|Year : 2017 | Volume
| Issue : 3 | Page : 282-290
|Shifting focus in the therapeutics of immunobullous disease
Abhishek De1, Asad Ansari2, Nidhi Sharma2, Aarti Sarda3
1 Associate Professor, Calcutta National Medical College, Kolkata, West Bengal, India
2 Senior Resident, Calcutta National Medical College, Kolkata, West Bengal, India
3 Senior Resident, KPC Medical College, Kolkata, West Bengal, India
|Date of Web Publication||12-May-2017|
Calcutta National Medical College, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Therapeutics of autoimmune bullous disease has seen a major shift of focus from more global immunosuppression to targeted immunotherapy. Anti CD 20 monoclonal antibody Rituximab revolutionized the therapeutics of autoimmune bullous disease particularly pemphigus. Though it is still being practiced off-label, evidences in the form of RCT and meta analysis are now available. Other novel anti CD 20 monoclonal antibodies like ofatumumab, veltuzumab, and ocrelizumab, tositumomab or obinutuzumab/GA101 may add to the therapeutic options in coming days. Beyond anti CD 20 monoclonal antibodies other options that show promise at least in select scenario are omalizumab, TNF inhibitors plasmapheresis and intravenous immunoglobulin. The present article will discuss the role of rituximab and other newer therapeutics in the treatment of autoimmune blistering disease, especially pemphigus and suggests their positions in the therapeutic ladder.
Keywords: Biological treatment, immunobullous disease, rituximab, TNF inhibitors
|How to cite this article:|
De A, Ansari A, Sharma N, Sarda A. Shifting focus in the therapeutics of immunobullous disease. Indian J Dermatol 2017;62:282-90
|How to cite this URL:|
De A, Ansari A, Sharma N, Sarda A. Shifting focus in the therapeutics of immunobullous disease. Indian J Dermatol [serial online] 2017 [cited 2020 Feb 28];62:282-90. Available from: http://www.e-ijd.org/text.asp?2017/62/3/282/206178
What was known?
- Anti CD 20 monoclonal antibody Rituximab is very effective in the treatment of autoimmune bullous disease especially pemphigus
- Intravenous immunoglobulin and plasmapheresis are also being used in the treatment of pemphigus beyond conventional medications like steroids and immunosuppressives.
| Introduction|| |
With the advent of anti-CD20 monoclonal antibodies, the therapeutics of autoimmune bullous disease have taken a leap in the past decade from more global immunosuppression to more targeted immunomodulation. As most of these conditions are rare, conducting larger randomized controlled trials (RCTs) for treatment is at times difficult, which is why achieving a consensus guideline based on meta-analysis or large RCTs can be a daunting task. Although there are a number of existing treatment modalities, all of them are associated with significant adverse effects upon long-term administration. Moreover, certain patients do not respond to traditional treatments and such cases pose a challenge to us. As our understanding of the molecular pathology underlying these diseases is improving, a number of new treatment modalities targeting different specific pathologic processes in the pathogenesis of these diseases are coming up. These newer modalities promise lesser side effects with early and longer remission and are also effective in treatment-resistant cases. While anti-CD20 monoclonal antibody, rituximab, is getting popular in off-label use in pemphigus and other bullous diseases, this molecule too is not free of typical side effects of immunosuppression such as infections. Although resistance to rituximab is quite uncommon, relapse of the autoimmune blistering disease is very commonly encountered. The present article will discuss the role of rituximab and other newer therapeutics in the treatment of autoimmune blistering disease, especially pemphigus and suggests their positions in the therapeutic ladder.
| Pathogenesis|| |
The basic pathology behind these diseases is generation of autoantibodies to target antigens on keratinocytes and dermo-epidermal junctions. Recent researches have given deeper insight into the molecular mechanisms of blister formation in both pemphigus and pemphigoid. Desmoglein 1 and 3 are the prime targets in pemphigus group of patients, whereas antibodies to certain nondesmoglein antigens such as pemphaxin and anti-mitochondrial antibodies are suggested to play an auxiliary role. Epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mechanistic target of rapamycin, etc., are involved in the cell signaling in response to these antibodies, resulting in blistering eventually. Anti-desmocollin-3 has been shown to have a role in atypical pemphigus. Furthermore, the role of various cytokines such as interleukin-1α (IL)-1α and tumor necrosis factor-α (TNF-α) has been emphasized upon recently.
Bullous pemphigoid (BP) patients have autoantibodies against BP230 and BP180 antigen. These are part of the hemidesmosomal adhesion complex, resulting in subepidermal blister formation. IgG antibody to BP antigen activates complement, leads to mast cell degranulation, neutrophil infiltration of the basement membrane, and subsequent blister formation. Even the role of IgE antibodies against some epitope on BP180 antigen has been shown to play a part in blister formation.,, With these discoveries, many newer drugs have been tried in recent times. Some have shown promise, while others are still in the trial phase. However, rarity of the disease and lack of resources, especially in a country like India, have so far prevented us from conducting larger RCTs, which are the need of the hour.
| Principles of Treatment|| |
Treatment consists of three phases:
- Control phase - intensive therapy is given until no new lesions appear
- Consolidation phase - treatment is continued until the lesions completely clear
- Maintenance phase - lowest dose of the drug is given to prevent the appearance of any new lesions.
Choice of the drug depends on the severity of the symptoms and its side effects. Treatment must be individualized and chosen carefully depending on patient's profile, i.e., the presence of comorbidities.
Corticosteroids have perhaps the best evidence so far as initial treatment to induce remission. Used topically for localized disease and oral or intravenous (IV) for extensive involvement. They are given in doses ranging from 1 to 2 mg/kg body weight and continued till remission is achieved. After achieving remission, the doses are gradually tapered and maintained at lowest possible dose for maintenance. When the response is poor, we need to increase the dose of corticosteroids. However, continuous high doses (HDs) of corticosteroids can produce many side effects such as osteoporosis, sepsis, gastrointestinal problems, hyperglycemia, and hypothalamic-pituitary axis suppression. Hence, they are to be combined with steroid-sparing agents. Role of drugs such as azathioprine, mycophenolate mofetil (MMF), methotrexate, cyclophosphamide, cyclosporine, and chlorambucil as steroid-sparing drug is very important to keep the untoward side effects of bullous disease to the minimal level. At present, a combination of steroids and a steroid-sparing agent forms the standard treatment regimen for most of the immunobullous diseases. However, with the advent of targeted therapeutics including monoclonal antibodies, the role of conventional treatment with corticosteroid and immunosuppressive has been put to challenge in the recent past.
Newer therapies for immunobullous diseases
Steroids with other steroid-sparing immunosuppressives form the backbone of management of immunobullous diseases. However, the search for newer therapies has continued, for not all the cases respond to the above therapy, and also to avoid side effects associated with the conventional drugs. As the pathogenesis of immunobullous diseases is becoming clearer, some very promising therapies have been tried in recent times.
| Rituximab|| |
Rituximab is a chimeric murine/human monoclonal antibody against CD20, a surface antigen present on all B lymphocytes. The molecule targets the B-cells specific CD20 to deplete normal and pathogenic B-cells, while sparing terminally differentiated plasma cells. The drug has been conventionally used for lymphomas and rheumatoid arthritis (RA). The antibody is neither internalized by the B-cell nor shed from the plasma membrane, contributing to its persistence on the cell surface.
Its use in immunobullous diseases is new found and off label. From the data available so far, rituximab has shown great promise in the treatment of recalcitrant pemphigus vulgaris (PV), BP, and mucous membrane pemphigoid (MMP). The drug is clinically well tolerated and encountered with adverse events very rarely. The US Food and Drug Administration (US FDA) approved rituximab usage only in refractory low-grade follicular B-cell lymphoma in 1997 and RA refractory to TNF-α inhibitors in 2006. However, the drug is being used increasingly in immunobullous diseases with encouraging results.
Mechanism of action: rituximab acts by depleting CD20+ B-cells. It acts through three possible mechanisms.
- Complement-dependent cytotoxicity (CDC)
- antibody-dependent cell-mediated cytotoxicity (ADCC),
- Inhibition of signaling and apoptosis of antibody-coated B-cells and eventual shift to a normal B-cell repertoire.
The above mechanisms work to deplete CD20+ mature B-cells. However, it spares the hematopoietic stem cells as they do not express CD20 antigen. Therefore, B-cells do get regenerated in about 6–12 months after stopping the therapy. Beyond these mechanisms, rituximab has also been found to downregulate autoreactive CD41 T helper cells indirectly through deprivation of antigen presenting signals.
It is also surprising to find that while there is a fall in anti-desmoglein antibody levels; antimicrobial antibodies' levels in blood are not affected. Studies suggest that protective antimicrobial antibodies are produced by the long-lived CD20− plasma cells in the bone marrow, whereas autoreactive antibodies are produced by short-lived CD20+ plasma cells in peripheral compartments. This may explain the comparative lower incidence of infection after treatment with rituximab even after causing B-cell depletion.
The US FDA recommends two regimens for rituximab:
- 375 mg/m 2 IV infusion once a week for 4 weeks, for non-Hodgkin's lymphoma
- 1000 mg at 2-week interval (D1 and D15) for RA.
A relatively new drug for dermatologists, there are still no consensus guidelines. The most common regimen followed by dermatologists at present is 375 mg/m 2 administered as a slow IV infusion weekly for 4 consecutive weeks as used in non-Hodgkin's lymphoma. However, even the rheumatologic protocol is also being followed by many dermatologists.
The evidence for rituximab in the treatment of immunobullous diseases has been promising though large RCTs are needed [Table 1].
|Table 1: Evidence of rituximab in the treatment of immunobullous diseases|
Click here to view
Rituximab is now regarded an alternative to the long-term use of systemic steroids and immunosuppressives in patients with pemphigus leading to complete sustained remission as shown in five prospective studies ,,, and in two retrospective cohort studies., Ahmed and Shetty analyzed the cumulative data on treatment of PV with rituximab and immunosuppressive and found that clinical remission on rituximab therapy was seen in 90%–95% of patients within 6 weeks. Complete resolution was seen in 3–4 months. However, serious adverse effects, including infection and septicemia, were seen in 4.8%–2.1% of patients in the lymphoma and RA protocols, respectively.
| Monitoring and Therapeutic Guidelines|| |
- Complete blood count - every 2 weeks during the treatment and 1–3 monthly afterwards
- CD20+ B-cell count - in patients developing infections
- HCV and HBV screening - due to increased risk of reactivation
- Premedication - acetaminophen and diphenhydramine or 100 mg of methylprednisolone to prevent infusion reactions.
Adverse effects of rituximab
Serious adverse events are uncommon with rituximab though infusion-related reactions including anaphylaxis, hypotension, fever, headache, and pruritic rash were reported. Moderate-to-severe infusion reactions occur in 10% of patients during the first infusion. Rituximab increases the risk of infection; data suggest that 19% developed bacterial infections, 10% developed viral infections, and 1% developed fungal infections after rituximab therapy. Side effects reported include hypotension during infusion, sepsis, and herpes zoster in various case reports and case series.
Relapse and resistance with rituximab
In a study with rituximab, it was found 9 patients out of 21 patients relapsed, requiring retreatment. Hammers et al . found that persistence of anti-desmoglein -3 B-cell clones contributed to rituximab resistance in patients with PV. Destruction of the remaining clones with additional doses of rituximab or another autoantibody-obliterating agent is, therefore, the goal in treating resistance.
| Tumor Necrosis Factor-α Inhibitors|| |
The earliest use of this group of drugs has been in recalcitrant cases of MMP. The three drugs in this group, i.e., etanercept, adalimumab, and infliximab have been used traditionally in psoriasis and psoriatic arthritis. The new found use in immunobullous diseases has been backed by evidence suggesting the role of TNF-α in the pathogenesis of pemphigus and pemphigoid. Increased levels of TNF-α along with IL-1β, IL-2, 6, and 10 has been shown in skin/serum of patients with pemphigus and pemphigoid. Their levels correlate with disease activity. Early studies showed promise in treating a fair number of treatment-resistant cases in smaller series and case reports, especially those of cicatricial pemphigoid. However, recent studies have failed to live up to the expectations raised by initial success of TNF-α blockers in the treatment of immunobullous diseases [Table 2]. Larger RCTs may be needed before their role in treatment is established.
|Table 2: Evidence of TNF inhibitors in the treatment of immunobullous diseases|
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| Omalizumab|| |
Omalizumab is a humanized IgG monoclonal antibody that binds to free IgE in the serum and thus decreases the amount of IgE present for binding to high-affinity IgE receptors (FcεRI receptors) on mast cells, basophils, and other inflammatory cells. This prevents the release of inflammatory mediators from these cells and reduces the inflammatory response. The major dermatological indications of omalizumab have been the treatment of IgE-mediated disorders including severe atopic dermatitis and chronic urticaria. As there are circulating IgE antibodies against BP antigen 2 in BP, there is a role of omalizumab in its management. There are many case reports and case series of omalizumab being used in BP with reasonable success.,,
| Plasmapheresis and Immunoadsorption|| |
Plasmapheresis is a method of removing circulating autoantibodies present in blood of patients with immunobullous diseases by a filtration process. This modality was used based on the observation that the severity of immunobullous diseases usually correlates with the levels of circulating autoantibodies. It is especially useful in cases which are resistant to steroid therapy. This procedure rapidly reduces the level of pathogenic antibodies in the blood. However, because of the rapid fall in antibody levels, a rebound phenomenon is usually observed. The rebound can be avoided by giving an additional immunosuppressant. The studies conducted mostly have been on plasmapheresis in combination with some other drugs, mostly low-dose steroids or drugs such as azathioprine and cyclophosphamide [Table 3]. Plasmapheresis helps in gaining rapid control of the disease in steroid-resistant patients. Immunoadsorption is claimed to be safer and more efficacious than plasmapheresis.
|Table 3: Evidence of plasmapheresis and immunoadsorptionin the treatment of immunobullous diseases|
Click here to view
| Intravenous Immunoglobulins|| |
Intravenous immunoglobulin (IVIG) has already proved beneficial in the management of many autoimmune diseases. However, its use in autoimmune blistering diseases does not have much evidence. However, there are small studies, in which IVIG has been shown to be beneficial in steroid-resistant cases of PV, pemphigus foliaceus, BP, and linear IgA bullous dermatosis. IVIG acts by reducing the levels of circulating autoantibodies by increasing their catabolism rate and by preventing apoptosis of keratinocytes. It is usually administered in a dose of 400 mg/kg/day for 5 consecutive days. Total dose in each cycle is 2 g/kg. Four such cycles of IVIG are usually given once every 4 weeks. This dosage usually produces remission in recalcitrant cases of immunobullous disorders. IVIG can be given alone or with conventional immunosuppressives which enhance its effects. In one study, HD-IVIG was combined with rituximab, and rapid resolution of lesions was seen without the usual side effects of rituximab. It has been seen that effect of IVIG is dose-dependent and higher doses of IVIG (400 mg/kg/day) produces a greater effect than lower doses (200 mg/kg/day). In certain studies, IVIG was tapered slowly and continued 6 monthly after inducing clinical remission. IVIG also has steroid-sparing effect and helps in preventing side effects due to long-term administration of immunosuppressives. IVIG is generally well tolerated though there are also a number of potential side effects. Most frequently observed side effects are mild and include nausea, headache, myalgia, flushing, hypertension, and tachycardia. These reactions can be reduced premedication with IV steroids and antihistaminic and by giving a slow infusion over four to five hours. Serious adverse effects such as renal failure, blood–borne diseases, aseptic meningitis, thromboembolic episodes, and anaphylaxis are rarely seen.
A major benefit of IVIG is that there is no increased risk of infections as seen with other treatment modalities. However, the cost of therapy with IVIG is high.
Recent studies seem to combine newer modalities such as IVIG, immunoadsorption [Table 4], and rituximab. One study combined all three modalities in seven pemphigus patients, and rapid improvement in lesions was observed in all the patients.
|Table 4: Evidence of intravenous immunoglobulin,in the treatment of immunobullous disease|
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Novel anti-CD20 monoclonal antibodies beyond rituximab
Anti-CD20 antibodies can be categorized as Type I (e g., rituximab, ofatumumab, veltuzumab, and ocrelizumab) or Type II (e g., tositumomab or obinutuzumab/GA101), depending on cellular response. Type I antibodies cause a clustering of CD20 that enhances the recruitment and activation of complement for a potent CDC response. On the other hand, Type II antibodies exhibit stronger homotypic adhesion and induction of direct cell death but with a minimal CDC response. Humanized anti-CD20 monoclonal antibodies have the advantage of being less immunogenic than rituximab. Of the next-generation anti-CD20 biologics, only veltuzumab has published literature on the treatment of refractory pemphigus, and only obinutuzumab/GA101 is currently being tested in clinical trials for pemphigus.
Veltuzumab is a Type I, second-generation humanized anti-CD20 monoclonal antibody. A major advantage of veltuzumab over rituximab is its ability to be administered subcutaneously in low doses (about 20% of the dose of rituximab). Subcutaneous veltuzumab (two 320 mg doses 3 weeks apart) was administered in one patient with pemphigus not responding to rituximab. The patient had complete remission off therapy at 22 months, relapsed at 24 months, and achieved continuous remission after the second administration of veltuzumab. At 35 months of follow-up, the patient experienced no injection site reactions, constitutional symptoms, or adverse events.
Obinutuzumab/GA101 is a third-generation, Type II humanized anti-CD20 monoclonal antibody with a 50-fold higher binding affinity effector cells and a resultant 10- to 100-fold increase in ADCC against target B-cells. Results from a Phase III, randomized trial of GA101 on patients with chronic lymphocytic leukemia and coexisting conditions demonstrated superior response rates compared to chlorambucil monotherapy or rituximab-chlorambucil therapy. Obinutuzumab/GA101 can be a powerful tool in treating patients with refractory PV in coming days.
| Conclusions|| |
Treatment of immunobullous disease has come up a long way from global immunosuppression to more targeted immunotherapy. Rituximab has revolutionized the treatment of immunobullous disease in recent years; however, cost of administration of an intravenous immunotherapy under in-patient basis may limit its uses. Subcutaneous administrable anti-CD20 antibodies, such as veltuzumab, if proven equally or more effective and safer than rituximab, may lead the future of immunotherapy in the field of autoimmune blistering disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kitajima Y. Current and prospective understanding of clinical classification, pathomechanisms and therapy in pemphigus. Arch Dermatol Res 2003;295 Suppl 1:S17-23.
Femiano F. Pemphigus vulgaris: Recent advances in our understanding of its pathogenesis. Minerva Stomatol 2007;56:215-23.
Grando SA, Bystryn JC, Chernyavsky AI, Frusic-Zlotkin M, Gniadecki R, Lotti R, et al.
Apoptolysis: A novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis. Exp Dermatol 2009;18:764-70.
Feliciani C, Toto P, Amerio P, Pour SM, Coscione G, Shivji G, et al. In vitro
and in vivo
expression of interleukin-1alpha and tumor necrosis factor-alpha mRNA in pemphigus vulgaris: Interleukin-1alpha and tumor necrosis factor-alpha are involved in acantholysis. J Invest Dermatol 2000;114:71-7.
Schmidt E, Bröcker EB, Zillikens D. New aspects on the pathogenesis of bullous pemphigoid. Hautarzt 2000;51:637-45.
Chen R, Ning G, Zhao ML, Fleming MG, Diaz LA, Werb Z, et al.
Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J Clin Invest 2001;108:1151-8.
Ishiura N, Fujimoto M, Watanabe R, Nakashima H, Kuwano Y, Yazawa N, et al.
Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid. J Dermatol Sci 2008;49:153-61.
Fairley JA, Burnett CT, Fu CL, Larson DL, Fleming MG, Giudice GJ. A pathogenic role for IgE in autoimmunity: Bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice. J Invest Dermatol 2007;127:2605-11.
Harman KE, Albert S, Black MM; British Association of Dermatologists. Guidelines for the management of pemphigus vulgaris. Br J Dermatol 2003;149:926-37.
Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L, et al.
Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol 2008;58:1043-6.
Feliciani C, Joly P, Jonkman MF, Zambruno G, Zillikens D, Ioannides D, et al.
Management of bullous pemphigoid: The European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol 2015;172:867-77.
Zambruno G, Borradori L. Rituximab immunotherapy in pemphigus: Therapeutic effects beyond B-cell depletion. J Invest Dermatol 2008;128:2745-7.
Heelan K, Al-Mohammedi F, Smith MJ, Knowles S, Lansang P, Walsh S, et al.
Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol 2014;150:703-8.
Eming R, Nagel A, Wolff-Franke S, Podstawa E, Debus D, Hertl M. Rituximab exerts a dual effect in pemphigus vulgaris. J Invest Dermatol 2008;128:2850-8.
Sinistro A, Calabresi V, Lupi F, Sera F, Frezzolini A, Ruffelli M, et al.
The pathogenic activity of anti-desmoglein autoantibodies parallels disease severity in rituximab-treated patients with pemphigus vulgaris. Eur J Dermatol 2015;25:578-85.
Mei HE, Frölich D, Giesecke C, Loddenkemper C, Reiter K, Schmidt S, et al.
Steady-state generation of mucosal IgA+plasmablasts is not abrogated by B-cell depletion therapy with rituximab. Blood 2010;116:5181-90.
Zakka LR, Shetty SS, Ahmed AR. Rituximab in the treatment of pemphigus vulgaris. Dermatol Ther (Heidelb) 2012;2:17.
Schmidt E, Goebeler M, Zillikens D. Rituximab in severe pemphigus. Ann N
Y Acad Sci 2009;1173:683-91.
Kasperkiewicz M, Shimanovich I, Ludwig RJ, Rose C, Zillikens D, Schmidt E. Rituximab for treatment-refractory pemphigus and pemphigoid: A case series of 17 patients. J Am Acad Dermatol 2011;65:552-8.
Craythorne E, du Viver A, Mufti GJ, Warnakulasuriya S. Rituximab for the treatment of corticosteroid-refractory pemphigus vulgaris with oral and skin manifestations. J Oral Pathol Med 2011;40:616-20.
Kim MR, Kim HC, Kim SC. Long-term prognosis of pemphigus in Korea: Retrospective analysis of 199 patients. Dermatology 2011;223:182-8.
Kanwar AJ, Tsuruta D, Vinay K, Koga H, Ishii N, Dainichi T, et al.
Efficacy and safety of rituximab treatment in Indian pemphigus patients. J Eur Acad Dermatol Venereol 2013;27:e17-23.
Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, Caux F, Pascal F, Doan S, et al.
Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol 2011;147:843-9.
Crichlow SM, Mortimer NJ, Harman KE. A successful therapeutic trial of rituximab in the treatment of a patient with recalcitrant, high-titre epidermolysis bullosa acquisita. Br J Dermatol 2007;156:194-6.
Wallet-Faber N, Franck N, Batteux F, Mateus C, Gilbert D, Carlotti A, et al.
Epidermolysis bullosa acquisita following bullous pemphigoid, successfully treated with the anti-CD20 monoclonal antibody rituximab. Dermatology 2007;215:252-5.
Niedermeier A, Eming R, Pfütze M, Neumann CR, Happel C, Reich K, et al.
Clinical response of severe mechanobullous epidermolysis bullosa acquisita to combined treatment with immunoadsorption and rituximab (anti-CD20 monoclonal antibodies). Arch Dermatol 2007;143:192-8.
Sadler E, Schafleitner B, Lanschuetzer C, Laimer M, Pohla-Gubo G, Hametner R, et al.
Treatment-resistant classical epidermolysis bullosa acquisita responding to rituximab. Br J Dermatol 2007;157:417-9.
Mercader P, Rodenas JM, Peña A, Mascaro JM Jr. Fatal Pseudomona pneumonia following rituximab therapy in a patient with epidermolysis bullosa acquisita. J Eur Acad Dermatol Venereol 2007;21:1141-2.
Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 2006;355:1772-9.
Joly P, Mouquet H, Roujeau JC, D'Incan M, Gilbert D, Jacquot S, et al.
A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007;357:545-52.
Cianchini G, Corona R, Frezzolini A, Ruffelli M, Didona B, Puddu P. Treatment of severe pemphigus with rituximab: Report of 12 cases and a review of the literature. Arch Dermatol 2007;143:1033-8.
Lunardon L, Tsai KJ, Propert KJ, Fett N, Stanley JR, Werth VP, et al.
Adjuvant rituximab therapy of pemphigus: A single-center experience with 31 patients. Arch Dermatol 2012;148:1031-6.
Heelan K, Hassan S, Bannon G, Knowles S, Walsh S, Shear NH, et al.
Cost and resource use of pemphigus and pemphigoid disorders pre- and post-rituximab. J Cutan Med Surg 2015;19:274-82.
Ahmed AR, Shetty S. A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab. Autoimmun Rev 2015;14:323-31.
Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: Rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2). J Am Acad Dermatol 2007;56:e55-79.
Fatourechi MM, el-Azhary RA, Gibson LE. Rituximab: Applications in dermatology. Int J Dermatol 2006;45:1143-55.
Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005;31:456-73.
Hammers CM, Chen J, Lin C, Kacir S, Siegel DL, Payne AS, et al.
Persistence of anti-desmoglein 3 IgG(1) B-cell clones in pemphigus patients over years. J Invest Dermatol 2015;135:742-9.
Sacher C, Rubbert A, König C, Scharffetter-Kochanek K, Krieg T, Hunzelmann N. Treatment of recalcitrant cicatricial pemphigoid with the tumor necrosis factor alpha antagonist etanercept. J Am Acad Dermatol 2002;46:113-5.
Ludwig RJ, Schmidt E. Cytokines in autoimmune bullous skin diseases. Epiphenomena or contribution to pathogenesis? G Ital Dermatol Venereol 2009;144:339-49.
Labrecque PG, Null M. Cicatricial pemphigoid and therapy with the TNF inhibitor etanercept. J Am Acad Dermatol 2004;50 Suppl:P48.
Canizares MJ, Smith DI, Conners MS, Maverick KJ, Heffernan MP. Successful treatment of mucous membrane pemphigoid with etanercept in 3 patients. Arch Dermatol 2006;142:1457-61.
Berookhim B, Fischer HD, Weinberg JM. Treatment of recalcitrant pemphigus vulgaris with the tumor necrosis factor alpha antagonist etanercept. Cutis 2004;74:245-7.
Shetty A, Marcum CB, Glass LF, Carter JD. Successful treatment of pemphigus vulgaris with etanercept in four patients. J Drugs Dermatol 2009;8:940-3.
Fiorentino DF, Garcia MS, Rehmus W, Kimball AB. A pilot study of etanercept treatment for pemphigus vulgaris. Arch Dermatol 2011;147:117-8.
Hall RP 3rd
, Fairley J, Woodley D, Werth VP, Hannah D, Streilein RD, et al.
A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone. Br J Dermatol 2015;172:760-8.
Incorvaia C, Mauro M, Russello M, Formigoni C, Riario-Sforza GG, Ridolo E. Omalizumab, an anti-immunoglobulin E antibody: State of the art. Drug Des Devel Ther 2014 7;8:197-207.
Romano C, Sellitto A, De Fanis U, Balestrieri A, Savoia A, Abbadessa S, et al.
Omalizumab for difficult-to-treat dermatological conditions: Clinical and immunological features from a retrospective real-life experience. Clin Drug Investig 2015;35:159-68.
van Beek N, Lüttmann N, Huebner F, Recke A, Karl I, Schulze FS, et al.
Correlation of serum levels of IgE autoantibodies against BP180 with bullous pemphigoid disease activity. JAMA Dermatol 2017;153:30-8.
Yu KK, Crew AB, Messingham KA, Fairley JA, Woodley DT. Omalizumab therapy for bullous pemphigoid. J Am Acad Dermatol 2014;71:468-74.
Gönül MZ, Keseroglu HO, Ergin C, Özcan I, Erdem Ö. Bullous pemphigoid successfully treated with omalizumab. Indian J Dermatol Venereol Leprol 2016;82:577-9.
London VA, Kim GH, Fairley JA, Woodley DT. Successful treatment of bullous pemphigoid with omalizumab. Arch Dermatol 2012;148:1241-3.
Aksu D, Peksari Y, Arica IE, Gurgey E. Assessing the autoantibody levels in relation to disease severity and therapy response in pemphigus patients. Indian J Dermatol 2010;55:342-7.
] [Full text]
Shimanovich I, Herzog S, Schmidt E, Opitz A, Klinker E, Bröcker EB, et al.
Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption. Clin Exp Dermatol 2006;31:768-74.
Schmidt E, Klinker E, Opitz A, Herzog S, Sitaru C, Goebeler M, et al.
Protein A immunoadsorption: A novel and effective adjuvant treatment of severe pemphigus. Br J Dermatol 2003;148:1222-9.
Eming R, Rech J, Barth S, Kalden JR, Schuler G, Harrer T, et al.
Prolonged clinical remission of patients with severe pemphigus upon rapid removal of desmoglein-reactive autoantibodies by immunoadsorption. Dermatology 2006;212:177-87.
Kasperkiewicz M, Schulze F, Meier M, van Beek N, Nitschke M, Zillikens D, et al.
Treatment of bullous pemphigoid with adjuvant immunoadsorption: A case series. J Am Acad Dermatol 2014;71:1018-20.
Kasperkiewicz M, Meier M, Zillikens D, Schmidt E. Linear IgA disease: Successful application of immunoadsorption and review of the literature. Dermatology 2010;220:259-63.
Westermann L, Hügel R, Meier M, Weichenthal M, Zillikens D, Gläser R, et al.
Glucocorticosteroid-resistant pemphigoid gestationis: Successful treatment with adjuvant immunoadsorption. J Dermatol 2012;39:168-71.
Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K, Aiba S, et al.
A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol 2009;60:595-603.
Lolis M, Toosi S, Czernik A, Bystryn JC. Effect of intravenous immunoglobulin with or without cytotoxic drugs on pemphigus intercellular antibodies. J Am Acad Dermatol 2011;64:484-9.
Ahmed AR. Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001;45:825-35.
Wittstock M, Benecke R, Zettl UK. Therapy with intravenous immunoglobulins: Complications and side-effects. Eur Neurol 2003;50:172-5.
Sami N, Qureshi A, Ahmed AR. Steroid sparing effect of intravenous immunoglobulin therapy in patients with pemphigus foliaceus. Eur J Dermatol 2002;12:174-8.
Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 2001;45:679-90.
Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: A preliminary study. Ophthalmology 1999;106:2136-43.
Sami N, Bhol KC, Razzaque Ahmed A. Intravenous immunoglobulin therapy in patients with multiple mucosal involvement in mucous membrane pemphigoid. Clin Immunol 2002;102:59-67.
Gourgiotou K, Exadaktylou D, Aroni K, Rallis E, Nicolaidou E, Paraskevakou H, et al.
Epidermolysis bullosa acquisita: Treatment with intravenous immunoglobulins. J Eur Acad Dermatol Venereol 2002;16:77-80.
Letko E, Bhol K, Foster CS, Ahmed AR. Linear IgA bullous disease limited to the eye: A diagnostic dilemma: Response to intravenous immunoglobulin therapy. Ophthalmology 2000;107:1524-8.
Shimanovich I, Nitschke M, Rose C, Grabbe J, Zillikens D. Treatment of severe pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins. Br J Dermatol 2008;158:382-8.
Klein C, Lammens A, Schäfer W, Georges G, Schwaiger M, Mössner E, et al.
Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs 2013;5:22-33.
Negrea GO, Elstrom R, Allen SL, Rai KR, Abbasi RM, Farber CM, et al.
Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin's lymphoma. Haematologica 2011;96:567-73.
Ellebrecht CT, Choi EJ, Allman DM, Tsai DE, Wegener WA, Goldenberg DM, et al.
Subcutaneous veltuzumab, a humanized anti-CD20 antibody, in the treatment of refractory pemphigus vulgaris. JAMA Dermatol 2014;150:1331-5.
Czuczman MS, Gregory SA. The future of CD20 monoclonal antibody therapy in B-cell malignancies. Leuk Lymphoma 2010;51:983-94.
Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al.
Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370:1101-10.
What is new?
- Novel anti CD 20 antibodies like ofatumumab, veltuzumab, and ocrelizumab, tositumomab or obinutuzumab/GA101 are under trial, some of them may find role in the management of psoriasis in the days to come
- Omalizumab and TNF inhibitors also have role in the treatment of immunobullous disease at least in some selected scenario.
[Table 1], [Table 2], [Table 3], [Table 4]