Anthony A. Gaspari, Stephen K. Tyring and Daniel H. Kaplan (eds.)Clinical and Basic Immunodermatology10.1007/978-3-319-29785-9_44

44. Therapy of Immunobullous Disorders

Kyle Amber¹ and Michael Hertl²

(1)

Department of Dermatology, UC Irvine Health, Irvine, CA, USA

(2)

Department of Dermatology, Philipps University Marburg, Marburg, D-35043, Germany

Michael Hertl

Email: Hertl@med.uni-marburg.de

Abstract

Immunobullous disorders are chronic-relapsing diseases of the skin and mucous membranes with high morbidity and mortality which are linked to IgG autoantibodies that target adhesion molecules of the skin. In most instances, therapeutic approaches comprise the application of general immunosuppressive drugs. Treatment with high-dose systemic glucocorticoids and adjuvant immunosuppressive drugs is effective, but also bears the risk of considerable side-effects. In light of recent advances in the pathogenic understanding of immunobullous disorders, additional therapeutic targets including pro-inflammatory cytokines (TNF- α) and peripheral B cells have been identified. Herein we review the role of biologic inhibitors of these two processes.

Keywords

Immunobullous disordersPemphigusPemphigoidRituximabInfliximabAdalimumabEtanercept

Introduction (Therapeutic Targets in Immunobullous Disorders)

Immunobullous disorders are chronic-relapsing diseases of the skin and mucous membranes with high morbidity and mortality [1, 2]. They are caused by a loss of intercellular adhesion of epidermal keratinocytes or dermal epidermal basement membrane, respectively, as a result of the binding of IgG or IgA autoantibodies against components of desmosomes, hemidesmosomes or components of the dermal-epidermal junction and dermal anchoring fibrils, respectively. Despite remarkable progress in understanding the immune pathogenesis of these disorders, the thorough characterization of their autoantigens and a general understanding of the immunological network which eventually leads to the formation of pathogenic autoantibodies is rather limited [3, 4].

In most instances, therapeutic approaches comprise the application of general immunosuppressive drugs [3, 4]. Treatment with high-dose systemic glucocorticoids and adjuvant immunosuppressive drugs is effective but also bears the risk of considerable side-effects. Due to their rarity, only few prospective controlled clinical trials are available in pemphigus and bullous pemphigoid (BP) which are limited by the low numbers of patients studied and the lack of statistically significant differences in many studies [5, 6]. A few studies compared different doses of prednisolone, i.v. corticosteroid pulses versus placebo, azathioprine versus mycophenolate mofetil, and the use of adjuvant treatment with methotrexate, cyclosporine, cyclosphosphamide, and high-dose intravenous immunoglobulins [7–9]. The combination of systemic corticosteroids (prednisolone, 1.0–1.5 mg/kg/d) and corticosteroid-sparing immunosuppressive drugs, mostly azathioprine and mycophenolate mofetil, is regarded as standard first-line therapy by most dermatologists. Derived from an advanced pathogenetic understanding, additional therapeutic procedures such as the depletion of peripheral B cells with rituximab or the removal of pathogenic IgG autoantibodies by immunoadsorption has proved to be efficacious in some of these disorders, such as pemphigus, but have not yet been fully validated [10–12]. We here focus on two specific therapeutic approaches, i.e. the blockade of pro-inflammatory cytokines, i.e. tumor necrosis factor-alpha (TNF-α) and therapeutic depletion of autoaggressive B cells with the anti-CD20 monoclonal antibody, rituximab, which has shown major promise in achieving long-term remissions in pemphigus [13–15].

Blockers of Pro-inflammatory Cytokines

Tumor necrosis factor alpha (TNF-α) is a cytokine involved in systemic inflammation that primarily acts on NK-kB pathway and the MAPK pathways. TNF- α levels have been shown to be elevated in numerous autoimmune diseases, providing an avenue for treatment by decreasing these levels [16]. The finding that TNF- α levels are increased in the sera of pemphigus and pemphigoid patients [17, 18] has led to research in the area of TNF- α inhibition in immunobullous diseases. In pemphigus, TNF- α serum levels correlate with both the number of lesions as well as the IgG autoantibody titers [19, 20]. In patients with bullous pemphigoid, TNF- α serum levels are likewise elevated compared to healthy controls and correlate with the number of lesions [21, 22]. Studies of blister fluid in both PV and BP have demonstrated increased levels of TNF- α compared to serum [22–24].

Despite the clear increase of TNF- α in immunobullous disease, its functional role in the disease process is not entirely clear. In vitro studies have demonstrated that TNF- α increases the IgG autoantibody-mediated acantholysis of pemphigus vulgaris (PV). This was likewise demonstrated in a murine model [25, 26]. This increased acantholysis was demonstrated with TNF- α dependent increases in complement activation [25] which is a common finding histologically in PV patients. Yet, these data only demonstrate TNF- α’s synergy with pathogenic IgG autoantibodies.

Initial reports of treatment with biologic TNF- α inhibitors appeared promising for the treatment of PV, pemphigus foliaceus (PF) and pemphigoid with success reported using infliximab [27–29], adalimumab [30] and etanercept [31–36]. Formal studies, though limited in size, have not been quite as promising. A randomized controlled trial of standard therapy with adjuvant etanercept failed to demonstrate any improved efficacy compared to standard therapy plus placebo in PV patients [37]. Likewise, a randomized study of pemphigus patients treated with infliximab with prednisone failed to demonstrate any clinical advantage over prednisone alone, though those patients treated with infliximab did IgG experience a significant decrease in anti-Dsg3 and anti-Dsg1 titers [38]. Oddly, studies using adjuvant sulfasalazine and pentoxifylline, a non-biologic and less specific TNF- α inhibitor, demonstrated improved patient outcomes compared to the standard therapy plus placebo group [39]. Likewise, in a randomized controlled trial of ocular cicatricial pemphigoid patients, adjuvant pentoxyfylline was associated with improved clinical and histopathologic outcomes [40]. The efficacy of non-biologic and less specific TNF- α inhibitors may suggest a therapeutic target that involves TNF- α, but does not solely deplete it.

While the efficacy of biologic anti-TNF- α appears limited, there have been additional reported cases of paradoxical development of immunobullous disease secondary to beginning anti-TNF- α biologic agents [41–44]. The paradoxical development of certain diseases following the initiation of TNF- α inhibitors has been well documented, with psoriasiform dermatoses, granulomatous eruptions, and uveitis being most frequently reported [45]. The paradoxical development of pemphigus may be explained by the observation that in one study, TNF- α negatively correlated with anti-desmoglein IgG autoantibodies in pemphigus patients in remission [46]. Thus, certain TNF- α levels may be required to keep the disease in check.

Rituximab in Pemphigus and the Pemphigoids

Rituximab is a chimeric monoclonal IgG that targets CD20, a glycosylated phosphoprotein expressed on the surface of all B-cells starting at the pro-B-cell phase. As B-cells mature, their expression of CD20 increases. Once B-cells mature into plasma cells, however, expression of CD20, as well as many other common B-cell surface antigens ceases. Rituximab therefore destroys B-cell progenitors, but not antibody secreting plasma cells or stem cells. Short-lived plasma cells are more dependent on CD20 memory B-cells for replenishment than long-lived plasma cells. Thus, rituximab has a greater effect on depletion of short-lived plasma cells. This can be demonstrated by the relative decrease in serum IgG autoantibodies to total immunoglobulin levels seen clinically, as IgG autoantibodies appear to be produced more frequently by short-lived plasma cells [47–49]. Likewise, IgG against common pathogens does not decrease following treatment with rituximab, indicating a failure to deplete long-lived plasma cells [47, 50]. Rituximab additionally exerts an effect on autoreactive T-cells in a less direct manner [51, 52].

The process of rituximab mediated B-cell depletion takes approximately 2–4 weeks, while B-cell repopulation occurs 5–6 months after infusion [14, 52–54]. With the destruction of the late pro-B-cells, new generations of immature B-cells replace the old, undergoing VDJ heavy chain arrangement and VJ light chain arrangement, which results in a novel antibody repertoire [53].

The loss of autoreactivity following treatment with rituximab is likely second to the changes in IgG reactivity against particular subdomains within Dsg3. Thus clinically, patients may maintain IgG antibodies against the ectodomain of Dsg3 despite treatment, yet these antibodies will not be pathogenic. As such, anti-Dsg1 IgG titers may be a more reliable marker of clinical status than anti-Dsg3 IgG [55].

Clinical Application

The efficacy of rituximab in the treatment of PV has been well documented through numerous large sized studies [13, 14, 56–60], with approximately 60–80 % of PV and PF patients experiencing complete remission [61–63]. Likewise, the use of rituximab in mucous membrane pemphigoid has additionally been well documented. Le Roux-Villet et al. demonstrated complete response in all affected sites in 68 % (17/25) of patients while Heelan et al. reported 75 % (6/8) patients to have a complete remission following a single cycle of rituximab [64, 65]. Fewer studies have been conducted in the other immunobullous disorders. In a review of 16 BP patients treated with rituximab, Shetty et al. demonstrated that 69 % of patients experienced complete remission, which remains comparable to that seen in PV and PF [66]. Likewise, numerous case reports have demonstrated successful clinical outcomes in patients with epidermolysis bullosa acquisita (EBA) treated with rituximab [67–75]. As EBA remains extremely rare with an estimated incidence of 0.2 per million per year [76], it is unlikely that larger studies will be possible. Despite the paucity of reported clinical outcomes in EBA patients treated with rituximab, efficacy appears comparable to that of other immunobullous disorders.

In contrast to the other immunobullous disorders, paraneoplastic pemphigus does not exhibit as consistent of a response to treatment, with most studies demonstrating only a marginal clinical improvement [77]. This is curious, as paraneoplastic pemphigus, like PF and PV, is an IgG mediated disease with numerous autoantibodies present. Additionally, paraneoplastic pemphigus most commonly occurs secondary to lymphoproliferative disorders, particularly non-Hodgkin lymphoma which is often responsive to rituximab on its own [77]. Thus, the effect of rituximab could be twofold by targeting the lymphoproliferative disease process while also leading to the destruction of B-cells before they develop into IgG autoantibody secreting plasma cells. Schadlow et al., however, presented a case that demonstrates that this may not be the case. They described a patient with long standing B-cell lymphoma who did not experience clinical improvement with rituximab [78]. It is thus possible that the length of time with the primary malignancy may affect the response to rituximab in paraneoplastic pemphigus. Nevertheless, paraneoplastic pemphigus is a complex disease that does not entirely follow the pathogenic steps seen in other immunobullous disorders.

Treatment Protocols

Standard treatment protocols for immunobullous disorders include the lymphoma protocol (375 mg/m² × 4 weeks) and the rheumatology protocol (1000 mg weekly × 2 weeks), with some less common protocols halving the dosage or duration of treatment. In one review by Zakka et al., patients treated with the lymphoma protocol demonstrated a slightly lower response rate with a higher mortality rate, yet a low rate of infection and relapse protocol than those patients receiving the rheumatology protocol [62]. Our analysis, however, demonstrated that patients responding to a single cycle of rituximab had a greater disease free period when treated with the lymphoma protocol rather than the rheumatology protocol. We additionally found the half rheumatology protocol (500 mg weekly × 2 weeks), to be the least efficacious of protocols, with a shorter time until relapse and fewer patients experiencing complete response [79]. Kanwal et al. likewise demonstrated this in a prospective blinded study comparing the full rheumatology protocol to the half rheumatology protocol [80]. Heelan et al. demonstrated success with a modified rheumatology protocol whereby patients receive 1 g on day 1 and 15, with 500 mg given at 6 month intervals when clinically necessary [60]. With this protocol, they achieved 89 % remission with or without adjuvant, and 28 % remission that did not necessitate adjuvant therapy. Nevertheless, treatment preferences vary widely between physicians and there still remains significant controversy regarding protocol selection [81].

Adjuvant therapies may additionally be used with these rituximab protocols, both during the initial cycle of rituximab and as maintenance. While more traditional immunosuppressants such as corticosteroids, azathioprine, mycophenolate and cyclophosphamide have been used, newer adjuvants such as immunoadsorption or IVIG have proven to be efficacious as well [13, 15].

Safety

The most common adverse reaction to rituximab is a mild transfusion reaction [82, 83], with more severe complications including cardiac toxicity and pulmonary toxicity [84, 85]. The most common associated adverse event remains infection. The risks of rituximab in the treatment of immunobullous disorders must, however, be compared to those associated with chronic steroid suppression and non-biologic immunosuppressive medications. In a review of 153 pemphigus patients treated with rituximab, Feldman et al. demonstrated that only 7 % developed serious infections with 1.3 % fatalities [61]. Similarly, a large study of rituximab treatment for systemic lupus erythematosus (SLE) demonstrated a 9.5 % risk of serious infection [86]. However, in a large scale review of patients treated with rituximab for varying autoimmune disease, those with autoimmune blistering disease had a significantly greater mortality rate (10.4 % vs. 2.4 %) than those with other autoimmune diseases [84]. In contrast, an alternative study demonstrated the highest incidence of opportunistic infection in patients treated for SLE [87]. While the incidence of adverse events is reasonably a cause for concern, these values must be weighed against the risks of alternate therapies

Patients treated with corticosteroids demonstrated an 8 % incidence of mild to severe infections and patients treated with corticosteroids plus mycophenolate mofetil demonstrated a 21 % incidence of infection [88]. Interestingly, of the mucous membrane pemphigoid patients treated with rituximab, only those on concomitant immunosuppressants and high-dose corticosteroids experienced severe infectious complications [64]. As the classification of infection severity varies between individual studies, it remains challenging to truly compare the risks of infection in rituximab to traditional, non-biologic therapies.

Hepatitis B reactivation additionally remains a concern when starting a patient on rituximab. It is thus recommended to screen patients for hepatitis B before beginning therapy [89]. Chronic or high dosed systemic steroid therapy, however, also increases the risk of hepatitis B reactivation, though routine screening is not considered equally essential [90].

While IVIG has demonstrated efficacy in treating immunobullous disorders, it has also been suggested as a useful adjuvant to rituximab in decreasing the incidence of infections [13, 91]. While IVIG in theory repletes serum IgG at the time of B cell depletion, it is unclear how the two medications interact with each other, complement and the Fc receptor. Additionally, the use of IVIG in itself comes with certain risks ranging in severity from mild infusion reactions to aseptic meningitis [92].

Treatment Resistance

Resistance to rituximab can occur through the formation of anti-chimeric antibodies, as the murine sequences of the chimeric IgG₁ may contain immunogenic sequences. These anti-drug antibodies were more often observed in patients treated for autoimmune diseases rather than lymphoma. These anti-drug antibodies interfere with the ability of rituximab to bind to B-cells in vitro [93], leading to a decreased clinical response to treatment [94]. Additionally, these anti-drug antibodies are associated with the development of serum-like sickness and infusion reactions.

Fc receptor polymorphisms may additionally lead to treatment resistance by decreasing the affinity of receptor binding to IgG. For example, the FcγRIIIa polymorphism and FcγRIIa polymorphism are associated with a decreased response to rituximab in patients treated for lymphoma [95]. Similar findings were seen in SLE, where the FcγRIIIa polymorphism was predictive of decreased treatment efficacy, with a tenfold increase in rituximab serum level necessary to achieve comparable B-cell depletion. While these polymorphisms have known effects in other disease processes such as lymphoma and SLE, it is unclear what effect they have in immunobullous disorders. For example, while the spliced mRNA transcript of CD20 (D393-CD20) has been associated with treatment resistance in lymphoma patients, this transcript was not associated with treatment failure in patients with pemphigus [96].

The presence of central memory cells occupying the bone marrow compartment as well as long-lived B memory may lead to a decreased response to treatment, as these are not viable targets for rituximab [97]. This is consistent with our finding that an increase in the duration of disease was associated with a decrease in clinical response to treatment in patients with PV and PF treated with rituximab [79]. Lunardon et al. likewise found that patients treated with rituximab earlier in the course of the disease had better outcomes [58].

Relapse

Despite its immediate effectiveness in a majority of patients, rituximab does not necessarily appear to alter the long-term relapse rate [55]. In fact, in one large retrospective study of 92 pemphigus patients, 61 % of patients relapsed following a single cycle of the rheumatology protocol, with a mean duration of 15 months [60]. Interestingly, patients who required adjuvant immunosuppression experienced relapse sooner than those only receiving rituximab. We did not, however, find a correlation between adjuvants used and time to relapse [79]. Studies in mucous membrane pemphigoid have additionally demonstrated significant relapse rates necessitating further cycles in a fairly short period of time [65, 98].

Relapse rates may, however, be tied to the underlying genetic aberrations leading to clinical disease. For example, following multiple treatments with rituximab over an extended course of time, patients no longer express anti-Dsg3 B-cell response. Once this lineage of B-cells is successfully removed from the patient’s immune repertoire, clinical disease ceases [99]. Likewise, there is an increase in the expression of the VH1-46 mutation in pemphigus patients, a mutation of a gene involved in heavy chain VDJ recombination. This mutation leads to Dsg3 autoreactivity with few to no mutations necessary [100]. Thus in these patients, rituximab may not effectively prevent relapse, as new anti-Dsg-3 clones will simply reform following B-cell depletion.

Certain therapeutic options may exist to increase the length of time until relapse such as immunoadsorption [79] or minimal maintenance therapy. The use of intermittent rituximab following an initial cycle has proven controversial. Gregoriou et al. showed that purely prophylactic rituximab given 6 months following the initial rituximab cycle was ineffective in preventing relapse in pemphigus patients [101]. In cases of impending relapse however, Cianchini et al. demonstrated that repeated cycles of rituximab sufficiently mitigated clinical relapses without necessitating the use of concomitant immunosuppression [59].

Questions

1.
What is the most common adverse reaction occurring with rituximab administration?
A.

Mild transfusion reactions
2.
Does rituximab directly deplete plasma cells?
A.

No. It destroys pre-B-cells and mature B cells which eventually develop into plasma cells, but it has no direct effect on plasma cells or stem cells
3.
What are the two most common dosing protocols for rituximab in the treatment of immunobullous disease?
A.

The lymphoma protocol (375 mg/m² × 4 weeks) and the rheumatology protocol (1000 mg weekly × 2 weeks)

References

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