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Side effects of steroid-sparing agents in patients with bullous pemphigoid and pemphigus: A systematic review

Open AccessPublished:September 01, 2022DOI:https://doi.org/10.1016/j.jdin.2022.07.005

      Background

      Systemic glucocorticoids are first-line treatment options for autoimmune blistering diseases; however, their long-term use is associated with significant toxicities.

      Objective

      To evaluate the side effects of steroid-sparing agents and compare them with those of steroids.

      Methods

      We searched Cochrane Reviews, Embase, MEDLINE, and Scopus between October 1978 and May 2020 using the keywords “bullous pemphigoid,” “pemphigus,” “autoimmune blistering diseases,” and “side effects.” A total of 31 randomized controlled trials and retrospective case series were critically appraised.

      Results

      This review includes a total of 1685 patients with autoimmune blistering diseases, of whom 781 had bullous pemphigoid and 904 had either pemphigus vulgaris or pemphigus foliaceous.

      Limitations

      A major limitation is that because adjuvants are generally used in combination with steroids, only 12 of the studies reviewed included a “steroid-only” arm to allow for a direct comparison of side effects. Additionally, there is inadequate literature and lack of standardized grade reporting of specific side effects of each steroid-sparing agent.

      Conclusion

      In the future, researchers should consider implementing the Common Terminology Criteria for Adverse Events, version 5.0, for reporting of all side effects to allow for consistency and standardization. It would be useful to have an index similar to the Glucocorticoid Toxicity Index to quantify these side effects.

      Key words

      Abbreviations used:

      AE (adverse event), AIBD (autoimmune blistering disease), AZA (azathioprine), BP (bullous pemphigoid), CsA (cyclosporin), CTCAE (Common Terminology Criteria for Adverse Events), GC (glucocorticoid), RCS (retrospective case series), RCT (randomized controlled trial), TPMT (thiopurine methyltransferase)
      • Future researchers should consider implementing the Common Terminology Criteria for Adverse Events, version 5.0, for reporting of all side effects to allow for consistency and standardization.
      • The development of a steroid-sparing agents toxicity index, similar to the Glucocorticoid Toxicity Index, would be useful for quantifying the side effects of steroid-sparing agents, especially given their increasing popularity.

      Introduction

      Autoimmune blistering diseases (AIBDs) are a heterogeneous group of skin diseases that are characterized and caused by autoantibodies targeting adhesion molecules on the skin and/or mucous membranes.
      • Izumi K.
      • Bieber K.
      • Ludwig R.J.
      Current clinical trials in pemphigus and pemphigoid.
      Systemic steroids are the cornerstone of the management of AIBDs and have considerably improved the survival of patients with these diseases.
      • Kirtschig G.
      • Middleton P.
      • Bennett C.
      • Murrell D.F.
      • Wojnarowska F.
      • Khumalo N.P.
      Interventions for bullous pemphigoid.
      ,
      • Meurer M.
      Immunosuppressive therapy for autoimmune bullous diseases.
      However, long-term and high-dose treatment with systemic glucocorticoids (GCs) carries the risk of significant side effects, which contribute to morbidity and mortality in patients with AIBDs.
      • Bilgic A.
      • Murrell D.F.
      The toxicity of glucocorticosteroids in autoimmune blister disease.
      Therefore, a major goal of the management of AIBDs is to reduce the patient’s cumulative exposure to systemic steroids with the use of adjuvant steroid-sparing agents.
      • Izumi K.
      • Bieber K.
      • Ludwig R.J.
      Current clinical trials in pemphigus and pemphigoid.
      ,
      • Bilgic A.
      • Murrell D.F.
      The toxicity of glucocorticosteroids in autoimmune blister disease.
      ,
      • Bertani N.
      • Joly P.
      • Golinski M.L.
      • et al.
      B-cell depletion induces a shift in self antigen specific B-cell repertoire and cytokine patterns in patients bullous pemphigoid.
      This review focuses on the treatment of bullous pemphigoid (BP) and pemphigus. Given that pharmacologic side effects are crucial limitations while treating diseases, the objective is to assess the side effect profiles of steroid-sparing adjuvant therapies.

      Guidelines for therapeutic use of steroid-sparing adjuvant therapies

      The primary treatment option for AIBDs is GCs, as mentioned above. Adjuvant agents are primarily used to reduce a patient’s total, cumulative GC dosage and are also considered in circumstances in which monotherapy with GCs is inadequate to induce remission of the disease or when there is relapse during a dose-reduction period of GCs.
      • Feliciani C.
      • Joly P.
      • Jonkman M.F.
      • et al.
      Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology.
      ,
      • Joly P.
      • Roujeau J.C.
      • Benichou J.
      • et al.
      A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.
      The choice of adjuvant treatment is largely dependent on the availability, price, and practical experience of the treating dermatologist as well as the presence of specific contraindications. The use of an immunosuppressive or immunomodulatory agent with potentially GC-sparing ability should be considered, especially when a high, cumulative GC dosage is anticipated or when there are contraindications to oral steroids and comorbidities such as hypertension, diabetes mellitus, osteoporosis, and psychosis.

      Bullous Pemphigoid

      The recommendations for the choice of adjuvant drug and its dosage can be classified into 2 groups based on the clinical presentation of BP: extensive BP or localized and mild BP.
      • Feliciani C.
      • Joly P.
      • Jonkman M.F.
      • et al.
      Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology.
      According to the 2015 consensus by the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology, steroids are first-line treatment options, followed by steroids in combination with any 1 of the adjuvant agents listed below as second-line treatment options.
      • Feliciani C.
      • Joly P.
      • Jonkman M.F.
      • et al.
      Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology.
      For extensive BP, the adjuvant agents are as follows:
      • 1.
        Doxycycline alone or in combination with daily oral nicotinamide
        • Fivenson D.P.
        • Breneman D.L.
        • Rosen G.B.
        • Hersh C.S.
        • Cardone S.
        • Mutasim D.
        Nicotinamide and tetracycline therapy of bullous pemphigoid.
      • 2.
        Azathioprine (AZA) (according to thiopurine methyltransferase [TPMT] activity)
        • Guillaume J.C.
        • Vaillant L.
        • Bernard P.
        • et al.
        Controlled trial of azathioprine and plasma exchange in addition to prednisolone in the treatment of bullous pemphigoid.
        • Beissert S.
        • Werfel T.
        • Frieling U.
        • et al.
        A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid.
        • Bystryn J.C.
        Comparative effectiveness of azathioprine or mycophenolate mofetil as an adjuvant for the treatment of bullous pemphigoid.
      • 3.
        Mycophenolate mofetil or mycophenolic acid
        • Beissert S.
        • Werfel T.
        • Frieling U.
        • et al.
        A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid.
        ,
        • Bystryn J.C.
        Comparative effectiveness of azathioprine or mycophenolate mofetil as an adjuvant for the treatment of bullous pemphigoid.
      • 4.
        Methotrexate
        • Du-Thanh A.
        • Merlet S.
        • Maillard H.
        • et al.
        Combined treatment with low-dose methotrexate and initial short-term superpotent topical steroids in bullous pemphigoid: an open, multicentre, retrospective study.
      • 5.
        Dapsone
        • Bouscarat F.
        • Chosidow O.
        • Picard-Dahan C.
        • Sakiz V.
        • Crickx B.
        • Prost C.
        Treatment of bullous pemphigoid with dapsone: a retrospective study of thirty-six cases.
      • 6.
        Cyclosporin
        • Barthelemy H.
        • Thivolet J.
        • Cambazard F.
        • et al.
        Cyclosporin in the treatment of bullous pemphigoid: preliminary study.
      For localized and mild BP, the adjuvant agents include doxycycline and nicotinamide, methotrexate, or dapsone in the same dosages as those for extensive BP.

      Pemphigus

      An international panel of experts has recommended GCs as a first-line treatment option for pemphigus and anti-CD20 monoclonal antibodies, such as rituximab, as a first-line treatment option for new-onset, moderate-to-severe pemphigus and/or in patients who fail to achieve clinical remission with systemic GCs and/or immunosuppressive agents.
      • Murrell D.F.
      • Pena S.
      • Joly P.
      • et al.
      Diagnosis and management of pemphigus: recommendations of an international panel of experts.
      A course of rituximab is given intravenously, either 1000 mg twice (2 weeks apart) or 375 mg/m2 4 times (1 week apart).
      • Murrell D.F.
      • Pena S.
      • Joly P.
      • et al.
      Diagnosis and management of pemphigus: recommendations of an international panel of experts.
      The first-line, corticosteroid-sparing agents are AZA and mycophenolate mofetil. The recommended AZA dosage varies with TPMT activity: patients with high TPMT activity are given a normal AZA dosage of up to 2.5 mg/kg daily, whereas patients with intermediate or low TPMT activity should receive between 0.5 and 1.5 mg/kg/d (patients with no TPMT activity should not be given AZA). The suggested dosage for mycophenolate mofetil is 30 to 45 mg/kg daily,1440 mg daily for mycophenolic acid.
      The International Blistering Diseases Consensus Group has listed intravenous immunoglobulin (2 g/kg over 2-5 days each month), immunoadsorption, and cyclophosphamide as “other” alternative adjuvant agents, which likely collectively refer to second-line treatment and so forth. The latter 2 do not have recommended dosages. Generally, these agents are not favored either because of their poor side effect profile or associated high costs.

      Methods

      The OVID MEDLINE, OVID Embase, Cochrane Reviews, and Scopus databases were searched between October 1978 and May 2020 for “bullous pemphigoid,” “pemphigus,” “autoimmune blistering diseases,” and “side effects.” Retrospective case series (RCS) with a minimum of 5 cases and randomized controlled trials (RCTs) with a minimum population size of 9 patients were screened by 2 investigators (FAPZ, TS). A single reviewer (FAPZ) independently evaluated each retrieved report. A total of 31 RCTs and RCSs were critically evaluated. The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist for abstracts and systematic reviews was used (Supplementary Materials 1 and 2, available via Mendeley at https://data.mendeley.com/datasets/hn4hn9yx4g/1). A flowchart outlining the steps taken, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, to identify studies for review in this article is shown in Fig 1.
      Figure thumbnail gr1
      Fig 1Flowchart illustrating the results of the search strategy. AIBD, Autoimmune blistering disease; BP, bullous pemphigoid.
      The Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, was used to grade adverse events (AEs) recorded in the studies when possible (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/hn4hn9yx4g/1).

      Common terminology criteria for adverse events (CTCAE) version 5.0. National Institutes of Health. Accessed April 2021. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf

      The common side effects of steroids were referenced using the Glucocorticoid Toxicity Index.
      • Miloslavsky E.M.
      • Naden R.P.
      • Bijlsma J.W.
      • et al.
      Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis.
      Tables I
      • Fivenson D.P.
      • Breneman D.L.
      • Rosen G.B.
      • Hersh C.S.
      • Cardone S.
      • Mutasim D.
      Nicotinamide and tetracycline therapy of bullous pemphigoid.
      ,
      • Beissert S.
      • Werfel T.
      • Frieling U.
      • et al.
      A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid.
      ,
      • Du-Thanh A.
      • Merlet S.
      • Maillard H.
      • et al.
      Combined treatment with low-dose methotrexate and initial short-term superpotent topical steroids in bullous pemphigoid: an open, multicentre, retrospective study.
      ,
      • Burton J.L.
      • Harman R.R.
      • Peachey R.D.
      • Warin R.P.
      Azathioprine plus prednisone in the treatment of pemphigoid.
      • Sticherling M.
      • Franke A.
      • Aberer E.
      • et al.
      An open, multicentre, randomized clinical study in patients with bullous pemphigoids comparing methylprednisolone and azathioprine with methylprednisolone and dapsone.
      • Gual A.
      • Iranzo P.
      • Mascaró Jr., J.M.
      Treatment of bullous pemphigoids with low-dose oral cyclophosphamide: a case series of 20 patients.
      • Schmidt E.
      • Kraensel R.
      • Goebeler M.
      • et al.
      Treatment of bullous pemphigoid with dapsone, methylprednisolone, and topical clobetasol propionate: a retrospective study of 62 cases.
      • Amagai M.
      • Ikeda S.
      • Hashimoto T.
      • et al.
      A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.
      • Kjellman P.
      • Eriksson H.
      • Berg P.
      A retrospective analysis of patients with bullous pemphigoids treated with methotrexate.
      • Delaumenie S.
      • Assikar S.
      • Prudhomme R.
      • et al.
      Methotrexate is a safe and efficient long-term treatment for bullous pemphigoid.
      • Polansky M.
      • Eisenstadt R.
      • DeGrazia T.
      • Zhao X.
      • Liu Y.
      • Feldman R.
      Rituximab therapy in patients with bullous pemphigoid: a retrospective study of 20 patients.
      and II
      • Williams H.C.
      • Wojnarowska F.
      • Kirtschig G.
      • et al.
      Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomized controlled trial.
      • Rose E.
      • Wever S.
      • Zilliken D.
      • Linse R.
      • Haustein U.F.
      • Brocker E.B.
      Intravenous dexamethasone-cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus: results of a multicenter, prospectively randomized study.
      • Kakuta R.
      • Yamagami J.
      • Funakoshi T.
      • Takahashi H.
      • Ohyama M.
      • Amagai M.
      Azathioprine monotherapy in autoimmune blistering diseases: a feasible option for mild-to-moderate cases.
      • Dastgheib L.
      • Sadati M.S.
      • Baghernejhad M.
      Assessment of the adjuvant effect of tacrolimus in the management of pemphigus vulgaris: a randomized controlled trial.
      • Chams-Davatchi C.
      • Esmaili N.
      • Daneshpazhooh M.
      • et al.
      Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris.
      • Olszewska M.
      • Kolacinska-Strasz Z.
      • Sulej J.
      • et al.
      Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris.
      • Cummins D.L.
      • Mimouni D.
      • Anhalt G.J.
      • Nousari C.H.
      Oral cyclophosphamide for the treatment of pemphigus vulgaris and foliaceus.
      • Sharma V.K.
      • Khandpur S.
      Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroids in the management of pemphigus vulgaris.
      • Khandpur S.
      • Singh S.
      • Mallick S.
      • et al.
      Urocytological evaluation of pemphigus patients on long-term cyclophosphamide therapy: a cross-sectional study.
      • Ioannides D.
      • Chrysomallis F.
      • Bystryn J.C.
      Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus.
      • Baum S.
      • Debby A.
      • Gilboa S.
      • Trau H.
      • Barzilai A.
      Efficacy of dapsone in the treatment of pemphigus vulgaris: a single-center case study.
      • Werth V.P.
      • Fivenson D.
      • Pandya A.G.
      • et al.
      Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris.
      • Bashir M.M.
      • Sharma M.R.
      • Werth V.P.
      UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription.
      • Beissert S.
      • Mimouni D.
      • Kanwar A.J.
      • Solomons N.
      • Kalia V.
      • Anhalt G.J.
      Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial.
      • Ioannides D.
      • Apalla Z.
      • Lazaridou E.
      • Rigopoulos D.
      Evaluation of mycophenolate mofetil as a steroid-sparing agent in pemphigus: a randomized, prospective study.
      • Baum S.
      • Greenberger S.
      • Samuelov L.
      • et al.
      Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris.
      • Tran K.D.
      • Wolverton J.E.
      • Soter N.A.
      Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients.
      • Chen D.M.
      • Odueyungbo A.
      • Csinady E.
      • et al.
      Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.
      • Kurihara Y.
      • Yamagami J.
      • Funakoshi T.
      • et al.
      Rituximab therapy for refractory autoimmune bullous diseases: a multicenter, open-label, single-arm, phase 1/2 study on 10 Japanese patients.
      • McCarty M.
      • Fivenson D.
      Two decades of using the combination of tetracycline derivatives and niacinamide as steroid-sparing agents in the management of pemphigus: defining a niche for these low toxicity agents.
      illustrate summarized compilations of the RCTs and RCSs carried out to evaluate the adjuvant therapies used in patients with BP and pemphigus, respectively. The confidence of the data presented in this systematic review is ensured based on clear inclusion and exclusion criteria; the search was comprehensive, in that, appropriate databases were used, and there was neither a language bias (no restriction of inclusion based on language) nor restriction of inclusion based on publication status. The included data are recent and up to date.
      Table ISummary of randomized controlled trials and retrospective case studies evaluating adjuvant therapy in bullous pemphigoids
      Author; year; country
      The corresponding studies for each drug are arranged in chronologic order, ie, most recent to least recent.
      TypeSteroid (GC); adjuvant
      The drugs are presented in alphabetical order by steroid-sparing adjuvant agent.
      Study armsStudy population and indicationCTCAE grading of AEs
      Burton et al
      • Burton J.L.
      • Harman R.R.
      • Peachey R.D.
      • Warin R.P.
      Azathioprine plus prednisone in the treatment of pemphigoid.
      ; 1978; England
      RCT, nonblindedPrednisone; AZAGC only; GC, AZA25 patients with newly diagnosed BPGrade 2: 2/12 patients (17%)
      Beissert et al
      • Beissert S.
      • Werfel T.
      • Frieling U.
      • et al.
      A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid.
      ; 2007; Germany
      RCT, multicenter, nonblindedMethylprednisolone; AZA/MMFGC, AZA; GC, MMF73 patients with newly diagnosed mild-to-severe BPAZA
      Grade 3: 8/36 patients (22%)
      Grade 4: 3/36 patients (8%)
      MMF
      Grade 3: 11/34 patients (32%)
      Grade 4: 2/34 patients (6%)
      Sticherling et al
      • Sticherling M.
      • Franke A.
      • Aberer E.
      • et al.
      An open, multicentre, randomized clinical study in patients with bullous pemphigoids comparing methylprednisolone and azathioprine with methylprednisolone and dapsone.
      ; 2017; Germany
      RCT, multicenter, nonblindedMethylprednisolone; AZA/dapsoneGC, AZA; GC, dapsone54 patients with newly diagnosed BPAZA
      >Grade 1: 18/27 patients (67%)
      Dapsone
      >Grade 1: 13/27 patients (48%)
      Gual et al
      • Gual A.
      • Iranzo P.
      • Mascaró Jr., J.M.
      Treatment of bullous pemphigoids with low-dose oral cyclophosphamide: a case series of 20 patients.
      ; 2014; Spain
      Retrospective case seriesPrednisone; CTXGC, CTX20 patients with moderate-to-severe BP, initially treated with STS or systemic GCs and with CsA as first-, second-, or third-line adjuvantGrade 2: 3/20 patients (15%)
      Schmidt et al
      • Schmidt E.
      • Kraensel R.
      • Goebeler M.
      • et al.
      Treatment of bullous pemphigoid with dapsone, methylprednisolone, and topical clobetasol propionate: a retrospective study of 62 cases.
      ; 2005; Austria and Germany
      Retrospective case seriesMethylprednisolone; dapsoneGC, dapsone62 patients with untreated or refractory BPGrade 1: 10/62 patients (16%)
      Grade 2: 9/62 patients (15%)
      Grade 5: 5/62 patients (8%)
      Amagai et al
      • Amagai M.
      • Ikeda S.
      • Hashimoto T.
      • et al.
      A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.
      ; 2017; Japan
      RCT, multicenter, double-blindedPrednisone; IVIgGC only; GC, IVIg56 patients with BP were on a stable regimen, which included GCsAEs were recorded as the number of events per AE and not all AEs experienced per patient
      Kjellman et al
      • Kjellman P.
      • Eriksson H.
      • Berg P.
      A retrospective analysis of patients with bullous pemphigoids treated with methotrexate.
      ; 2008; Sweden
      Retrospective case seriesPrednisone; MTXGC, MTX; MTX only98 patients with newly diagnosed mild-to-severe BPGrade 2: 5/98 patients (5%)
      Du-Thanh et al
      • Du-Thanh A.
      • Merlet S.
      • Maillard H.
      • et al.
      Combined treatment with low-dose methotrexate and initial short-term superpotent topical steroids in bullous pemphigoid: an open, multicentre, retrospective study.
      ; 2011; France
      Retrospective case seriesSTS, bethamethasone propionate, or clobetasol proprionate; MTXGC, MTX70 patients initially treated with short-term STS and low-dose MTX, followed by long-term, low-dose MTXGrade 1: 2/70 patients (3%)
      Grade 2: 3/70 patients (4%)
      Grade 3: 2/70 patients (3%)
      Grade 4: 8/70 patients (11%)
      Grade 5: 1/70 patients (3%)
      Delaumenie et al
      • Delaumenie S.
      • Assikar S.
      • Prudhomme R.
      • et al.
      Methotrexate is a safe and efficient long-term treatment for bullous pemphigoid.
      ; 2019; France
      Retrospective case seriesTPC; MTXGC, MTX51 patients with moderate-to-severe BP, initially treated with TPC as first lineGrade 1 and 2: NA (48%)
      Grade 3: NA (22%)
      Polansky et al
      • Polansky M.
      • Eisenstadt R.
      • DeGrazia T.
      • Zhao X.
      • Liu Y.
      • Feldman R.
      Rituximab therapy in patients with bullous pemphigoid: a retrospective study of 20 patients.
      ; 2019; US
      Retrospective case seriesPrednisone; RTXGC, RTX20 patients with untreated severe or refractory BPAEs could not be graded because of inadequate information
      Williams et al
      • Williams H.C.
      • Wojnarowska F.
      • Kirtschig G.
      • et al.
      Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomized controlled trial.
      ; 2017; UK and Germany
      RCT, multicenterPrednisone; tetracyclineGC only; tetracycline only234 patients with newly diagnosed BPGrade 0/1/2: 99/121 patients (81%)
      Grade 3: 14/121 patients (12%)
      Grade 4: 5/121 patients (4%)
      Grade 5: 3/121 patients (3%)
      Fivenson et al
      • Fivenson D.P.
      • Breneman D.L.
      • Rosen G.B.
      • Hersh C.S.
      • Cardone S.
      • Mutasim D.
      Nicotinamide and tetracycline therapy of bullous pemphigoid.
      ; 1994; US
      Randomized, open-label trialPrednisone; TCNGC only; TCN only18 patients with BP with no systemic GC therapy within 2 wk of enrollmentGrade 2: 2/12 patients (17%)
      Grade 3 or 4: 1/12 (possibly treatment related) (8%)
      AE, Adverse event; AZA, azathioprine; BP, bullous pemphigoid; CsA, Cyclosporin; CTCAE, Common Terminology Criteria for Adverse Events; CTX, cyclophosphamide; GC, glucocorticoid; IVIg, intravenous immunoglobulin; MMF, mycophenolate mofetil; MTX, methotrexate; NA, not available; RCT, randomized control trial; RTX, rituximab; STS, superpotent topical steroid; TCN, tetracycline and nicotinamide; UK, United Kingdom; US, United States.
      The corresponding studies for each drug are arranged in chronologic order, ie, most recent to least recent.
      The drugs are presented in alphabetical order by steroid-sparing adjuvant agent.
      Table IISummary of randomized controlled trials and retrospective case studies evaluating adjuvant therapy in patients with pemphigus
      Author; year; country
      Drugs are presented in alphabetical order of steroid-sparing adjuvant agent and the corresponding studies for each drug is arranged in chronological order, ie, most recent to least recent.
      TypeSteroid; adjuvantStudy armsStudy population and indicationCTCAE grading of AEs
      Rose et al
      • Rose E.
      • Wever S.
      • Zilliken D.
      • Linse R.
      • Haustein U.F.
      • Brocker E.B.
      Intravenous dexamethasone-cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus: results of a multicenter, prospectively randomized study.
      ; 2005; Germany
      RCT, multicenter, nonblindedMethylprednisolone/dexamethasone; AZA/CTXMethylprednisolone, AZA; dexamethasone, CTX22 patients with newly diagnosed PV/PFAEs were recorded as the number of events per AE and not all AEs experienced per patient
      Kakuta et al
      • Kakuta R.
      • Yamagami J.
      • Funakoshi T.
      • Takahashi H.
      • Ohyama M.
      • Amagai M.
      Azathioprine monotherapy in autoimmune blistering diseases: a feasible option for mild-to-moderate cases.
      ; 2018; Japan
      Retrospective case seriesNone; AZAAZA only8 patients with newly diagnosed PV/PFGrade 2: 2/8 patients (25%)
      Dastgheib et al
      • Dastgheib L.
      • Sadati M.S.
      • Baghernejhad M.
      Assessment of the adjuvant effect of tacrolimus in the management of pemphigus vulgaris: a randomized controlled trial.
      ; 2015; Iran
      RCTPrednisone; AZA/tacrolimusGC, AZA; GC, tacrolimus41 patients with PVAZA
      Grade 2: 3/21 patients (14%)
      Grade 3: 1/21 patients (5%)
      Tacrolimus
      Grade 1: 1/20 patients (5%)
      Grade 2: 1/20 patients (5%)
      Chams-Davatchi et al
      • Chams-Davatchi C.
      • Esmaili N.
      • Daneshpazhooh M.
      • et al.
      Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris.
      ; 2007; Iran
      RCT, nonblindedPrednisone; AZA/MMF/CsAGC only; GC, AZA; GC, MMF; GC, CTX90 patients with newly diagnosed PVAEs were not described for each treatment arm; it was noted just that there was no significant difference in AE profiles across the 4 groups
      Olszewska et al
      • Olszewska M.
      • Kolacinska-Strasz Z.
      • Sulej J.
      • et al.
      Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris.
      ; 2007; Poland
      Retrospective case seriesPrednisone; AZA/CTX/CsAGC only; GC, AZA; GC, CTX; GC, CsA101 patients with moderate-to-severe PVAEs were recorded as the number of events per AE and not all AEs experienced per patient
      Cummins et al
      • Cummins D.L.
      • Mimouni D.
      • Anhalt G.J.
      • Nousari C.H.
      Oral cyclophosphamide for the treatment of pemphigus vulgaris and foliaceus.
      ; 2003; US
      RCT, nonblindedPrednisone; CTXGC, CTXA total of 23 with refractory PV/PFGrade 2: 11/23 patients (47%)
      Grade 3: 3/23 patients (13%)
      Sharma and Khandpur
      • Sharma V.K.
      • Khandpur S.
      Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroids in the management of pemphigus vulgaris.
      ; 2013; India
      RCT, nonblindedPrednisone; CTX IV pulse therapyGC only; GC, CTX60 patients with mild-to-moderate PVAEs were recorded as the percentage difference compared with control arm
      Khandpur et al
      • Khandpur S.
      • Singh S.
      • Mallick S.
      • et al.
      Urocytological evaluation of pemphigus patients on long-term cyclophosphamide therapy: a cross-sectional study.
      ; 2017; India
      Cross-sectional, prospective, clinical, laboratory investigationalDexamethasone; CTX IV pulse therapyGC, CTX44 patients with PV/PF who have been on CsA for at least 1 yGrade 2: 23/44 patients (52%)
      Ioannides et al
      • Ioannides D.
      • Chrysomallis F.
      • Bystryn J.C.
      Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus.
      ; 2000; Greece
      RCTPrednisone; CsAGC only; GC, CsA33 patients with newly diagnosed PV/PFAEs were recorded as the number of events per AE and not all AEs experienced per patient
      Baum et al
      • Baum S.
      • Debby A.
      • Gilboa S.
      • Trau H.
      • Barzilai A.
      Efficacy of dapsone in the treatment of pemphigus vulgaris: a single-center case study.
      ; 2016; Israel
      Retrospective case seriesPrednisone; dapsoneGC, dapsone125 patients who received dapsone between 1984 and 2013; for the purpose of this review, excluded patients will be evaluated as they experienced early AEs and, thus, were not included in the studyGrade 2: 99/125 patients (79%)
      Werth et al
      • Werth V.P.
      • Fivenson D.
      • Pandya A.G.
      • et al.
      Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris.
      ; 2008; US
      RCT, multicenter, double-blindPrednisone; dapsoneGC only; GC, dapsone19 patients with chronic PV in the maintenance phase
      The maintenance phase is defined as disease controlled with steroids and/or stable dosages for at least 2 months on cytotoxic agents, including AZA, MMF, or MTX.37
      Grade 1: 1/9 patients (11%)
      Grade 2: 1/9 patients (11%)
      Svecova; 2016
      • Svecova D.
      IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects.
      ; Slovakia
      Retrospective case seriesPrednisone; IVIgGC, IVIg10 patients with PV with at least 3 consecutive courses of IVIgGrade 2: 8/10 patients (80%)
      Beissert et al
      • Beissert S.
      • Mimouni D.
      • Kanwar A.J.
      • Solomons N.
      • Kalia V.
      • Anhalt G.J.
      Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial.
      ; 2010; Canada, Germany, India, Israel, Turkey, Ukraine, UK, US
      RCT, nonblindedPrednisone; MMFGC only; GC, MMFA total of 94 with existing mild-to-moderate PVGrade 3: 3/58 patients (5%)
      Ioannides et al
      • Ioannides D.
      • Apalla Z.
      • Lazaridou E.
      • Rigopoulos D.
      Evaluation of mycophenolate mofetil as a steroid-sparing agent in pemphigus: a randomized, prospective study.
      ; 2012; Greece
      RCT, nonblindedMethylprednisolone; MMFGC only, GC, MMF47 patients with newly diagnosed PV/PFGrade 1: 11/24 patients (46%)
      Baum et al
      • Baum S.
      • Greenberger S.
      • Samuelov L.
      • et al.
      Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris.
      ; 2012; Israel
      Retrospective case seriesPrednisone; MTXGC, MTX30 patients with untreated or refractory PVGrade 2: 4/30 patients (13%)
      Tran et al
      • Tran K.D.
      • Wolverton J.E.
      • Soter N.A.
      Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients.
      ; 2013; US
      Retrospective case seriesPrednisone; MTXGC, MTX23 patients with PV with refractory PV and subsequently on MTX for at least 3 consecutive moGrade 2: 2/23 patients (9%)
      Chen et al
      • Chen D.M.
      • Odueyungbo A.
      • Csinady E.
      • et al.
      Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.
      ; 2020; France
      RCT, phase 3 open-labelPrednisone; RTXGC only; GC, RTXA total of 74 patients with newly diagnosed PVGrade 1/2: 22/38 patients (58%) all attributed to Infusion-Related Reaction
      Grade 3: 10/38 patients (29%) from drug itself; 1/38 patients (3%) from IRR
      Grade 4: 2/38 patients (5%)
      Kurihara et al
      • Kurihara Y.
      • Yamagami J.
      • Funakoshi T.
      • et al.
      Rituximab therapy for refractory autoimmune bullous diseases: a multicenter, open-label, single-arm, phase 1/2 study on 10 Japanese patients.
      ; 2019; Japan
      Multicenter, phase 1/2 open-labelPrednisolone; RTXGC, RTX9 patients with refractory PV/PFGrade 3/4: 9/9 patients had at least one AE in this grade
      McCarty and Fivenson
      • McCarty M.
      • Fivenson D.
      Two decades of using the combination of tetracycline derivatives and niacinamide as steroid-sparing agents in the management of pemphigus: defining a niche for these low toxicity agents.
      , 2014; US
      Retrospective case seriesNot specified; TCNGC, TCNA total of 51 with/without initial GC therapy and at least 3 mo of TCNGrade 2: 3/51 patients (6%)
      AE, Adverse event; AZA, azathioprine; BP, bullous pemphigoid; CTCAE, Common Terminology Criteria for Adverse Events; CsA, cyclosporin; CTX, cyclophosphamide; GC, glucocorticoid; IV, intravenous; IVIg, intravenous immunoglobulin; MMF, mycophenolate mofetil; MTX, methotrexate; PF, pemphigus foliaceous; PV, pemphigus vulgaris; RTX, rituximab; RCT, randomized control trial; STS, superpotent topical steroids; TCN, tetracycline and nicotinamide; UK, United Kingdom; US, United States.
      Drugs are presented in alphabetical order of steroid-sparing adjuvant agent and the corresponding studies for each drug is arranged in chronological order, ie, most recent to least recent.
      The maintenance phase is defined as disease controlled with steroids and/or stable dosages for at least 2 months on cytotoxic agents, including AZA, MMF, or MTX.
      • Werth V.P.
      • Fivenson D.
      • Pandya A.G.
      • et al.
      Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris.

      Results

      A total of 781 participants with BP were included in the selected RCTs and RCSs (Table I).
      • Fivenson D.P.
      • Breneman D.L.
      • Rosen G.B.
      • Hersh C.S.
      • Cardone S.
      • Mutasim D.
      Nicotinamide and tetracycline therapy of bullous pemphigoid.
      ,
      • Beissert S.
      • Werfel T.
      • Frieling U.
      • et al.
      A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid.
      ,
      • Du-Thanh A.
      • Merlet S.
      • Maillard H.
      • et al.
      Combined treatment with low-dose methotrexate and initial short-term superpotent topical steroids in bullous pemphigoid: an open, multicentre, retrospective study.
      ,
      • Burton J.L.
      • Harman R.R.
      • Peachey R.D.
      • Warin R.P.
      Azathioprine plus prednisone in the treatment of pemphigoid.
      • Sticherling M.
      • Franke A.
      • Aberer E.
      • et al.
      An open, multicentre, randomized clinical study in patients with bullous pemphigoids comparing methylprednisolone and azathioprine with methylprednisolone and dapsone.
      • Gual A.
      • Iranzo P.
      • Mascaró Jr., J.M.
      Treatment of bullous pemphigoids with low-dose oral cyclophosphamide: a case series of 20 patients.
      • Schmidt E.
      • Kraensel R.
      • Goebeler M.
      • et al.
      Treatment of bullous pemphigoid with dapsone, methylprednisolone, and topical clobetasol propionate: a retrospective study of 62 cases.
      • Amagai M.
      • Ikeda S.
      • Hashimoto T.
      • et al.
      A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.
      • Kjellman P.
      • Eriksson H.
      • Berg P.
      A retrospective analysis of patients with bullous pemphigoids treated with methotrexate.
      • Delaumenie S.
      • Assikar S.
      • Prudhomme R.
      • et al.
      Methotrexate is a safe and efficient long-term treatment for bullous pemphigoid.
      • Polansky M.
      • Eisenstadt R.
      • DeGrazia T.
      • Zhao X.
      • Liu Y.
      • Feldman R.
      Rituximab therapy in patients with bullous pemphigoid: a retrospective study of 20 patients.
      Of those whose side effects could be assigned a single grade classification according to the CTCAE definitions, 12 participants (1.5%) experienced grade 1 AEs, 24 participants (3.1%) experienced grade 2 AEs, 35 participants (4.5%) experienced grade 3 AEs, 18 participants (2.3%) experienced grade 4 AEs, and 9 participants (1.2%) experienced grade 5 AEs. For pemphigus, there were a total of 904 participants from the selected RCTs and RCSs (Table II).
      • Williams H.C.
      • Wojnarowska F.
      • Kirtschig G.
      • et al.
      Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomized controlled trial.
      • Rose E.
      • Wever S.
      • Zilliken D.
      • Linse R.
      • Haustein U.F.
      • Brocker E.B.
      Intravenous dexamethasone-cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus: results of a multicenter, prospectively randomized study.
      • Kakuta R.
      • Yamagami J.
      • Funakoshi T.
      • Takahashi H.
      • Ohyama M.
      • Amagai M.
      Azathioprine monotherapy in autoimmune blistering diseases: a feasible option for mild-to-moderate cases.
      • Dastgheib L.
      • Sadati M.S.
      • Baghernejhad M.
      Assessment of the adjuvant effect of tacrolimus in the management of pemphigus vulgaris: a randomized controlled trial.
      • Chams-Davatchi C.
      • Esmaili N.
      • Daneshpazhooh M.
      • et al.
      Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris.
      • Olszewska M.
      • Kolacinska-Strasz Z.
      • Sulej J.
      • et al.
      Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris.
      • Cummins D.L.
      • Mimouni D.
      • Anhalt G.J.
      • Nousari C.H.
      Oral cyclophosphamide for the treatment of pemphigus vulgaris and foliaceus.
      • Sharma V.K.
      • Khandpur S.
      Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroids in the management of pemphigus vulgaris.
      • Khandpur S.
      • Singh S.
      • Mallick S.
      • et al.
      Urocytological evaluation of pemphigus patients on long-term cyclophosphamide therapy: a cross-sectional study.
      • Ioannides D.
      • Chrysomallis F.
      • Bystryn J.C.
      Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus.
      • Baum S.
      • Debby A.
      • Gilboa S.
      • Trau H.
      • Barzilai A.
      Efficacy of dapsone in the treatment of pemphigus vulgaris: a single-center case study.
      • Werth V.P.
      • Fivenson D.
      • Pandya A.G.
      • et al.
      Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris.
      • Bashir M.M.
      • Sharma M.R.
      • Werth V.P.
      UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription.
      • Beissert S.
      • Mimouni D.
      • Kanwar A.J.
      • Solomons N.
      • Kalia V.
      • Anhalt G.J.
      Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial.
      • Ioannides D.
      • Apalla Z.
      • Lazaridou E.
      • Rigopoulos D.
      Evaluation of mycophenolate mofetil as a steroid-sparing agent in pemphigus: a randomized, prospective study.
      • Baum S.
      • Greenberger S.
      • Samuelov L.
      • et al.
      Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris.
      • Tran K.D.
      • Wolverton J.E.
      • Soter N.A.
      Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients.
      • Chen D.M.
      • Odueyungbo A.
      • Csinady E.
      • et al.
      Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.
      • Kurihara Y.
      • Yamagami J.
      • Funakoshi T.
      • et al.
      Rituximab therapy for refractory autoimmune bullous diseases: a multicenter, open-label, single-arm, phase 1/2 study on 10 Japanese patients.
      • McCarty M.
      • Fivenson D.
      Two decades of using the combination of tetracycline derivatives and niacinamide as steroid-sparing agents in the management of pemphigus: defining a niche for these low toxicity agents.
      Of those whose side effects could be assigned a single grade classification according to the CTCAE definitions, 13 participants (1.4%) experienced grade 1 AEs, 155 participants (17%) experienced grade 2 AEs, 17 participants (1.9%) experienced grade 3 AEs, 17 participants (1.9%) experienced grade 4 AEs, and no participant experienced grade 5 AEs.

      Discussion

      The CTCAE (versions 5.0, 4.0, and 3.0) and its predecessor, the Common Toxicity Criteria (versions 2.0 and 1.0), were developed under the direction of the Cancer Therapy Evaluation Program of the National Cancer Institute in an effort to provide a standard language for reporting AEs that occur in sponsored clinical trials.
      • Edgerly M.
      • Fojo T.
      Is there room for improvement in adverse event reporting in the era of targeted therapies?.
      However, this limits the use of the CTCAE in National Cancer Institute-sponsored trials and creates a disparity between National Cancer Institute-sponsored and nonsponsored trials. The authors recommend that researchers use the CTCAE, version 5.0, while reporting AEs in future clinical studies.
      One major limitation of this analysis is that adjuvant interventions are almost always used in combination with steroids and rarely used as monotherapy. Of the 31 selected studies, only 12 included a “steroid-only” arm, which allowed for a direct comparison of the side effects of steroid-sparing agents with those of steroids. This posed a challenge of identifying the true side effects of the adjuvants from those of steroids. To overcome this, commonly accepted steroid-induced side effects were referenced to exclude side effects that are more likely to be caused by steroids than by the adjuvant drugs.
      • Oray M.
      • Abu Samra K.
      • Ebrahimiadib N.
      • Meese H.
      • Foster C.S.
      Long-term side effects of glucocorticoids.
      These common steroid-induced side effects according to organ system are presented in Table III.
      • Van Staa T.
      • Leufkens H.G.
      • Abenhaim L.
      • Zhang B.
      • Cooper C.
      Oral corticosteroids and fracture risk: relationship to daily and cumulative doses.
      • Weinstein R.S.
      Glucocorticoid-induced osteoporosis and osteonecrosis.
      • Schakman O.
      • Gilson H.
      • Thissen J.P.
      Mechanisms of glucocorticoid-induced myopathy.
      • McMahon M.
      • Gerich J.
      • Rizza R.
      Effects of glucocorticoids on carbohydrate metabolism.
      • Olefsky J.M.
      • Kimmerling G.
      Effects of glucocorticoids on carbohydrate metabolism.
      • Arnaldi G.
      • Scandali V.M.
      • Trementino L.
      • Cardinaletti M.
      • Appolloni G.
      • Boscaro M.
      Pathophysiology of dyslipidemia in Cushing’s syndrome.
      • Fardet L.
      • Feve B.
      Systemic glucocorticoid therapy: a review of its metabolic and cardiovascular adverse events.
      • Werth V.P.
      Management and treatment with systemic glucocorticoids.
      • Da Silva J.A.
      • Jacobs J.W.
      • Kirwan J.R.
      • et al.
      Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data.
      • Brown E.S.
      • Chandler P.A.
      Mood and cognitive changes during systemic corticosteroid therapy.
      • Miller D.
      • Peczon J.D.
      • Whitworth C.G.
      Corticosteroids and functions in the anterior segment of the eye.
      • James E.R.
      The etiology of steroid cataract.
      • Dale D.C.
      • Petersdorf R.G.
      Corticosteroids and infectious diseases.
      Table IIICommon steroid-induced side effects are classified by organ system in alphabetical order
      • Van Staa T.
      • Leufkens H.G.
      • Abenhaim L.
      • Zhang B.
      • Cooper C.
      Oral corticosteroids and fracture risk: relationship to daily and cumulative doses.
      • Weinstein R.S.
      Glucocorticoid-induced osteoporosis and osteonecrosis.
      • Schakman O.
      • Gilson H.
      • Thissen J.P.
      Mechanisms of glucocorticoid-induced myopathy.
      • McMahon M.
      • Gerich J.
      • Rizza R.
      Effects of glucocorticoids on carbohydrate metabolism.
      • Olefsky J.M.
      • Kimmerling G.
      Effects of glucocorticoids on carbohydrate metabolism.
      • Arnaldi G.
      • Scandali V.M.
      • Trementino L.
      • Cardinaletti M.
      • Appolloni G.
      • Boscaro M.
      Pathophysiology of dyslipidemia in Cushing’s syndrome.
      • Fardet L.
      • Feve B.
      Systemic glucocorticoid therapy: a review of its metabolic and cardiovascular adverse events.
      • Werth V.P.
      Management and treatment with systemic glucocorticoids.
      • Da Silva J.A.
      • Jacobs J.W.
      • Kirwan J.R.
      • et al.
      Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data.
      • Brown E.S.
      • Chandler P.A.
      Mood and cognitive changes during systemic corticosteroid therapy.
      • Miller D.
      • Peczon J.D.
      • Whitworth C.G.
      Corticosteroids and functions in the anterior segment of the eye.
      • James E.R.
      The etiology of steroid cataract.
      • Dale D.C.
      • Petersdorf R.G.
      Corticosteroids and infectious diseases.
      Organ systemSide effects
      CardiovascularCoronary heart disease, heart failure, hypertension, ischemic heart disease
      DermatologicAcne, delayed wound healing, easy bruising, ecchymosis, erosion, hair loss, hirsutism, purpura, skin atrophy, striae
      Endocrine and MetabolicAdrenal suppression, Cushingoid features, diabetes mellitus, dyslipidemia, hyperglycemia, weight gain
      GastrointestinalGastritis, gastrointestinal bleeding, hepatic steatosis, pancreatitis, peptic ulcer disease, visceral perforation
      ImmunologicPredisposition to infections, reactivation of latent infections
      MusculoskeletalMyopathy, osteonecrosis, osteoporosis
      NeuropsychiatricAkathisia, anxiety, cognitive impairment, depression, euphoria, mood changes, mood lability
      OphthalmologicCataract, glaucoma
      Additionally, the side effects of the adjuvant drugs were extracted from their respective product information, certified by the Food and Drug Administration of the United States, to further guide the distinction between the side effects of the adjuvant drugs and those of steroids (Supplementary Material 3, available via Mendeley at https://data.mendeley.com/datasets/hn4hn9yx4g/1).
      The observed AEs for each steroid-sparing agent were then categorized based on how likely they were to be true side effects of the adjuvant drugs by comparing and contrasting data from the aforementioned datasets (Table IV).
      Table IVClassification of adverse events recorded in the reviewed randomized control trials and randomized case series according to how likely they are due to glucocorticosteroids or steroid-sparing adjuvant therapy for pemphigoid and pemphigus
      Adverse event
      The AEs are listed in alphabetical order.
      DrugLikely to be true GCAELikely to be true AEs of adjuvant therapy for pemphigoid and pemphigusUnable to be distinguished
      AZAAmenorrhea, cataract, cerebrovascular accident, Cushingoid features, depression, diabetes mellitus, duodenal ulcer, GI bleeding, GI ulcer, GI discomfort, glaucoma, hot flushes, hyperglycemia, hypertension, hypertrichosis, lumbar stenosis, mood changes, myopathy, edema, osteoporosis, pancreatitis, temporary psychosis, tendonitis, redistribution of fat, weight gainDiarrhea, liver function test abnormalities, myelosuppression (leukopenia, pancytopenia, thrombocytopenia), pharyngitis, vomitingArthralgia/myalgia, dizziness, deep venous thrombosis, drug-related exanthema, effluvium, infection
      CTXAcute myeloid leukemia, bladder symptoms (enuresis, frequency/urgency of urination, hematuria, incontinence, nocturia), myelosuppression (anemia, leukopenia, thrombocytopenia), nausea, vomitingAcute heart failure, dizziness, infection, headache
      CsAElevated transaminase, gingival hyperplasia, hyperbilirubinemia, nephrotoxicity (decreased creatinine clearance, increased urea/serum creatinine)N/A
      DapsoneAnemia, cyanosis, fever, liver function abnormalities, methemoglobinemia, paresthesiaArthralgia/myalgia, dizziness, drug-related exanthema, infection, renal failure
      IVIgChest pain, decreased blood alkaline phosphatase, depressed platelet count, elevated blood lactate dehydrogenase, fever, injection site erythema/pain, liver function test abnormalities, malaiseN/A
      MMFFatigue, hypokalemia, liver function test abnormalities, myelosuppression (lymphopenia, neutropenia)Arthralgia/myalgia, eye disease, infection
      MTXAlopecia, anemia, interstitial pneumopathy, liver function test abnormalities, myelosuppression (leukopenia, pancytopenia, thrombocytopenia)Alveolitis, asthenia, GI bleeding, GI ulcer, pulmonary embolism
      RTXArthralgia/myalgia, hypogammaglobulinemia, hypergamma glutamyltransferaseCerebrovascular accident, dental carries, headache, infection, nasal septum perforation, peripheral neuropathy, phlebitis, psoriatic arthropathy, pulmonary embolism, venous thrombosis
      TCNDiarrhea, nausea, vomitingDecubitus ulcers, deep venous thrombosis, erosive gastritis
      AE, Adverse event; AZA, azathioprine; CsA, cyclosporin; CTX, cyclophosphamide; GC, glucocorticosteroid; GCAE, glucocorticoid-induced adverse events; IVIg, intravenous immunoglobulin; GI, gastrointestinal; MMF, mycophenolate mofetil; MTX, methotrexate; N/A, not available; RTX, rituximab; RCT, randomized control trial; TCN, tetracycline and nicotinamide.
      The AEs are listed in alphabetical order.
      Because of lack of available data on specific side effects of each steroid-sparing agent and the lack of standardized grade reporting of such AEs, we were unable to accurately compare the severity of the side effects of steroid-sparing agents with those of the side effects of steroids.

      Conclusion

      The CTCAE could be used to define terms and could be measured as part of a steroid-sparing agent toxicity index, which could be developed using a similar methodology as that for the Glucocorticoid Toxicity Index. The long-term side effects of medications are otherwise challenging to quantify in patients with chronic autoimmune diseases.

      Conflicts of interest

      None disclosed.
      We would like to thank Colleen Hutchison, Academic Services Librarian at the University of New South Wales Library Sydney, for assistance with the literature search of related articles.

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