Clinical Implications•Pemphigus and pemphigoid can be severe life-threatening diseases that cause significant burden on the day-to-day lives of patients.•Access to therapy can remain an issue for patients because rituximab is only clinically approved for pemphigus vulgaris, so most therapies are prescribed off label.•Patients must weigh the burden of disease versus burden of therapy. The goal of therapy is to control disease without serious side effects.•Given the side effects of steroids, minimal therapy is the primary goal of therapy, and complete remission of disease is secondary. New therapies do not have to be perfect, as long as they provide meaningful benefits to patients.•Validated tools for measuring disease activity in pemphigus and pemphigoid have been published. The five-point Investigator’s Global Assessment scales in pemphigus and pemphigoid are not validated.•The definition of clear or almost clear disease is overly stringent and not fair compared with the endpoints used for clinical trials in other autoimmune diseases with pathophysiology similar to that of pemphigus. Clinical trial data indicate that patients’ QOL can be restored despite not achieving clear or almost clear disease activity. Clinical trials should use endpoints that reflect meaningful benefits to patients and consider the physical and psychological impact of treatments.•There has been a steady increase in clinical trials in pemphigus and pemphigoid over the last several years. The International Pemphigus and Pemphigoid Foundation seeks to continue its collaboration with the patient community, industry, and the United States Food and Drug Administration to improve access to treatment and QOL for all people affected with pemphigus and pemphigoid.Developing new treatments for intractable diseases is essential to improve patients’ health and QOL. The United States Food and Drug Administration (FDA) evaluates the safety and efficacy of treatments to ensure that the benefits of a new product outweigh its risks. Understanding what patients look for in new drugs and how patients and caregivers view the risks of therapy can help to identify areas of unmet need and guide the drug development process. Over the last decade, the FDA has incorporated patients’ perspectives and experiences into drug development process through Patient Listening Sessions and Patient-Focused Drug Development (PFDD) meetings. In contrast to Patient Listening Sessions, which are not open to the public, PFDD meetings aim to ensure that patients’ experiences, needs, and priorities are captured and meaningfully incorporated into drug development and evaluation. From the patient's perspective, PFDD meetings raise awareness and engagement in the patient community by discussing patient perspectives on the burden of disease, clinical trial participation, and risk−benefit tradeoffs of drugs used to treat their condition. From the drug development perspective, PFDD meetings can help the FDA to conduct risk−benefit assessments, advise drug sponsors on their development programs, and identify areas of unmet need or potential trial endpoints. Patients are the experts in these meetings, sharing their lived experiences so that clinicians and researchers can better understand the unmet needs of the patient community and develop tools that better assess the benefits of patient therapies. A summary of PFDD meetings relevant to dermatology is listed in Table 1.Table 1FDA and EL-PFDD Meetings Relevant to DermatologyDisease or ConditionType of MeetingMeeting DateAmyloidosisEL-PFDD Meeting16 November 2015PsoriasisFDA-led PFDD Meeting17 March 2016Alopecia areataFDA-led PFDD Meeting11 September 2017LupusEL-PFDD Meeting25 September 2017Hereditary angioedemaFDA-led PFDD Meeting25 September 2017HyperhidrosisEL-PFDD Meeting13 November 2017Hypereosinophilic syndromesEL-PFDD Meeting23 March 2018Pachyonychia congenitaEL-PFDD Meeting6 April 2018Dermatitis (eczema)EL-PFDD Meeting23 September 2019Systemic sclerosisFDA-led PFDD Meeting13 October 2020VitiligoFDA-led PFDD Meeting8 March 2021Gorlin syndromeEL-PFDD Meeting8 October 2021Pemphigus and pemphigoidEL-PFDD Meeting25 January 2023Abbreviations: EL, externally led; FDA, United States Food and Drug Administration; PFDD, Patient-Focused Drug Development.Data were obtained from https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience. Open table in a new tab •Pemphigus and pemphigoid can be severe life-threatening diseases that cause significant burden on the day-to-day lives of patients.•Access to therapy can remain an issue for patients because rituximab is only clinically approved for pemphigus vulgaris, so most therapies are prescribed off label.•Patients must weigh the burden of disease versus burden of therapy. The goal of therapy is to control disease without serious side effects.•Given the side effects of steroids, minimal therapy is the primary goal of therapy, and complete remission of disease is secondary. New therapies do not have to be perfect, as long as they provide meaningful benefits to patients.•Validated tools for measuring disease activity in pemphigus and pemphigoid have been published. The five-point Investigator’s Global Assessment scales in pemphigus and pemphigoid are not validated.•The definition of clear or almost clear disease is overly stringent and not fair compared with the endpoints used for clinical trials in other autoimmune diseases with pathophysiology similar to that of pemphigus. Clinical trial data indicate that patients’ QOL can be restored despite not achieving clear or almost clear disease activity. Clinical trials should use endpoints that reflect meaningful benefits to patients and consider the physical and psychological impact of treatments.•There has been a steady increase in clinical trials in pemphigus and pemphigoid over the last several years. The International Pemphigus and Pemphigoid Foundation seeks to continue its collaboration with the patient community, industry, and the United States Food and Drug Administration to improve access to treatment and QOL for all people affected with pemphigus and pemphigoid. Abbreviations: EL, externally led; FDA, United States Food and Drug Administration; PFDD, Patient-Focused Drug Development. Data were obtained from https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience. On January 25, 2023, the International Pemphigus and Pemphigoid Foundation hosted an externally led PFDD meeting with the FDA in collaboration with international patient advocacy organizations PEM Friends (United Kingdom), Association Pemphigus Pemphigoïde France, and Pemphigus/Pemphigoid Friends Association (Japan). This commentary discusses patient and physician perspectives relevant to PFDD in pemphigus and pemphigoid. Pemphigus vulgaris and pemphigus foliaceus are autoimmune blistering diseases caused by autoantibodies directed against desmosomal adhesion proteins (Schmidt et al., 2019Schmidt E. Kasperkiewicz M. Joly P. Pemphigus.Lancet. 2019; 394: 882-894Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). Pemphigoid encompasses a group of autoimmune blistering diseases caused by autoantibodies directed against various adhesion proteins of the dermal−epidermal junction (Egami et al., 2020Egami S. Yamagami J. Amagai M. Autoimmune bullous skin diseases, pemphigus and pemphigoid.J Allergy Clin Immunol. 2020; 145: 1031-1047Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Pemphigus and pemphigoid are orphan diseases. The rarity of the disease as well as limited access to specialty centers with experts in autoimmune blistering diseases often results in delays in diagnosis. The main complaints of patients are pruritus (particularly for bullous pemphigoid), pain from oral and genital erosions, dysphagia and weight loss, insomnia, fatigue, corticosteroid side effects, stigmatization from visible blisters and scarring, anxiety over the danger of treatment, and fear of relapse and having to take corticosteroids again. Pemphigoid can lead to erosions and scarring of the skin in addition to the eyes, larynx, esophagus, and genitourinary mucosa, in some cases resulting in blindness or death. Patients have elevated mortality relative to age-matched controls (Langan et al., 2008Langan S.M. Smeeth L. Hubbard R. Fleming K.M. Smith C.J. West J. Bullous pemphigoid and pemphigus vulgaris--incidence and mortality in the UK: population based cohort study.BMJ. 2008; 337: a180Crossref PubMed Scopus (472) Google Scholar). In addition, difficulties due to disease or complications of treatment can lead patients to lose work, income, and QOL (Sebaratnam et al., 2012Sebaratnam D.F. McMillan J.R. Werth V.P. Murrell D.F. Quality of life in patients with bullous dermatoses.Clin Dermatol. 2012; 30: 103-107Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Treatments for pemphigus and pemphigoid aim to stop the production of autoantibodies and inflammation. Corticosteroids are clinically approved for the treatment of pemphigus. Rituximab is clinically approved only for the pemphigus vulgaris subtype. Other therapies are prescribed off label for pemphigus, such as oral immunosuppressives and intravenous Ig. All therapies for pemphigoid (including immunosuppressives, anti-inflammatory agents, intravenous Ig, and mAbs such as omalizumab or dupilumab) are prescribed off label. The ideal goals of treatment are to have complete healing of blisters and resolution of the functional impairment associated with the disease, improve QOL, prevent disease recurrence, and limit treatment side effects related to corticosteroids and immunosuppressants. The efficacy of rituximab and corticosteroids for pemphigus is supported by two pivotal randomized controlled trials, indicating 40−90% rates of complete remission off corticosteroids with the use of maintenance rituximab infusions every 6 months (Chen et al., 2020Chen D.M. Odueyungbo A. Csinady E. Gearhart L. Lehane P. Cheu M. et al.Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.Br J Dermatol. 2020; 182: 1111-1119Crossref PubMed Scopus (40) Google Scholar; Joly et al., 2017Joly P. Maho-Vaillant M. Prost-Squarcioni C. Hebert V. Houivet E. Calbo S. et al.First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.Lancet. 2017; 389: 2031-2040Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar; Werth et al., 2021Werth V.P. Joly P. Mimouni D. Maverakis E. Caux F. Lehane P. et al.Rituximab versus mycophenolate mofetil in Patients with pemphigus vulgaris.N Engl J Med. 2021; 384: 2295-2305Crossref PubMed Scopus (35) Google Scholar). Real-world data have described temporal outcomes of rituximab therapy for pemphigus vulgaris when used as part of standard clinical care, indicating that 43% of patients who receive repeated cycles of rituximab for relapsed or refractory disease achieve complete remission off corticosteroids (Tovanabutra et al., 2022Tovanabutra N. Bax C.E. Feng R. Kushner C.J. Payne A.S. Temporal outcomes after rituximab therapy for pemphigus vulgaris.J Invest Dermatol. 2022; 142: 1058-1064.e7Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Limitations of rituximab and corticosteroids include their transient therapeutic effect, which necessitates repeated infusions for disease control. Chronic immune suppression can lead to serious infections and impaired response to vaccines. Studies have shown increased mortality from COVID-19 in patients with autoimmune blistering disease treated with immunosuppressive therapies (French study Group on auto immune bullous skin diseases, and the French network of rare diseases in Dermatology, 2022Joly P. French study Group on auto immune bullous skin diseases, and the French network of rare diseases in Dermatology (FIMARAD)Incidence and severity of COVID-19 in patients with autoimmune blistering skin diseases: A nationwide study.J Am Acad Dermatol. 2022; 86: 494-497Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). As a result, many patients feel that they can no longer safely do the things they used to do, such as gatherings with family and friends, vacation or work travel, dining out, and working in indoor office spaces. This has led to substantial social and professional isolation, in some cases forcing patients to seek other lines of work. In addition, chronic corticosteroid use can lead to numerous side effects, including weight gain, mood swings, insomnia, bruising, and stretch marks, in addition to serious medical complications such as hypertension, diabetes, glaucoma, cataracts, and bone fractures. These limitations highlight several unmet needs in pemphigus and pemphigoid therapy. The main problems in pemphigus management are relapsing and refractory disease, which require higher cumulative steroid doses and result in more side effects from therapy. Physicians and patients must remain vigilant for rare and potentially life-threatening infections due to immunosuppressive treatments. Patients are in need of drugs that are safe and well-tolerated, which avoid chronic immune suppression and the need for regular blood work. Oral, topical, or subcutaneous routes of administration would be beneficial to patients who may have difficulty arranging travel or logistics for intravenous infusions. Drugs that work fast to control disease would be important because most drugs for pemphigus and pemphigoid take several months to have therapeutic effects. For QOL, patients want to avoid the use of corticosteroids. Validated disease activity scales for pemphigus and pemphigoid have been developed over the last 15 years by an international panel of medical experts, who have performed studies to compare the reliability with the validity of different disease activity instruments (Hébert et al., 2019Hébert V. Boulard C. Houivet E. Duvert Lehembre S. Borradori L. Della Torre R. et al.Large international validation of ABSIS and PDAI pemphigus severity scores.J Invest Dermatol. 2019; 139: 31-37Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar; Masmoudi et al., 2021Masmoudi W. Vaillant M. Vassileva S. Patsatsi A. Quereux G. Moltrasio C. et al.International validation of the Bullous pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.Br J Dermatol. 2021; 184: 1106-1112Crossref PubMed Scopus (26) Google Scholar; Murrell et al., 2012Murrell D.F. Daniel B.S. Joly P. Borradori L. Amagai M. Hashimoto T. et al.Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.J Am Acad Dermatol. 2012; 66: 479-485Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar; Rosenbach et al., 2009Rosenbach M. Murrell D.F. Bystryn J.C. Dulay S. Dick S. Fakharzadeh S. et al.Reliability and convergent validity of two outcome instruments for pemphigus.J Invest Dermatol. 2009; 129: 2404-2410Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). These studies have identified indices with high inter-rater and intrarater reliability, such as the Pemphigus Disease Area Index (PDAI) and the Bullous Pemphigoid Disease Area Index (BPDAI). Using the consensus-based standards for the selection of health measurement instruments, the PDAI and BPDAI perform better than the PASI or eczema activity and severity index (EASI), which have been used by the FDA for drug approvals in their respective diseases. Patients would value 50% or 75% improvement in pemphigus or pemphigoid disease activity, similar to endpoints that have previously led to drug approvals for atopic dermatitis (EASI-50) and psoriasis (PASI-75). A major challenge for pemphigus and pemphigoid drug development is that recent clinical trials in pemphigus and pemphigoid are being required by FDA to use an endpoint of clear or almost clear disease using a five-point Investigator’s Global Assessment (IGA) scale. However, IGAs have not been validated for pemphigus and pemphigoid. Validated instruments that separate disease activity from damage and are sensitive to changes in disease activity are better to show a response to therapy than IGA five-point scales. Past experience with a similar scale known as the Physician Global Assessment (PGA) shows that the PGA is far less reliable than autoimmune bullous disease−specific instruments (Rosenbach et al., 2009Rosenbach M. Murrell D.F. Bystryn J.C. Dulay S. Dick S. Fakharzadeh S. et al.Reliability and convergent validity of two outcome instruments for pemphigus.J Invest Dermatol. 2009; 129: 2404-2410Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). In addition, in current IGA scales for pemphigus and pemphigoid, a single blister would be classified as mild disease and would prevent a patient from achieving the endpoint of clear or almost clear disease. For example, a patient with near total oral mucosal blistering (PDAI score = 42) could experience complete disease clearance with therapy but could develop one transient small blister (PDAI score = 1) on the day of the clinical trial assessment, which can easily occur given the skin and mucosal fragility in patients with pemphigus and pemphigoid. Despite a nearly 98% improvement in PDAI score, the single blister would result in an IGA score of 2 and would be counted as a treatment failure. Hence, the IGA definition of clear or almost clear disease is overly strict given the burden of disease and the risks and limitations of current therapies. Endpoints for pemphigus and pemphigoid clinical trials should be comparable with those used for other similar autoimmune diseases such as myasthenia gravis, which have received drug approvals on the basis of a two-point reduction in disease activity scales, without the requirement for complete or near complete disease clearance (Howard et al., 2021Howard Jr., J.F. Bril V. Vu T. Karam C. Peric S. Margania T. et al.Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial.Lancet Neurol. 2021; 20 ([published correction appears in Lancet Neurol 2021;20:e5]): 526-536Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Less stringent criteria for almost clear including up to three small blisters or a PDAI/BPDAI activity score of up to 5 should be considered, or endpoints could be based on a minimal clinically important difference or percentage reduction in disease-specific activity scores. Consensus outcome definitions and endpoints for pemphigus and pemphigoid have been published (Murrell et al., 2012Murrell D.F. Daniel B.S. Joly P. Borradori L. Amagai M. Hashimoto T. et al.Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.J Am Acad Dermatol. 2012; 66: 479-485Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, Murrell et al., 2008Murrell D.F. Dick S. Ahmed A.R. Amagai M. Barnadas M.A. Borradori L. et al.Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.J Amer Acad Dermatol. 2008; 58: 1043-1046Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar), which included definitions of complete or partial remission of systemic therapy or minimal doses of systemic therapy. These consensus definitions were intended to assess standard-of-care therapies (mainly oral immunosuppressives) because they were published before clinical trials for pemphigus and pemphigoid were in development in the United States. Endpoints for clinical trials may include complete or partial remission on minimal steroid doses or off steroids while remaining on the investigational therapy being evaluated. In pivotal clinical trials of rituximab for pemphigus, the last rituximab infusion was performed 6 months before assessment of the primary endpoint, a logical timepoint because the effect of rituximab on total B-cell counts lasts longer than 6 months. In the context of rituximab and corticosteroids, off therapy means off steroids for 8 weeks—this definition was not intended to indicate that clinical trials of other therapies with different mechanisms of action must achieve disease remission off the investigational therapy being tested. For example, medications with a shorter pharmacodynamic effect than rituximab (such as efgartigimod, whose effects on IgG begin to reverse within a week of stopping the drug) need to be continued to the endpoint to see the steroid-sparing effect. Minimal steroid doses for endpoints should also be considered carefully because prednisone doses of 10 mg or greater can have a substantial therapeutic effect. The oral Bruton’s tyrosine kinase inhibitor rilzabrutinib failed to show a significant difference compared with placebo in a phase 3 trial for pemphigus when a minimal steroid dose of 10 mg daily was evaluated in the comparator arm. A minimal steroid dose of 5 mg daily or a weight-based dose such as 0.1 mg/kg/day may be more appropriate to show a difference compared with steroids alone. Defining meaningful improvement is critical. In the PEMPHIX phase 3 randomized controlled trial of rituximab and corticosteroids, 40% of patients achieved the primary endpoint of complete remission off steroids. However, 87.2% of clinicians and 80.9% of patients rated the disease as very much improved at week 52, despite not having sustained a complete response to therapy. In the nomacopan clinical trial in bullous pemphigoid, a 75% reduction in BPDAI score was associated with a 100% improvement in QOL in some patients. These data indicate that patients’ QOL can be restored despite not achieving complete remission of disease activity. Hence, requiring complete disease clearance or an IGA endpoint of clear or almost clear for clinical trials in pemphigus and pemphigoid is not tied to meaningful response for patients. The use of nonvalidated and insensitive IGA scales will ultimately impede drug development for pemphigus and pemphigoid and prevent effective therapies from getting to patients. Dozens of patients with pemphigus and pemphigoid shared their experiences living with the disease. Current therapies present barriers to care that add to the already overwhelming burden patients face from the symptoms of the disease. Patients often have to try multiple therapies to find one that achieves disease remission. Many drugs used to treat pemphigus and pemphigoid have to be prescribed off label, which can create financial difficulty and delays in treatment. Additional and better treatment options are needed. Other challenges included delay in diagnosis, the physical and mental toll of the disease on themselves and their family, debilitating pain and itch from widespread lesions, limited access to blistering disease specialists or therapy, and the need to seek other lines of work owing to constraints imposed by disease or its therapy. The impact of disease on their QOL, patient perspectives on the limitations of current therapies, what characteristics they would look for in a new drug, and what outcomes of therapy are desirable were discussed. The PFDD meeting aims to highlight the physical, psychological, and emotional impact of disease on patients to identify what is most important to those living with these diseases. After the PFDD meeting, a Voice of the Patient Meeting Report will be published, summarizing input shared by patients and their caregivers, along with results of the patient polls and survey (https://www.fda.gov/industry/prescription-drug-user-fee-amendments/condition-specific-meeting-reports-and-other-information-related-patients-experience). Rebecca Strong: http://orcid.org/0009-0007-8957-3655 Dedee F. Murrell: http://orcid.org/0000-0003-2971-0199 PD is an employee with the International Pemphigus & Pemphigoid Foundation. PJ is a consultant for Roche, Amgen, Principia Biopharma, Argenx, AstraZeneca, Thermo Fisher, Sanofi Regeneron, Janssen, and Akari. DFM is a consultant/investigator for Roche, GlaxoSmithKline, Novartis, Principia Bio, Immune Pharmaceuticals, Eli Lilly, Sanofi, argenx, Astra Zeneca, Bristol Myers Squibb, Genentech, Janssen, Pfizer, and Regeneron. VPW is a consultant for AbbVie/Abbott, AnaptysBio, Argenx, Astra Zeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Galderma, Genentech, Gilead, GlaxoSmithKline, Horizon Therapeutics, Janssen, Kirin, Merck/Merck Sharp & Dohme, Nektar, Novartis, Octapharma, Pfizer, Principia, Regeneron, Rome Pharmaceuticals, and Sanofi and received grant/research support from Amgen, argenx, Biogen, Corbus, CSL Behring, Genentech, Horizon Therapeutics, Pfizer, Regeneron, and Syntimmune. ASP holds equity, grants, payments, and patent licensing from Cabaletta Bio and consults for Janssen. We would like to thank Amethyst Yale, Anna Lane, and the patients with pemphigus and pemphigoid who graciously gave their time and shared their experiences.