most common during the fifth and sixth decades of life, although a few cases have been reported in children [5].

In the majority of cases, PV initially presents with lesions on the oral mucosa [3]. Often the first sites affected are those exposed to frictional trauma including the buccal and lateral tongue mucosa along the occlusal level, or the gingiva, but PV can occur on any oral site particularly if exposed to sharp or acidic foods. The lesions start as vesicles which rupture easily leaving erosions and ulcers.

The pathogenesis of pemphigus involves the presence of circulating and tissue-bound autoantibodies to the keratinocyte cell surface desmosomal molecules desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). Dsg3 and Dsg1 belong to the cadherin superfamily involved in cell–cell adhesion. These autoantibodies cause loss of cell–cell adhesion between epithelial cells, which results in suprabasilar intraepithelial vesicle formation [4, 6].

Diagnostic tests include perilesional mucosal or skin biopsy for histologic examination and direct immunofluoresence testing. Histologic findings include presence of intraepithelial blisters and suprabasilar acantholysis; direct immunofluorescence findings include IgG deposits and less commonly IgM and C3 deposits in intercellular spaces in the epithelium. Blood tests include ELISA testing for Dsg3 and Dsg1 autoantibodies [7].

Prior to availability of corticosteroid therapy in the 1950s, PV had a very high fatality rate. While many treatment options are now available, corticosteroids in combination with other drugs still form the mainstay of treatment. Mortality from pemphigus has decreased significantly in the last half century and is now usually due to adverse effects of the medications used [8, 9].

As a result of the relative rarity of pemphigus, there are very few randomized controlled trials. However, numerous observational studies, case reports, and case series have been published that report on the treatment of pemphigus. The objective of this review was to summarize the findings from all of the reported human studies including observational studies and case reports.

Methods

Publications relating to treatment of PV were identified by searches of electronic databases including PubMed, Cochrane, and Google Scholar through May 2015. Keywords used included pemphigus vulgaris, autoimmune vesiculobullous disease, corticosteroids, azathioprine, rituximab, mycophenolate mofetil, methotrexate, and IVIg. The full-text versions of the papers identified were obtained. The bibliography of these papers was also reviewed to identify any additional papers that did not appear in the electronic search. Only English-language papers describing treatment outcomes of patients with PV were included in this review. A total of 89 papers, which included 21 case reports, 47 case series, 8 RCTs, and 13 observational studies, were included. These papers were reviewed to obtain information on publication date, type of study done, age of the patients, extent of lesion involvement (skin and mucosa), previous treatments if any, medications used, duration of use of previous medications before new ones were started, duration to first improvement after the start of medications, follow-up duration, concomitant medication used along with main drug, outcome, duration on medication, adverse effects of drugs, and antibody titer changes after treatment. This information is summarized in Tables 1, 2, 3, 4, 5 and 6.

Table 1

Corticosteroids

Author/year	Type of study	N M/F	Age at the beginning of follow-up period Range/mean (years)	Type of pemphigus vulgaris	Previous Rx	Duration of disease symptoms before CS were started	CS dose
	1	2	3	4	5	6	7
Ryan [40]/1972	Case series	N = 41  M/F = 23/18	26–80	Mucocutaneous	NM	NM	500–1000 mg cortisone equivalents
Berger et al. [41]/1973	Case report	1/M	3.5	Oral mucosal lesions	NM	NM	Prednisone = 15–120 mg/day
Rosenberg et al. [42]/1976	Case series	N = 85 PV + 5 P vegetans	14–88	Oral mucosa = 80, Skin = 52	NM	NM	Prednisone = 60–180 mg/day
Lozada, Silvermann, Cram [14]/1982	Case series	N = 6  M/F = 3/3	24–89	Mucocutaneous = 6	Pred	NM	Prednisone = 40–80 mg/day
Lever and Schaumburg-Lever et al. [12, 13]/1984	Case series	N = 84	20–79/mean = 51	Mucocutaneous	NM	NM	Prednisone = 40–350 mg/day
Aberer et al. [43]/1986	Case series	N = 29 M/F = 12/17	At onset of disease—mean 59.9 ± 9.0 years At initiation of therapy—61.6 ± 8.1 years	Mucocutaneous	Pred, MTX	NM	Prednisone = 80–200 mg/day
Seidenbaum et al. [44]/1988	Case series	N = 88 PV + 27 (PF, PE, P vegetans) M/F = 46/69	40–60	Oral mucosa = 50; Cutaneous = 33; Mucocutaneous = 32	NM	NM	Prednisone = 60–120 mg/day
David et al. [15]/1988	Case series	N = 4  M/F = 2/2	11–17	Mucocutaneous = 3, Oral mucosa = 1	NM	NM	Prednisone = 60–80 mg/day
Laskaris and Stoufi [45]/1990	Case report	1/F	6	Extensive oral mucosal lesions	None as no diagnosis was made when symptoms were first noted at age of 2	4	Prednisolone = 30 mg/day for 3 weeks. Prednisolone maintained to 10 mg/day every other day after clinical improvement
Lamey et al. [16]/1992	Case series	N = 30  M/F = 10/20	24–68/Mean = 48.1	Cutaneous = 4; Mucosal = 26 (Oral mucosa = 25)	NM	2–9 mo (Mean = 3.5 mo)	Prednisone = 20–120 mg/day in 29 pts. No Rx in 1 pt
Werth [46]/1996	Retrospective case controlled study	N = 15  M/F = 10/5	28–72	Mucosal = 6; Cutaneous = 1; Mucocutaneous = 8	None	Mean. Control grp = 3.1 ± 1.2 mo; Pulsed grp = 4.1 ± 1.0 mo	Control grp (N = 6) Pulsed grp (N = 9). Methylprednisolone sodium succinate pulse
							Pred = 95 ± 22.5 mg Pred before pulse = 82 ± 15.8, after pulse = 78 ± 7.6 mg/d. Pulse dose = 250–1000 mg/24 h
Robinson et al. [47]/1997	Case series	N = 12  M/F = 3/9	3–66/Mean = 32	Oral mucosa = 12, Cutaneous = 7	NM	NM (Newly diagnosed pts)	Prednisone = 10–80 mg/day
Kaur and Kanwar et al. [17]/1990	Case series	N = 45 PV + 5 PF M/F = 24/21	15–55	NM	NM	3 mo to 5 years	Dexamethasone = 136 mg dissolved in 5 % dextrose given by a slow iv drip over 1–2 h and repeated on 3 consecutive days
Mignogna et al. [48]/1999	Retrospective analysis	N = 16  M/F = 5/11	26–76/Mean = 51	Oral mucosa = 16, Cutaneous = 6	NM	1–3 mo (Mean = 55 days)	Deflazacort = 120 mg/daily
Scully et al. [49]/1999	Case series	N = 32, Additional 23 pts referred to dermatology and with limited available data M/F = 22/23	16–83/Mean = 50.2	Mucosal = 55, cutaneous lesions later developed = 13	NM	3–192 weeks (Mean = 27.2 weeks) from 42 patients with available data	Prednisolone = 20–80 mg/day
Herbst and Bystryn et al. [29]/2000	Case series	N = 40  M/F = 15/25	14–73/Mean = 51	Mucocutaneous	NM	NM	Prednisone = 15–90 mg/day
Kanwar et al. [18]/2002	Retrospective analysis	N = 32	21–75/Mean = 49	Mucocutaneous = 27; Mucosal = 1; Cutaneous = 4	NM	NM	136 mg iv Dexamethasone for 3 consecutive days (2–8 pulses required for PR) and (8–32 pulses required for CR) + 500 mg CyclP on day 2
Ljubojevic et al. [50]/2002	Retrospective analysis	N = 154  M/F = 57/97	19–89/Mean = 53	Mucocutaneous	NM	>5 years	Prednisone = 100–150 mg daily for first 4–6 weeks. Then gradually tapered to maintenance dose of 5–20 mg. In 14 pts with refractory PV I.M. gold given up to 50 mg per week
Femiano et al. [51]/2002	Case series	N = 20  M/F = 8/12	35–57/Mean = 43	Mucocutaneous	NM	NM	Oral Pred (N = 10) 125 mg/day to 5 mg once a week for 1 mo Oral Pred alternated with iv betamethasone (N = 10) Pred 50 mg/day to 5 mg/d once a week for 1 week/20 mg/d iv to to 8 mg/d iv for 4 days
Robinson et al. [32]/2004	Case report	1/M	47	Oral lesions	NM	3 mo	Prednisolone = 1 mg/kg/day (80 mg); topical 0.1 % triamcinolone acetonide
Chams davatchi et al. [38]/2005	Case series	N = 1111 M/F = 492/717	4–82/Mean = 42	Mucocutaneous = 782; Mucosal = 200; Cutaneous = 129. Oral cavity involved in 978 pts	None	NM	Prednisone dose NM
Alonso et al. [33]/2005	Case series	N = 14  M/F = 4/10	21–87	Oral mucosa = 9; Mucocutaneous = 5	NM	0.75–72 mo (Mean = 11.66 mo)	0.5 % Triamcinolone corticosteroids + 60 mg/day systemic Pred in 12 pts for 1 mo/Intralesional corticoid infiltration (parametasone) in 1 pt every 15 days during 45 days of therapy
Ben lagha et al. [31]/2005	Case report	1/F	71	Mucocutaneous	NM	4 mo	Prednisone = 0.5 mg/kg/d; 20–40 mg/day
Ariyawardana et al. [5]/2005	Case report	1/F	14	Oral mucosal lesions	None	10 days	Systemic Prednisolone = 10 mg/day; 0.1 % triamcinolone acetonide in orabase twice a day maintenance dose for 3 mo
Yazganoglu et al. [39]/2006	Case series	N = 5  M/F = 3/2	7–15 years	Mucocutaneous	NM	NM	Prednisolone = 1–2 mg/kg/day
Mentink et al. [19]/2006	Randomized controlled trial	N = 20  M/F = 13/7	26–71/Mean = 49	Mucocutaneous	Systemic and topical CS, AZA, antibiotics	NM	DP (Dexamethasone pulse therapy) (N = 11) Oral dexamethasone in 300 mg pulses 3 days/mo, 5.44 pulse courses
							PP (placebo pulse therapy) (N = 9) 6 Placebo tablets 3 days/mo, 6.44 pulse courses
Chaidemenos et al. [52]/2007	Prospective cohort study	N = 74 Studied = 68  M/F = 21/47	24–83 years	Oral mucosa = 68; cutaneous = 33; genital and nasal lesions = 14	NM	0.15–18 mo/mean = 3.6 mo	Prednisone = 40 mg/day
Chams davatchi et al. [53]/2007	Randomized controlled open label trial	N = 120 M/F = 71/40	Mean = 40 years	Mucocutaneous = 74; mucosal = 29; cutaneous = 8. Oral cavity involved in 76 pts	None	3–12 mo/1 year	Mean total dose (P = Prednisolone) Pred (30) 11631 mg (2 mg/kg/day) Pred/AZA (30) 7712 mg (2 mg/kg/day P + 2.5 mg/kg/day AZA Pred/MMF (30) 9798 mg (2 mg/kg/day P + 2 g/d MMF) Pred/CyclP (30) 8276 mg (2 mg/kg/day P + 1 g iv CyclP monthly)
Dagistan et al. [30]/2008	Case report	1/F	35	Oral lesions	Sultamisilin, flurbiprofen	2 mo	Prednisolone = 80 mg/day initially for 14 days and increased to 100 mg for a period of 14 days
Tran et al. [54]/2013	Retrospective chart	N = 23  M/F = 11/12	26–72/Mean = 54	Mucosal = 19, cutaneous = 4	Pred, AZA, MMF, dapsone, Rtx, IVIg, etanercept, chlorquine	2 mo to 10 years (Mean = 23 mo)	Prednisone = 35 mg/daily (mean dose)
Mignogna et al. [55]/2010	Case series	N = 35  M/F = 13/22	17–72/Mean = 45	Oral pharyngeal	NM	NM	Total CS + immunosuppressive therapy + PITAinjections (N = 16) 4894 mg (75–100 mg/day) + 2–8 sessions of PITA injections
							Total CS + Immunosuppressive therapy only (N = 19) 5312 mg (75–100 mg/day)

Pred prednisone, CS corticosteroid, MMF mycophenolate mofetil, AZA azathioprine, MTX methotrexate, DCP dexamethasone cyclophosphamide pulse, IVIg intravenous immunoglobulin, Rtx rituximab, CyclP cyclophosphamide, Pl plasmapheresis, CR off complete remission off therapy, CR on complete remission on therapy, PR partial remission, R relapse, F/U follow-up, d/c discontinue, mo months, wks weeks, d days, NM not mentioned, PITA perilesional/intralesional triamcinolone acetonide

aDuration on medication included the time period on medication prior to the start of follow-up to this paper

Table 2

Azathioprine

Author/year	Type of study	N M/F	Age range/mean (years)	Type of pemphigus vulgaris	Previous Rx	Duration of disease before AZA	AZA dose, prednisone dose
	1	2	3	4	5	6	7
Mourellou et al. [56]/1995	Retrospective analysis	N = 48	NM	NM	NM	NM	40–100 mg Pred	>100 mg Pred	40 mg Pred + 100 mg AZA
							25 pts	8 pts	15 pts
Chaidemenos et al. [1]/2010	Retrospective bi center comparative study	N = 36  M/F = 16/20	Mean = 54	Mucosal	NM	4 mo	Monotherapy of Pred (N = 17)		Alternate day Pred + daily AZA (N = 19)
							Starting dose = 1.5 mg/kg/day		40 mg Pred every other day + 100 mg/d AZA
Chams-Davatchi et al. [57]/2013	Randomized double blind controlled study	N = 56 M/F = 23/33	10–75	Mucocutaneous = 33; mucosal = 15; cutaneous = 8	None	5–10 mo	Placebo grp (Pred + placebo)		AZA grp (Pred + AZA)
							Pred: 2 mg/kg up to 120 mg/day		Pred: 2 mg/kg up to 120 mg/day
							Placebo: 2.5 mg/kg		AZA: 2.5 mg/kg

Pred prednisone, AZA azathioprine, CR off complete remission off therapy, CR on complete remission on therapy, PR partial remission, PR on partial remission on therapy, PR off partial remission off therapy, R relapse, NR no response, F/U follow-up, d/c discontinue, mo months, d days, pts patients, NM not mentioned

aDuration on medication included the time period on medication prior to the start of follow-up to this paper

Table 3

Mycophenolate mofetil

Author/year	Type of study	N M/F	Age range/mean (years)	Type of pemphigus vulgaris	Previous Rx	Duration of disease before MMFa	MMF dose
	1	2	3	4	5	6	7
Enk and Knop [58]/1999	Case series	N = 12  M/F = 5/7	42–64	NM	Pred, AZA	4–8 mo	2 g/day
Grundmann-Kollmann et al. [59]/1999	Case report	1/F	76	NM	Pred, AZA	7 years	2 g/day
Grundmann-Kollmann et al. [59]/1999	Case report	1/F	66	Cutaneous	Pred, AZA	2 years	2 g/day
Powell et al. [21]/2002	Case series	N = 12  M/F = 4/8	41–78	Mucocutaneous = 8; mucosal = 4	AZA, Pred, MTX, CyclP, IVIg, dapsone, gold, thalidomide, minocin	6–168 mo	750 mg to 3.5 g (Mean = 2.5 g/day)
Mimouni et al. [60]/2003	Case series	N = 31 PV + 11 PF M/F = 21/21	6–74 (Mean = 47.2)	NM	Pred, AZA	NM	35–45 mg/kg per day
S. Beissert et al. [61]/2006	Multicenter randomized controlled non-blinded clinical trial	N = 33 PV + 7 PF; 21 PV pts treated with MMF M/F = 16/23	Mean = 56.5	Cutaneous = 39; mucosal = 28	NM	NM	MMF = 1 g twice daily
							AZA = 2 mg/kg/d
Strowd et al. [62]/2010	Retrospective chart review	N = 18  M/F = 8/10	29–67/52	Mucocutaneous = 12, mucosal only = 6	Pred, Pred + MMF in 1 pt only	1–6 yrs	2–3 g/day
S. Beissert et al. [63]/2010	Multicenter placebo controlled non-blinded trial	N = 94  M/F = 38/56 75 completed study	18–70/45.5	Mucocutaneous	NM	Mean = 4 mo	Placebo + Pred	36pts
							MMF2 g/d + Pred	21 pts
							MMF3 g/d + Pred	37 pts
Bongiorno et al. [64]/2010	Case series	N = 9  M/F = 5/4	18–75	NM	Pred + AZA	14.4 mo	Enteric coated—mycophenolate sodium 1440 mg/day (given in 2 divided doses)
Ionnaides et al. [65]/2011	Randomized prospective non-blinded clinical trial	N = 36 PV + 11 PF M/F = 18/29	Mean = 53	Cutaneous = 47; oral = 24	NM	Monotherapy = 4.35 mo; combination = 4.04 mo	Pred alone	Pred + MMF
							1 mg/kg	1 mg/kg + 3 g/day

Mycophenolate used in patients with refractory pemphigus vulgaris (previous treatment with corticosteroids and azathioprine was unsuccessful in achieving remission) are reported in Table 3

Pred prednisone, MMF mycophenolate mofetil, AZA azathioprine, MTX methotrexate, IVIg intravenous immunoglobulin, CyclP cyclophosphamide, Pl plasmapheresis, CR off complete remission off therapy, CR on complete remission on therapy, PR partial remission, R relapse, F/U follow-up, d/c discontinue, mo months, d days, NM not mentioned

aMost patients had been previously treated with other medications before MMF was started

bDuration on medication included the time period on medication prior to the start of follow-up to this paper

Table 4

Intravenous immunoglobulin

Author/year	Type of study	N M/F	Age range/mean (years)	Type of pemphigus vulgaris	Previous Rx	Duration of disease before IVIg	IVIg dose
	1	2	3	4	5	6	7
Bystryn et al. [66]/2002	Case series	N = 6  M/F = 5/1	57–78	Mucocutaneous = 1; cutaneous = 3; mucosal = 2	Pred	2 mo to 5 years	400 mg/kg/day for 5 days. 1–3 courses
Amagai et al. [67]/2009	Multicenter randomized controlled double-blind trial	N = 40 PV + 21 PF M/F = NM	Mean: placebo grp = 53.1 yrs; 200 mg grp = 57 yrs; 400 mg grp = 50.1 yrs	Mucocutaneous	Pred	Mean 24 mo	IV infusion 200 or 400 mg/kg/day in divided doses over 5 days. IV saline for 5 days in Placebo grp
							Placebo grp	13 pts
							200 mg grp	14 pts
							400 mg grp	13 pts
Stojanovic et al. [68]/2009	Case report	1/F	44	NM	Pred, CyclP	3 years	400 mg/kg/day for 5 days followed by long term single doses of 400 mg/kg every 6 weeks for 1 year
Stojanovic et al. [68]/2009	Case report	1/F	64	NM	Pred, AZA	NM	400 mg/kg/day for 5 days followed by long term single doses of 400 mg/kg every 6 weeks for 6 mo

Pred prednisone, AZA azathioprine, IVIg intravenous immunoglobulin, CyclP cyclophosphamide, CR off complete remission off therapy, CR on complete remission on therapy, PR partial remission, PR on partial remission on therapy, PR off partial remission off therapy, R relapse, NR no response, F/U follow-up, d/c discontinue, mo months, d days, pts patients, NM not mentioned, IIF indirect Immunofluorescence, ELISA Enzyme linked immunosorbent assay, Dsg1 and Dsg3 desmoglein 1 and 3

aDuration on medication included the time period on medication prior to the start of follow-up to this paper

bNot mentioned whether on medication or not

Table 5

Methotrexate

Author/year	Type of study	N M/F	Age range/mean (years)	Type of pemphigus vulgaris	Previous Rx	Duration of disease before MTX	MTX dose
	1	2	3	4	5	6	7
Lever and Goldberg et al. [69]/1969	Case series	N = 5  M/F = 4/1	26–79	Mucocutaneous	Pred	11 mo to 7 years	25–150 mg/week
Jablonska et al. [70]/1970	Case series	N = 10	32–83 (mean = 58.8)	NM	Pred, triamcinolone	NM	25 mg/week
Piamphongsant and sivayathorn et al. [71]/1975	Case series	N = 3	33–48 (Mean = 43.8)	NM	Pred, MTX in 1 pt	NM	12.5–25 mg/week
Lever and Schaumburg-Lever, Lever et al. [72, 73]/1977	Case series	N = 41	20–79 (mean = 51)	Mucocutaneous	None	NM	20–50 mg/week
Mashkilleyson et al. [74]/1988	Case series	N = 53	26–75 (mean = 56)	NM	Pred	NM	25–50 mg/week
Smith and Bystryn et al. [75]/1999	Case series	N = 9 M/F = 8/1	Mean = 59	NM	Pred	NM	12.2 mg/week (13 courses)
Baum et al. [76]b/2012	Retrospective study	N = 30	NM	NM	NM	NM	15 mg/week

Pred prednisone, MTX methotrexate, CR off complete remission off therapy, CR on complete remission on therapy, PR partial remission, PR on partial remission on therapy, PR off partial remission off therapy, R relapse, NR no response, F/U follow-up, d/c discontinue, mo months, d days, pt patient, NM not mentioned, IIF indirect immunofluorescence, Dsg1 and Dsg3 desmoglein 1 and 3

aDuration on medication included the time period on medication prior to the start of follow-up to this paper

bOnly abstract is available for Baum et al. [75]/2012

Table 6

Rituximab

Author/year	Type of study	N M/F	Age range/mean (yrs)	Type of pemphigus vulgaris	Previous Rx	Duration of disease before Rtx	Rituximab dose
	1	2	3	4	5	6	7
Salopek et al. [77]/2002	Case report	1/F	29	Mucocutaneous	Pred, AZA, Pulsed iv CyclP, Pl, IVIg, MMF	9 mo	375 mg/m2 BSA—6 infusions over 8 weeks
Cooper et al. [78]/2002	Case report	1/M	54	Cutaneous	Pred, AZA, MMF, Pl, IVIg, CyclP	20 mo	375 mg/m2 BSAonce weekly for 4 weeks
Espana et al. [79]/2003	Case report	1/M	39	Mucocutaneous	Pred, AZA, Pl, CyclP	NM	375 mg/m2 BSAonce weekly for 4 weeks
Morrison et al. [80]/2004	Case report	1/M	51	Mucocutaneous	Pred, MTX, Dapsone, AZA, minocycline, IVIg MMF, CyclP	56 mo	375 mg/m2 BSAonce weekly for 4 weeks
Morrison et al. [80]/2004	Case report	1/M	37	Cutaneous	CyclP, Pred, Pl, Dapsone, IVIg	70 mo	375 mg/m2 BSAonce weekly for 4 weeks
Morrison et al. [80]/2004	Case report	1/F	47	Mucocutaneous	AZA, MMF, IVIg, CyclP,	30 mo	375 mg/m2 BSA once weekly for 4 weeks
Virgolini Marzocchi [25]/2007	Case report	1/F	53	Cutaneous	Pred, CyclP, MTX	120 mo	375 mg/m2 BSA once weekly for 4 weeks
Wenzel et al. [81]/2004	Case report	1/F	55	Cutaneous	Pred, AZA, CyclP, MTX, MMF, IVIg	156 mo	600 mg (corresponding 375 mg/m2 BSA) once weekly within 5 weeks
Dupuy et al. [82]/2004	Case report	1/F	34	Mucocutaneous	Pred, CyclP	144 mo	(375 mg/m2 BSA once weekly for 4 weeks) ×2 at 6 mo interval
Dupuy et al. [82]/2004	Case report	1/F	42	Mucocutaneous	AZA, MTX, Pred, MMF, IVIg, extracorporeal photopheresis cyclosporine	60 mo	(375 mg/m2 BSA once weekly for 4 weeks) ×2 at 6 mo interval
Dupuy et al. [82]/2004	Case report	1/M	20	Cutaneous	Pred, dapsone, gold compounds, MMF, IVIg, Pl	24 mo	375 mg/m2 BSA once weekly for 4 weeks
Kong et al. [83]/2005	Case report	1/F	17	Mucocutaneous	Pred, AZA, MMF, MP, IVIg, Pl	84 mo	375 mg/m2 BSA once weekly for 4 weeks
Arin et al. [34]/2005	Case report	1/F	60	Mucocutaneous	Pred, MMF, AZA	8 years	375 mg/m2 BSA once weekly for 4 weeks
Arin et al. [34]/2005	Case report	1/F	26	Mucocutaneous	Pred, MMF, AZA, MTX	3 years	375 mg/m2 BSA once weekly for 4 weeks
Arin et al. [34]/2005	Case report	1/F	27	Mucocutaneous	Pred, MMF, AZA, MTX	3 years	375 mg/m2 BSA once weekly for 4 weeks
Arin et al. [34]/2005	Case report	1/F	57	Mucocutaneous	Pred, MMF, AZA	14 years	375 mg/m2 BSA once weekly for 4 weeks
Schmidt et al. [84]/2005	Case report	1/M	14	Mucocutaneous	Pred, AZA. Dapsone, MMF, CyclP, staphyloccocal protein A immunoadsorption	2.5 years	375 mg/m2 BSA once weekly for 4 weeks
Schmidt et al. [85]/2006	Case report	1/F	17	Mucocutaneous	Pred, IVIg, AZA, MMF, MTX	30 mo	375 mg/m2 BSA once weekly for 4 weeks
Schmidt et al. [85]/2006	Case report	1/F	39	Mucocutaneous	Pred, IVIg, AZA	79 mo	375 mg/m2 BSA once weekly for 4 weeks
Schmidt et al. [85]/2006	Case report	1/F	68	Mucocutaneous	Pred, IVIg, MMF, dexamethasone-cyclP pulse	64 mo	375 mg/m2 BSA once weekly for 4 weeks
Schmidt et al. [85]/2006	Case report	1/F	81	Mucocutaneous	Dexamethasone-cyclP pulse	7 mo	375 mg/m2 BSA once weekly for 4 weeks
Ahmed et al. [86]/2006	Case series	N = 11 M/F = 5/6	15–68	Mucocutaneous	Pred, MMF, AZA, MTX, Dapsone, Gold,CyclP,Cyclosporine, colchine, tacrolimus	31–219 mo (mean = 68.8 mo)	375 mg/m2 BSA once weekly for 3 weeks; fourth week—IVIg; 10 infusions of Rtx in 9 pts
Goh et al. [87]/2007	Open label pilot study	N = 5  M/F = 3/2	46–62/57	Mucocutaneous	AZA, MMF, IVIg, Pl, iv cyclP, cyclosporine, gold	2–96 mo	375 mg/m2 BSA once weekly for 4 weeks
Marzano et al. [88]/2007	Case series	N = 3  M/F = 2/1	Pt1: 51 Pt2: 50 Pt3: 55	Mucocutaneous	AZA, MMF, IVIg, Pred, CyclP	Pt 1: 6 years; Pt 2: 5 years; Pt 3: 4 years	375 mg/m2 BSA once weekly for 4 weeks; 2 more infusions for pt 3 (one each mo)
Antonucci et al. [89]/2007	Case series	N = 5  M/F = 4/1	28–35	Mucocutaneous = 2 Cutaneous = 3	AZA, MMF, IVIg, Pred, CyclP, MTX Pl, Cyclosporine	3–7 years	375 mg/m2 BSA once weekly for 4 weeks
Cianchini et al. [90]/2007	Case series	N = 10  M/F = 5/5	27–63	Mucocutaneous	Pred, AZA, MMF, Pl, CyclP, cyclosporine, extracorporeal photopheresis	1–9 years	375 mg/m2 BSA once weekly for 4 weeks. Additional Rtx infusion in only one patient
Joly et al. [91]/2007	Case series	N = 14  M/F = NM	Mean = 53.7	Mucocutaneous	Pred, IVIg, AZA, MTX, MMF, cyclosporine	4–168 mo (mean = 70.2 mo)	375 mg/m2 BSA once weekly for 4 weeks
Shimanovich et al. [92]/2007	Case series	N = 5  M/F = 1/4	37–71	Mucocutaneous	Pred, AZA, MMF, Pl, MTX, cyclosporine, Cyclp dexamethasone, dapsone	3–76 mo	375 mg/m2 BSA once weekly for 4 weeks
Eming et al. [93]/2008	Case series	N = 11  M/F = 5/6	37–70/52.1	Mucocutaneous = 7, mucosal = 2; cutaneous = 2	Ped, AZA, MMF	NM	375 mg/m2 BSA once weekly for 4 weeks
Faurschou and Gniadecki [94]/2008	Case report	1/M	68	Mucocutaneous	Pred, MMF, IVIg	3 years	(375 mg/m2 BSA once weekly for 4 weeks) ×2 at 6 mo interval
Faurschou and Gniadecki [94]/2008	Case report	1/F	46	Mucosal	Pred, MTX, MMF, IVIg	NM	(375 mg/m2 BSA once weekly for 4 weeks) × 2 at 6 mo interval
Pfutze et al. [95]/2009	Case series	N = 5  M/F = 2/3	Mean = 55	Mucosal dominant	CS, MMF	NM	375 mg/m2 BSA once weekly for 4 weeks
Fuertes et al. [96]/2010	Case report	1/M	1.5	Mucocutaneous	Pred, AZA, Cyclosporine, Dapsone, Gold	Newly diagnosed	Mucocutaneous
Kasperkiewicz et al. [97]/2011	Pilot study	N = 17  M/F = 8/9	38–75/mean = 55	Mucocutaneous = 7; mucosal = 6; cutaneous = 4	AZA, cyclosporine, CyclP, MTX, MMF, dapsone, IVIg, PAIA, Pl, Pred, dexamethasone, hydroxychlorquine	3–144 mo	Two infusions of 1000 mg 2 wks apart. Additional Rtx cycle in 2 pts
Craythorne et al. [98]/2011	Case series	N = 6  M/F = 3/3	45–71	Mucocutaneous	Pred, AZA, MMF, cyclosporine	0–13 years	375 mg/m2 BSA once weekly for 8 weeks then monthly ranging from 4 to 10 mo in all pts
Kasperkiewicz et al. [99]/2011	Case series	N = 8  M/F = 4/4	43–65	Cutaneous = 1; Mucosal = 7	AZA, MMF, Pred, dapsone, cyclosporine, dexamethasone	3–72 mo	375 mg/m2 BSA once weekly for 4 weeks = 3 pts; 1000 mg twice 2 wks apart = 5
Kim et al. [100]/2011	Retrospective study	N = 25 PV + 2 PF M/F = 12/13	24–83	Mucocutaneous = 20; cutaneous = 3; mucosal = 2	AZA, MMF, IVIg, CyclP, steroid pulse therapy, cyclosporine	12–15.5 mo	(375 mg/m2 BSA once weekly)
							2 wks	11 pts
							3 wks	11 pts
							4 wks	1 pt
							5 wks	2 pts
Reguiai et al. [101]/2011	Case series	N = 9  M/F = 3/6	14–61	Mucocutaneous	Pred, IVIg, AZA, MMF	NM	375 mg/m2 BSA once weekly for 4 weeks
Horvath et al. [102]/2011	Case series	N = 12  M/F = 8/4	34–80	Mucocutaneous	AZA, Pred, MMF, dapsone, doxyycline, CyclP, IVIg, dexamethasone, nicotinic acid, mycophenolic acid	2–12 years	Two Rtx infusions of 500 mg at interval of 2 weeks in 10 pts and at an interval of 4 and 3 weeks in 2 pts
Feldman et al. [103]/2011	Retrospective analysis	N = 19  M/F = 14/5	Mean = 52	Mucocutaneous = 14; mucosal only = 5	Pred with or without immunosuppressive agent	NM	375 mg/m2 BSA once weekly—12 infusions over 6 mo period
Leshem et al. [104]/2012	Case series	N = 42 PV + 3 PF	18–83	Mucosal only = 40	Pred, MTX, AZA, IVIg, Dapsone, Rtx (lymphoma protocol), CyclP	0–163 mo (mean = 25 mo)	Two infusions of 1000 mg 2 wks apart
Cianchini et al. [37]/2012	Case series	N = 37 PV + 5 PF M/F = 13/29	27–75	Mucous or mucocutaneous involvement. No’s NM	Pred, immunosuppressants	1–13 years; (mean = 4.2 years)	Two infusions of 1000 mg 2 wks apart. Additional 500 mg Rtx infusion on PR or no response 6 mo after initial infusion
Lunardon et al. [105]/2012	Case series	N = 24  M/F = 13/11	26–86/50	Mucocutaneous	Pred, AZA, MMF, Dapsone, CyclP, IVIg, Cyclosporine	3–234 mo (mean = 41 mo)	(375 mg/m2 BSA once weekly for 4 weeks) ×13 pts. (Two infusions of 1000 mg 2 wks apart) × 11 pts. 1 Rtx cycle = 6 pts 2 Rtx cycle = 8 pts 3 Rtx cycle = 7 pts 4 Rtx cycle = 2 pts 6 Rtx cycle = 1 pt
Kasperkiewicz and Eming et al. [106]/2012	Case series	N = 33 PV + 3 PF M/F = 16/20	15–76/52	Mucosal = 29	Pred, AZA, MMF, Pl, MTX,PAIA, IVIg, CyclP, chloroquine, leflunomide	0.1–16 years (mean = 4)	4 × 375 mg/m2 = 9 pts. 2 × 1000 mg = 25 pts. Two cycles of 4 × 375 mg/m2 = 1 pt. 7 × 375 mg/m2 = 1 pt
Balighi et al. [107]/2013	Phase 2 clinical trial	N = 40  M/F = 33/7	40–50	Mucocutaneous	Pred, AZA, MMF, Dapsone, IVIg, CyclP	Mean = 35 ± 32 mo	375 mg/m2 BSA once weekly for 4 weeks
Kanwar et al. [108]/2013	Open label pilot study	N = 9  M/F = 5/4	9–60	Mucocutaneous	Pred, AZA, dapsone, dexamethasone pulse	4–72 mo (mean = 18 mo)	375 mg/m2 BSA once weekly for 4 weeks = 1 pt; Two infusions of 1000 mg 2 wks apart = 7 pts; 1 × 1000 mg + 1 × 140 mg = 1 pt
Kolesnik et al. [109]/2014	Case series	N = 6  M/F = 3/3	48–81	Mucocutaneous	Pred, AZA, MMF, Dapsone, PAIA, Rtx in 1 pt	1–240 mo	375 mg/m2 BSA once weekly for 3 to 6 weeks in combination with PAIA
Heelan et al. [35]/2014	Case series	N = 84 PV + 8 PF M/F = 37/55	13–77/43	Mucocutaneous = 61, mucosal = 20, cutaneous = 11	Pred, AZA, MMF, IVIg, MTX, dapsone, CyclP, gold, cyclosporine, cyclosporine, mycophenolate sodium	0–256 (mean = 24 mo)	Two infusions of 1000 mg 2 wks apart; 1000 or 500 mg 6 mo or more after induction if required
Kanwar et al. [110]/2014	Randomized, comparative, observer-blinded study	N = 15  M/F = 8/7	Mean = 33 years	Mucocutaneous	Dexamethasone pulse therapy, AZA, Pred, IVIg, MMF	0.3–6 years	High dose grp: Two infusions of 1000 mg 2 wks apart = 7 pts; Low dose grp: Two infusions of 500 mg 2 wks apart = 8 pts
Ojami et al. [111]/2014	Case series	N = 14  M/F = 7/7	30–75 (mean = 54.3)	Mucosal = 14;	MMF, AZA, Pred	NM	Two infusions of 1000 mg 2 wks apart; 375 mg/m2 BSA once weekly for 4 weeks

Rtx rituximab, Pred prednisone, AZA azathioprine, IVIg intravenous immunoglobulin, CyclP cyclophosphamide, Pl plasmapheresis, MTX methotrexate, CR off complete remission off therapy, CR on complete remission on therapy, PR partial remission, PR on partial remission on therapy, PR off partial remission off therapy, CI (PR) clinical Improvement (PR) on doses greater than minimal therapy, R relapse, NR no response, F/U follow-up, d/c discontinue, mo months, d days, pts patients, NM not mentioned, IIF indirect immunofluorescence, ELISA enzyme linked immunosorbent assay, Dsg1 and Dsg3 desmoglein 1 and 3

aDuration on medication included the time period on medication prior to the start of follow-up to this paper

Death related to PV or drug = 28; Death unrelated to PV = 9

48 survivors. Many d/c therapy and fewer required 15 mg of Pred

1 year

Nine were lost to F/U

CR off = 5; CR on = 22; death = 12, still being treated = 6, lost to follow-up = 3

14/15 pts treated effectively in AZA + Pred grp. No deaths in that grp

Monotherapy grp = mean 19. 2 days;

Pred + AZA grp = mean 58.53 days

24 mo

CR and PR on therapy in mean 119.6 days and off therapy in 234.4 days

CR on = 14; MMF failed in 4 pts of which Rtx given to 2 of which CR on = 1; CR off = 1; referred elsewhere = 2;

Total CR off = 3/18 pts eventually after therapy

Monotherapy: CR on within 144.5 days = 12; CR off within 186.83 days = 6; PR on within 132 days = 2; PR off within 150 days = 3

Combination: CR on within 141.9 days = 13; CR off within 175 days = 7; PR on within 144.5 days = 2; PR off within 129.6 days = 2

IIF: Pt1—1:640 to 1:80 to 1:10 to neg

Pt2—1:40 to 1:10

Pt3—1:40 to 1:10

Pt4—1:20 to 1:40 to 0

Pt5—1:80 to 1:40 to 0 to 1:10

IIF: first course: 1:200 to 0 in 2 mo to 1:500 in 11 mo

second course: 0 in 6 mo

Anti Dsg1: 0–20

Anti Dsg3: 100 to 75 to 100 again

Anti Dsg1: 15 to 0 to 15

Anti Dsg3: 100 to 0

Anti Dsg1: 20 no change

Anti Dsg3: 100 to 75 to 100 again

Anti Dsg1: 200 to 100

Anti Dsg3: 175 to 8

Pt 1: 24 mo;

Pt 2: 21 mo;

Pt 3: 2 mo

Pt 1: CR on;

Pt 2: PR;

Pt 3:MR (minimal response)

Pt 1: R after 12 mo of CR; CR off again after second cycle of Rtx with no relapse

Pt2: CR off in 4 weeks after Rtx therapy Pt3: CR on Pt4: CR off in 12 mo after Rtx therapy Pt5: CR on

CR on within 6 mo after Rtx infusion = 2

CR on within 2 mo after Rtx infusion = 2

CR on within 1 mo after Rtx infusion = 2

CR on within 1 yr after Rtx infusion = 2

PR within 6 mo after Rtx infusion = 2

Anti Dsg1:

Pt1:125-0 in 18 mo Pt2: stable at 0

Pt3: 175-10 in 12 mo

Pt4: 150-0 in 12 mo

Pt5: 200-100 in 12 mo Pt6: 240-140 in 6 mo pt7: 260-75 in 6 mo Pt8: 250-0 in 6 mo Pt9: 210-75 in 6 Pt10: 25-0 in 6 mo Anti Dsg3: Pt1: 290-75 in 18 mo Pt2: 175-0 in 18 mo Pt3: 120-0 in 15 mo Pt4: 140-25 in 15 mo Pt5: 120-25 in 15 mo Pt6: 200-50 in 6 mo Pt7: 150-0 in 6 mo Pt8: 100-25 in 6 mo Pt9: 200-50 in 6 mo Pt10: 140-60 in 6 mo

CR on = 14 PV pts within 3 mo in 12 pts; within 6 mo in 1 pt; within 12 mo in 1 pt

R in 6 pts after a mean of 18.9 mo. CR at end of F/U in 18/21 pts with PV and PF

ELISA: Anti Dsg1: Negative in all 5 pts at end of F/U

Anti Dsg3:

Pt1: 465-neg in 27 mo Pt2: 1179-40 in 30 mo Pt3: 1170-44 in 21 mo Pt4: 257-neg in 13 mo Pt5: 230-23 in 27 mo

Anti Dsg3 IgG:

100 to 25 in 12 mo in 8 CR pts

60 to 25 in 6 mo to 75 in 12 mo in 3 R pts

Anti Dsg1:40 ± 9.5 % to 6.1 ± 11.5 % in 12 mo

Anti Dsg3:44 ± 34.7 % to 8.3 ± 22.1 % in 12 mo

Anti Dsg1: 176.2–18.9

Anti Dsg3: 189.2–66.3

Anti Dsg1: returned to normal in 14/24 pts

Anti Dsg3: returned to normal in 11/32 pts

Initial PR = 21, CR on = 19, R = 21 in mean 8 mo

Final, CR = 40 within mean 10.13 mo (between 0.5 and 23 mo) after start of therapy

ELISA Index values: Anti Dsg1: Pt1: 1372-0.12 Pt2: 327-0.73; Pt3: 34.69- 10.01; Pt3: 32.55-2.2; Pt4: 1517.2-23.05; Pt5: 95.7-0; Pt6: 117.3-14.15.

Anti Dsg3: Pt1:888-42; Pt2: 872-82; pt3: 1162-3; pt4: 124-132; Pt5: 63-0.97; Pt6: 25-0; pt7: 839-138

Anti Dsg1: decreased by 3–85 %

Anti Dsg3: decreased by 0.3–107 %

ELISA Index values: High Dose grp:

Anti Dsg1: 400 to 150 in 48 wks; Anti Dsg3: 90 to 20 in 48 wks

Low dose grp:

Anti Dsg1: 310 to 60 in 48 wks

Anti Dsg3: 180 to 70 in 48 wks

Definitions for some of the terms relating to treatment outcomes listed in the tables are described in a consensus statement published in 2008 [10] as follows:

Complete remission off therapy: Absence of new and/or established lesions while the patient is off all systemic therapy for at least 2 months.

Complete remission on therapy: Absence of new or established lesions while the patient is receiving minimal therapy.

Minimal therapy: Less than, or equal to, 10 mg/day of prednisone (or the equivalent) and/or minimal adjuvant therapy for at least 2 months.

Minimal adjuvant therapy: Half of the dose required to be defined as treatment failure.

Failure of therapy: Failure to control disease activity (i.e., relapse/flare) with full therapeutic doses of systemic treatments.

Partial remission off therapy: Presence of transient new lesions that heal within 1 week without treatment and while the patient is off all systemic therapy for at least 2 months.

Partial remission on minimal therapy: Presence of transient new lesions that heal within 1 week while the patient is receiving minimal therapy, including topical steroids [10].

However not all papers included in this review have described their specific definition for these terms. If these terms were mentioned in the publication, we have listed them in the tables as mentioned in the publication.

This article is based on previously conducted studies and does not involve any studies of human or animal subjects performed by any of the authors.

Results

Corticosteroids (CS)

Since the time of their approval in the 1950s, corticosteroids have been the mainstay of treatment of PV.

Mechanism of Action

Corticosteroids have strong anti-inflammatory and immunosuppressive effects. They affect almost every aspect of the immune system. They are potent inhibitors of NFkappa B activation and have effects on leukocyte movement, leukocyte function, and humoral factors. In addition they have inhibitory effects on many known cytokines [11].

The first case series on corticosteroid use in PV was published in 1972.

The publications reporting use of corticosteroids in PV are summarized in Table 1. This table includes papers that had systemic corticosteroids as the primary medication used. Topical steroids were also used in many of the reports. In addition, adjuvant drugs were added in most cases. These adjuvants included azathioprine, methotrexate, cyclophosphamide, dapsone, gold, levamisole, cyclosporine, and mycophenolate. Adjuvants were usually administered one at a time; however, they were changed when lack of response was noted, and therefore some patients had multiple adjuvants used sequentially over the period of treatment.

Publication Type, Patient Profiles, and Sample Sizes

Seventeen case series were found, with the number of cases included in the individual papers ranging from 4 to 1111 cases (a total of 1704 patients were included in the 17 case series, of which 1681 had PV and 23 had either pemphigus foliaceous, pemphigus vegetans, or pemphigus erythematous). Six case reports describing single patients, one prospective cohort study (n = 74), two randomized controlled trials (n = 20 and n = 120), and five retrospective cohort studies (n = 15, n = 16, n = 23, n = 32, and n = 154) are summarized in the Table 1. In all, the total number of cases in these 31 publications was 2164 out of which 2141 were PV patients, and the rest had pemphigus foliaceous or pemphigus vegetans or pemphigus erythematous. These 31 reports originated from the USA, Israel, Iran, Sri Lanka, India, Scotland, Italy, Greece, Spain, the Netherlands, Germany, France, Singapore and Turkey.

Age at initial diagnosis of PV in these publications ranged from 4 to 89 years.

Medication Use

Prednisone and prednisolone were the most commonly used corticosteroids. Starting doses ranged from 15 to 180 mg prednisone equivalent daily in all but one of the reports where doses as high as 400 mg daily were used [12, 13].

Duration of PV Before Corticosteroids Were Started

This ranged from 0.15 months to 6 years.

Duration of Total Follow-up

Duration of total clinical follow-up of the individual patients ranged from 9 months to 22 years.

Duration Before Any Clinical Improvement Was Noted

Seven publications reported on the duration before any clinical improvement after the start of corticosteroids was apparent, and this ranged from 3 days to 19 weeks [14-20].

Duration to Start of Taper of Corticosteroids

Information regarding tapering of corticosteroids was reported in seven publications. The duration before the start of taper of corticosteroids ranged from 0.5 to 12 months in these seven publications comprising of 156 patients.

Duration to Complete Remission (On and Off Therapy)

Duration to complete remission on therapy was reported in 15 articles, and ranged from 1.5 to 42 months (3.5 years), in 797 patients.

Duration to complete remission off therapy was reported in 15 articles, and ranged from 4 to 120 months (10 years) in 321 patients.

Remission

Of a total of 2141 patients reported on in Table 1, at the end of follow-up 97 patients had achieved partial remission on therapy, 797 patients had achieved complete remission on therapy, and 321 patients had achieved complete remission off therapy. A total of 485 patients were still being treated at the time of publication, 156 patients were lost to follow-up, death occurred in 177 patients, and 47 patients were classified as non-responders and referred elsewhere for treatment.

Duration of Medication Use

Total duration of medication use for all reported patients including those still on therapy at the time of publication ranged from 1.5 to 240 months (20 years).

Follow-up Duration After Discontinuation of Medications

Follow-up ranged from 2 to 156 months (13 years) after discontinuation of treatment in the 321 patients with complete remission off therapy, during which time there was no recurrence.

Mortality

Death occurred in a total of 177 of 2141 patients (8.26 %) with PV in all reports. These included deaths from all causes. Of these, the reports published between 1970 and 1980 included 127 patients with 61 deaths (48.03 %), between 1981 and 1990 included 183 patients with 26 deaths (14.2 %), between 1991 and 2000 included 190 patients with 7 deaths (3.6 %), and those published between 2001 and 2010 included 1589 patients with 83 deaths (5.2 %).

Adverse Effects

Adverse effects from corticosteroids reported in these papers included Cushingoid symptoms, diabetes mellitus, osteoporosis, hypertension, insomnia, GI upset, increased weight, candidiasis, tuberculosis, mood change, abnormal liver function test, fungal and viral infection, fatigue, acute psychosis, hyperglycemia, electrolyte imbalance, hypocalcemia, acidosis, hyperkalemia, phlebitis, herpes simplex, hyperlipidemia, bone marrow depression, cataract, and myopathy.

Azathioprine (AZA)

Azathioprine was approved by the US Food and Drug Administration (FDA) in 1968 as an immunosuppressant to prevent organ transplant rejection.

This drug restricts synthesis of DNA, RNA, and proteins by inhibiting metabolism of purine. It also interferes with cellular metabolism and mitosis [8].

The studies reporting use of AZA in PV are summarized in Tables 1 and 2. Of the 31 papers in Table 1, 17 had included azathioprine as one of the treatment modalities. Table 2 includes only those publications that reported on comparative analyses of outcomes for patients on prednisone alone vs. those on prednisone in combination with azathioprine. The first case series on use of AZA in PV was published in 1986.

One randomized double blind controlled study (n = 56) and two retrospective cohort studies (n = 48 and n = 36) are summarized in Table 2. In all, a total of 140 patients were included in these three reports.

Age at initial diagnosis of PV in these publications ranged from 16 to 83 years.

The dosage of azathioprine used was 40 mg/day up to 3 mg/kg/day in all reports. Prednisone was used concomitantly with azathioprine in all reports. Azathioprine was added at the onset of treatment in the three reports in Table 2 and sometime after onset of corticosteroid use in the reports in Table 1.

Duration of PV Before Azathioprine Was Started in the Reports Summarized in Table 2

This ranged from 4 to 10 months.

Duration of Follow-up in the Reports Summarized in Table 2

Duration of clinical follow-up of the individual patients on azathioprine in these reports ranged from 12 months to 10 years.

Duration to Complete Remission (On and Off therapy) for the Azathioprine Plus Prednisone Group in Table 2

Duration to complete remission on therapy was reported in three articles and, ranged from 6 to 12 months, in 67 patients.

Duration to complete remission off therapy was reported in two articles and, ranged from 6 to 12 months, in eight patients.

Patients on prednisone and azathioprine had better responses as compared to patients on prednisone alone, with more patients achieving remission, and with fewer side effects.

Of a total of 140 patients, at the end of follow-up 11 patients had achieved partial remission and mean duration to achieve that was 234.4 days, 67 patients had achieved complete remission on therapy, and eight patients had achieved complete remission off therapy. Six patients were still being treated at the time of publication. No response was seen in 17 patients. Treatment failed in five patients. Death occurred in 13 patients and 13 patients were lost to follow-up.

Adverse Effects Reported in Table 2

Adverse effects in patients on azathioprine and corticosteroids reported in these publications included leukopenia, anemia, thrombocytopenia, pancytopenia, hepatotoxicity, hypertension, gastrointestinal problems, lethargy, weight gain, muscle weakness, adrenal suppression, alopecia, and rash-like skin disorders.

Mycophenolate Mofetil (MMF)

Mycophenolate Mofetil was approved by the FDA in 1995 as an immunosuppressant to prevent organ transplant rejection.

After oral administration, mycophenolate is absorbed rapidly and then gets converted to the active metabolite mycophenolic acid (MPA). This active metabolite inhibits inosine monophosphate dehydrogenase selectively and hence inhibits de novo pathway of purine synthesis in T and B cells, which results in inhibition of T and B cell proliferation [20].

Publications reporting use of MMF as an adjuvant to corticosteroids in PV were included in Table 1. Additional papers which have reported on the use of mycophenolate in patients with refractory PV (previous treatment with corticosteroids and azathioprine was unsuccessful in achieving remission) are summarized in Table 3. Of 31 papers in Table 1, three had included MMF as one of the treatment modalities.

The first case series on use of MMF in PV patients was published in 1999.

Four case series were included, with the number of cases included in the individual papers ranging from 9 to 31 cases (a total of 64 patients in four case series); two were case reports describing single patients and two were randomized prospective trials (n = 94 and n = 21, respectively). One additional randomized clinical trial enrolled both PV and PF patients [n = 36 (PV) + 11 (PF); results were not reported separately for the PV and PF patients in this study] and one retrospective analysis (n = 18) is summarized in the tables. The total number of patients treated with MMF in these 10 reports was 247.

Age at initial diagnosis of PV in these publications ranged from 6 to 78 years.

Medication Use and Duration of PV Before MMF Was Started

Medication use and duration of PV before MMF was started ranged from 1 month to 14 years. During this period patients were on a combination of corticosteroids and azathioprine. At the time mycophenolate was added, the azathioprine was discontinued; however, the patients continued to be on corticosteroids. One publication (Powell et al.) reported on patients in whom multiple medications like methotrexate, cyclophosphamide, IVIg, dapsone, gold, thalidomide, and minocycline along with azathioprine and corticosteroids were tried prior to addition of mycophenolate [21].

The starting dosage of mycophenolate mofetil used was 2–3 g/day in all reports.

Duration of Follow-up

Duration of clinical follow-up of the individual patients after the start of MMF therapy ranged from 5 to 130 months.

First improvement in lesions was noted after 2–24 weeks after addition of mycophenolate to the existing medication regimen.

Duration to Complete Remission (On and Off Therapy) After Addition of MMF

Duration to complete remission on therapy was reported in six articles and, ranged from 2 to 16 months, in 104 patients.

Duration to complete remission off therapy was reported in one article and, ranged from 24 to 36 months, in 17 patients.

Of a total of 247 patients, 104 patients achieved complete remission on therapy and 17 patients achieved complete remission off therapy. A total of 76 patients achieved partial remission, and the duration to achieve that ranged from 129 to 150 days after the start of therapy. Failure of MMF was mentioned in four reports (N = 176) in 18 patients who were referred for treatment with rituximab or IVIg. Two patients were still being treated at the time of publication, 29 patients were lost to follow-up or withdrawn from study, and death occurred in one patient.

Adverse effects in patients on mycophenolate and corticosteroids reported in these publications included gastrointestinal problems, myalgia, neutropenia, and lymphopenia, which were the most common side effects reported. Headache, increased fasting blood glucose level, and hypertension, nausea, depression, pyrexia, redistribution of body fat, eye disease, weight gain, fatigue, and arthralgia were also reported.

In the one publication where enteric coated mycophenolate sodium was used, the side effects reported were headache and increased fasting blood glucose level.

Intravenous Immunoglobulin (IVIg)

IVIg was approved by the FDA for primary immune deficiency in 1952 [22].

Intravenous immunoglobulins (IVIg) are obtained from a plasma pool of thousands of donors [22].

These immunoglobulins neutralize and slow down the production of circulating pemphigus antibodies [23].

The studies reporting use of IVIg in PV are summarized in Table 4. The first case series on IVIg in PV was published in 2002.

One case series (n = 6), two case reports describing single patients, and one randomized placebo-controlled double-blind trial (n = 40) are summarized in Table 4, with a total of 48 patients included in these four papers. These reports included patients previously treated with corticosteroids, cyclophosphamide, azathioprine, and methotrexate without adequate response, prior to start of IVIg.

Age at initial diagnosis of PV in these publications ranged from 41 to 78 years.

The dosage of IVIg used was 400 mg/kg/day for 5 days followed by long- or short-term single doses of 400 mg/kg/day every 6 weeks for 6 months to 1 year. Concomitant drugs mainly used were corticosteroids in the published studies.

Duration of PV Before IVIg Was Started

This ranged from 2 months to 5 years.

Duration of total clinical follow-up of the individual patients ranged from 2 months to 2 years.

First improvement in lesions was reported within 2–3 weeks of first IVIg infusion in all 48 patients.

Only one case series of six patients described the duration to the start of taper of corticosteroids and only mentioned that the median time was 16 days after the start of IVIg infusions.

This information was not available from the publications. However, all reports discussed improvement in all patients treated with IVIg; in six patients this was achieved within 3 weeks and in 29 patients within 3–12 months. Thirteen patients in the placebo group had no improvement.

Adverse Effects in Patients on IVIg Reported in Table 4

Headache, abdominal discomfort, nausea, constipation, lymphopenia, hepatitis C, and palpitations.

Methotrexate

Methotrexate was approved by the FDA for psoriasis in 1971 and for rheumatoid arthritis in 1988.

Methotrexate inhibits the metabolism of folic acid and is used as a chemotherapeutic and immunosuppressive agent. Methotrexate allosterically inhibits dihydrofolate reductase, which plays a role in tetrahydrofolate synthesis. As folic acid is essential for normal cell growth and replication, methotrexate is effective against malignant cell growth and has anti-inflammatory effects [24].

The studies reporting use of methotrexate in PV are summarized in Table 5. The first case series on MTX in PV was published in 1969.

Publications reporting use of methotrexate in PV were included in Table 1 (7 of 31 papers included methotrexate), and additional papers that reported on the use of methotrexate as the initial adjunctive treatment to corticosteroids are summarized in Table 5.

Six case series were included, with the number of cases included in the individual papers ranging from 3 to 53 cases (total of 121 patients in six case series), and one retrospective cohort study (n = 30) are summarized in the tables. In all, a total of 151 patients treated with MTX are reported in seven studies.

Age at initial diagnosis of PV in these publications ranged from 20 to 83 years.

The dosage of MTX used in these publications ranged from 12.5 to 150 mg/week. Concomitant drug used along with methotrexate was prednisone.

Duration of PV Before Methotrexate Was Started

This ranged from 11 months to 7 years.

Duration of clinical follow-up of the individual patients after the start of MTX ranged from 5 to 15 years.

First improvement in lesions was reported within 1–30 weeks after the start of methotrexate therapy.

Duration to complete remission on therapy was reported in six articles and, ranged from 1 to 30 weeks, in 51 patients.

Duration to complete remission off therapy was reported in one article and, ranged from 3 months to 8 years, in 14 patients.

Of a total of 151 patients, at the end of follow-up, 56 patients had achieved partial remission and the duration to achieve that was within 6 months after the start of MTX therapy; 51 patients had achieved complete remission on therapy; and 14 patients had achieved complete remission off therapy. Twelve patients were lost to follow-up. Treatment was not effective in nine patients. Death unrelated to MTX occurred in six patients.

Adverse Effects in Patients on MTX Reported in Table 5

Nausea, leukopenia, GI upset, fatigue, bacterial infection, bronchopneumonia, septicemia, necrotizing gingivitis, diarrhea, and pyoderma.

Rituximab

Rituximab was approved in 1997 by the FDA to treat B cell non-Hodgkin lymphoma and in 2006 to treat rheumatoid arthritis.

Rituximab is a human–mouse chimeric monoclonal antibody to CD20 antigen on B cells. CD20 is a membrane protein that is involved in activation and proliferation of B cell [25].

The studies reporting use of rituximab in PV are summarized in Table 6. The first case series on PV treated by rituximab was published in 2002.

Publications which have reported on the use of rituximab in patients with refractory PV (previous treatment with corticosteroids, azathioprine, methotrexate, mycophenolate, IVIg, and cyclophosphamide were unsuccessful in achieving remission) are summarized in Table 6.

Nineteen case series were included, with the number of cases included in the individual papers ranging from 3 to 84 cases (total of 339 patients in 19 case series), 24 were case reports describing single patients, three open label pilot studies (n = 5, n = 9, and n = 17), one randomized prospective trial (n = 15), two retrospective analysis (n = 25 and n = 19), and one phase 2 clinical trial (n = 40) are summarized in the tables. In all, a total of 493 patients were treated with rituximab.

Age of patients treated with rituximab for PV in these publications ranged from 15 to 86.

The dosage of rituximab used was 375 mg/m2 body surface area (BSA) once weekly for 4 weeks or two infusions of 1000 mg at 2 weeks apart. Previously failed treatments before rituximab were prednisone, MMF, AZA, IVIg, MTX, dapsone, CyclP, plasmapheresis, protein A immunoadsorption, cyclosporine, dexamethasone, and gold. Concomitant drug used was prednisone, MMF, AZA, and IVIg.

Duration of PV Before Rituximab Was Started

This ranged from 1 months to 23 years.

Duration of clinical follow-up of the individual patients after the start of rituximab therapy ranged from 6 to 80 months.

First improvement in lesions was reported within 2 weeks to 8 months after the first rituximab infusion.

Duration to complete remission on therapy was reported in 32 articles and, ranged from 1 to 36 months, in 184 patients.

Duration to complete remission off therapy was reported in 22 articles and, ranged from 2 to 59 months, in 229 patients.

Of a total of 493 patients reported in Table 6, at the end of follow-up, 80 patients had achieved partial remission, and duration to achieve that ranged from 3 to 27 months; 184 patients achieved complete remission on therapy; and 229 patients achieved complete remission off therapy. Death due to sepsis occurred in three patients. Relapses were seen in nine patients. No response to rituximab was seen in 11 patients. However, these patients had response after addition of IVIg or additional cycles of rituximab.

Adverse Effects in Patients on Rituximab Reported in Table 6

Local pain, nausea, cough, chills, sepsis, and angioedema related to infusion.

Other Medications

Other Less Commonly Used Adjuvants from Studies Listed in Table 1

Gold salts These are widely used in treatment of rheumatoid arthritis. Their action is related to their T cell-mediated immunosuppressive properties [23].

Plasmapheresis This is used for removing antibodies from the circulation. Reduction in antibodies triggers production of new antibodies as a result of a feedback mechanism [23].

Immunoadsorption With plasmapheresis protective immunoglobulins, albumin, and clotting factors are removed along with harmful pemphigus antibodies. Immunoadsorption selectively traps the harmful pemphigus antibodies through the sulfhydryl filtering membrane. Thus, protective antibodies and plasma components are returned [23].

Cyclophosphamide It has been widely used in the treatment of cancer and also as an immunosuppressant. This drug is converted in the liver to its active metabolites aldophosphamide and phosphoramide mustard. These bind to DNA and inhibit its replication, which leads to cell death. It can be given orally as well as intravenously. One report described cyclophosphamide use in seven patients for treating PV in combination with corticosteroids and azathioprine [26].

Nicotinamide and tetracycline These were used as steroid-sparing agent in combination with corticosteroids and azathioprine in one study of six patients with PV. Their mechanism of action is unclear [27].

Discussion

In this paper, we have summarized the published literature on the management of PV. The published papers were mostly case reports, case series, observational studies, and only eight randomized controlled trials.

As a result of the relative rarity of pemphigus, published randomized trials are limited, which makes it difficult to evaluate the efficacy of different treatment regimens in this disease. This also precludes conduct of a meta-analysis. A Cochrane review published in 2009 concluded that “there is inadequate information available at present to ascertain the optimal therapy for pemphigus vulgaris” [28]. While this remains the case, a summary of the literature provides information on disease course and prognosis as well as medication options, treatment responses, and side effects, which are of relevance to clinicians who treat this disease and patients who suffer from it.

The treatment options for PV have increased over the years. The early publications from the 1970s reported use of high corticosteroid doses over prolonged intervals and significant associated side effects. Later reports on PV management described use of corticosteroids along with steroid-sparing adjuvants, which allows a reduction in the total dose of corticosteroids used over the course of the treatment with a reduction in observed morbidity. The more commonly used steroid-sparing medications in the published reports include azathioprine, methotrexate, and mycophenolate mofetil. More recently, IVIg and rituximab have been used, mainly in patients with recalcitrant PV.

Overall, the mortality and morbidity from PV and the medications used in its treatment are considerably lower in the more recent publications than in the early reports.

The reported treatment response in patients with PV has varied significantly. Prognostic factors that have been identified include initial severity and extent of disease, with higher severity being predictive of poorer prognosis. [29]. Perhaps related to this is the fact that early initiation of treatment before the disease becomes too severe or widespread has been associated with improved prognosis [30, 31]. Once treatment is initiated, good initial response to treatment has also been found to be indicative of a better prognosis [32].

Most reports described medication courses of long duration before remission off therapy was achieved (between 5 and 10 years in the majority of patients with the range across all studies being 3 months to 27 years). However, Herbst and Bystryn described a group of 40 patients in whom 10 (25 %) patients achieved complete and long-lasting remission within 2 years of treatment; a subgroup of patients with PV, with a mild course of the disease requiring short courses of systemic medications or topical medication alone to induce remission [5, 32, 33]; and at the other extreme a subgroup that is resistant to treatment and required high doses and prolonged therapy have also been described [29, 32, 35].

The role of baseline laboratory tests, such as quantification of antibodies as predictors of disease course, has not been established. A recent study reported that a higher level of anti-Dsg1 autoantibodies (≥100 U/mL) at diagnosis was associated with poorer prognosis in univariate analyses; however, this did not remain significant after adjustment for age [36].

Periodic antibody titers measured by indirect immunofluorescence or ELISA testing have not consistently shown correlation with clinical activity of PV [37]. Most authors in the listed papers reported using clinical response alone to guide medication taper.

Reports using rituximab described remission off therapy in a shorter time frame (ranging from 2 months to 5 years) as compared to other medication combinations; this observation suggested that while the initial side effects may be significant, a shorter total duration of therapy may be possible with use of rituximab. Because rituximab is a more recent drug, first introduced in 1997, long-term side effects are not well characterized at this time.

Conclusion

The findings from this review emphasize the importance of early diagnosis of PV, early initiation of treatment, and use of a treatment regimen which includes a steroid-sparing adjuvant to allow a reduced total dose and duration on corticosteroids. For the majority of patients in these reports, a long-term course on medications lasting about 5–10 years was observed; however, subgroups of patients requiring shorter courses or those needing longer-term therapy were also described. In recent publications, commonly used initial regimens include corticosteroids in combination with mycophenolate or azathioprine; whereas, for patients with inadequate response to these regimens, adjuvants such as IVIG or rituximab were used [21, 38, 39]. This review also highlights the need for more controlled trials to determine optimal treatment regimens for patients with PV.