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IJD SYMPOSIUM |
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| Year : 2017 | Volume
: 62
| Issue : 3 | Page : 282-290 |
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| Shifting focus in the therapeutics of immunobullous disease |
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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 |
Correspondence Address:
Abhishek De
Calcutta National Medical College, Kolkata, West Bengal
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijd.IJD_199_17
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 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 |
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,[1] whereas antibodies to certain nondesmoglein antigens such as pemphaxin and anti-mitochondrial antibodies are suggested to play an auxiliary role.[2] 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.[3] 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.[4]
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.[5] Even the role of IgE antibodies against some epitope on BP180 antigen has been shown to play a part in blister formation.[6],[7],[8] 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.[9]
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.
Conventional treatment
Corticosteroids have perhaps the best evidence so far as initial treatment to induce remission.[10] 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).[11] The antibody is neither internalized by the B-cell nor shed from the plasma membrane, contributing to its persistence on the cell surface.[12]
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).[13] 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.[12] 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.[14]
- 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.[14]
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.[15] 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.[16] This may explain the comparative lower incidence of infection after treatment with rituximab even after causing B-cell depletion.
Dosage
The US FDA recommends two regimens for rituximab:[17]
- 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.[17] 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 [14],[29],[30],[31] and in two retrospective cohort studies.[32],[33] 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.[34]
| Monitoring and Therapeutic Guidelines | | |
[20]
- 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.[35] 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.[36] Side effects reported include hypotension during infusion, sepsis, and herpes zoster in various case reports and case series.[37]
Relapse and resistance with rituximab
In a study with rituximab, it was found 9 patients out of 21 patients relapsed, requiring retreatment.[37] 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.[38]
| Tumor Necrosis Factor-α Inhibitors | | |
The earliest use of this group of drugs has been in recalcitrant cases of MMP.[39] 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.[40] 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
Click here to view |
| 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.[47] 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.[48] As there are circulating IgE antibodies against BP antigen 2 in BP, there is a role of omalizumab in its management.[49] There are many case reports and case series of omalizumab being used in BP with reasonable success.[50],[51],[52]
| 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.[53] 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.[60] 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.[29] 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).[60] In certain studies, IVIG was tapered slowly and continued 6 monthly after inducing clinical remission.[61] IVIG also has steroid-sparing effect and helps in preventing side effects due to long-term administration of immunosuppressives.[62] 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.[63] 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.[70] | Table 4: Evidence of intravenous immunoglobulin,in the treatment of immunobullous disease
Click here to view |
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.[71] 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
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).[72] 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.[73]
Obinutuzumab/GA101
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.[74] 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.[75]
| 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
Nil.
Conflicts of interest
There are no conflicts of interest.
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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] |
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