Fig. 10.1
Rituximab leads to B-cell depletion by a combination of antibody-dependent cell-mediated cytotoxicity, complement-mediated lysis, and direct apoptosis secondary to the binding of the monoclonal antibody to CD20. This decrease in the B-cell population leads to a subsequent decrease in the development of antibody-secreting plasma cells. IVIG targets pathogenic IgG autoantibodies in pemphigus by inducing an increased Ig catabolism via binding to the neonatal Fc receptor, as well as acting on numerous other immunologic sites. Immunoadsorption removes serum IgG with a very high specificity, reducing the circulation of pathogenic autoantibodies
10.2 Immunoadsorption (IA)
Immunoadsorption has recently gained major interest as a therapeutic option for pemphigus since it directly targets pathogenic IgG autoantibodies [14, 15]. In contrast to nonselective plasmapheresis, immunoadsorption removes serum IgG with a very high specificity. At present, the availability of immunoadsorption is limited since this therapeutic regimen is not available in many countries. A variety of immunoadsorption devices have been utilized including tryptophan adsorbers and regenerative adsorbers such as protein A or synthetic ligands (e.g., PGAM146, Globaffin) that have a high affinity to the Fc portion of human IgG. The efficacy of therapeutic immunoadsorption in pemphigus largely depends on the adsorber utilized and the treatment protocol. Depending on the absorption device, serum concentrations of IgG antibodies against desmogleins 1 and 3 are reduced by 30–80 % [16–19].
At present, the clinical efficacy of immunoadsorption in pemphigus is based on observations from uncontrolled single-case studies and case series. In most instances, immunoadsorption is performed in an adjuvant setting in combination with immunosuppressive drugs such as azathioprine, mycophenolate, methotrexate, or cyclosporin as 4-day cycles which can be repeated in monthly intervals [20]. There is generally agreement that removal of serum IgG autoantibodies by immunoadsorption is associated with improvement of mucocutaneous blistering. The long-term effects of immunoadsorption are not yet well characterized; long-term improvement after immunoadsorption has been reported in some studies. In patients with refractory pemphigus, immunoadsorption was successfully combined with treatment with rituximab and/or intravenous immunoglobulins [20, 21]. Most patients appear to tolerate immunoadsorption well. Among the reported adverse effects are hypotension, bradycardia, anaphylaxis, sepsis from the central catheter, and venous thrombosis [22]. Currently, a prospective multicenter trial in 24 German dermatology departments addresses the question of whether adjuvant treatment with immunoadsorption is superior to treatment with systemic glucocorticoids plus azathioprine or mycophenolate alone in patients with acute onset, chronic active, or relapsing pemphigus. The primary endpoint is time to clinical remission based on the initial observation that removal of pathogenic serum IgG autoantibodies by immunoadsorptions leads to faster clinical remissions.
10.3 High-Dose Intravenous Immunoglobulins (IVIG)
Similar to immunoadsorption, treatment with high-dose intravenous immunoglobulins (IVIG) has been introduced in pemphigus based on the contention that exogenous IgG blocks the action of pathogenic IgG autoantibodies [23, 24]. Current concepts suggest that IVIG targets pathogenic IgG autoantibodies in pemphigus by inducing an increased Ig catabolism via binding to the neonatal Fc receptor. Many single-case reports and case series suggest that IVIG, mostly applied in an adjuvant setting in combination with immunosuppressants such as azathioprine, mycophenolate, cyclophosphamide, and methotrexate, is efficacious [25]. In most instances, patients received IVIG at a dose of 2 g/kg/cycle over two to four consecutive days, and IVIG cycles were repeated in 4- to 6-week intervals. A glucocorticoid-sparing effect of adjuvant IVIG was suggested by a small retrospective study that found a significant reduction of systemic glucocorticoids upon IVIG treatment [26, 27]. IVIG therapy is well tolerated; side effects include headache and aseptic meningitis. Prior to initiating treatment, total IgA deficiency and reduced kidney function need to be excluded.
The best evidence for a beneficial therapeutic effect of IVIG in pemphigus is provided by a Japanese randomized multicenter trial in 61 adults with glucocorticoid-resistant pemphigus (defined as a failure to respond to ≥20 mg prednisolone/day) [28]. Patients either received 400 mg IVIG/kg/day over 5 consecutive days, 200 mg IVIG/kg/day over 5 days, or placebo infusions for 5 days. The primary endpoint of the trial was the time that the patients could be maintained on the previous treatment protocol (i.e., time to escape protocol). The study showed that the time to escape protocol was significantly longer in patients who had received 400 mg IVIG/kg/day compared to patients who had received the lower IVIG dose or placebo. However, the difference in the time to escape protocol for the 200 mg IVIG group and the placebo group was not statistically significant. Side effects are usually mild to moderate adverse events such as headache, back pain, increased blood pressure, and abdominal discomfort. Aseptic meningitis is a serious side effect of IVIG therapy that requires immediate termination of treatment. Anaphylaxis is a potential risk of IVIG treatment in patients with IgA deficiency.
10.4 Rituximab
10.4.1 B-Cell Depletion and Repopulation
Rituximab is a chimeric murine-human monoclonal IgG that targets CD20, approved by the Food and Drug Administration for the treatment of many B-cell lymphomas as well as rheumatoid arthritis and granulomatosis with polyangiitis. The off-label use of rituximab has been vast, including immunobullous disorders, systemic lupus erythematosus (SLE), and dermatomyositis. CD20 is a glycosylated phosphoprotein that is expressed on the surface of all B cells starting at the pro-B-cell phase which also corresponds with heavy chain variable, diversity, and joining region (VDJ) rearrangement. A case of a CD20-deficient patient suggests CD20 is also involved in T-cell-independent antibody response [29].
As B cells mature, CD20 expression increases. When mature B cells differentiate into plasma cells, expression of many common B-cell surface antigens, including CD20, is lost. Thus, rituximab destroys B-cell progenitor cells but not stem cells or antibody-secreting plasma cells. Peripheral B-cell depletion typically takes place between 2 and 4 weeks following infusion. B-cell repopulation takes place a mean 5–6 months following infusion, though in some cases B-cell depletion persists for up to 15 months [30–33]. As late pro-B cells are destroyed by rituximab, the new generation of immature B cells undergoes VDJ heavy chain arrangement and VJ light chain arrangement resulting in a novel antibody repertoire [30]. In PV, this likely results in the observed changes in IgG reactivity against particular subdomains within Dsg3, whereby patients may lose reactivity to certain subdomains following treatment, despite maintaining IgG antibodies against the ectodomain of Dsg3. Clinically, the recurrence of IgG autoantibodies targeting the patient’s original pathogenic domain, most commonly Dsg3EC1, results in relapse [34]. Interestingly, anti-Dsg1 IgG titers also appear to be a more reliable indicator of clinical status of pemphigus than total anti-Dsg3 IgG [35].
Repopulation first occurs with the development of CD5+/CD38high naive B cells, followed by immature B cells (CD19−/IgD−/CD38high/CD10low/CD24high). The return of CD27+ memory B cells can remain reduced following treatment for up to 2 years [31, 36]. Repopulation with certain ratios of circulating B-cell subsets appears to have a predictive effect on disease relapse, with higher ratios of memory B cells at the time of repopulation related to relapse. Repopulation with certain subtypes additionally may predict treatment success. PV patients who achieved complete remission following treatment with rituximab had a greater number of transitional B cells and IL-10 secreting regulatory B cells as well as a higher ratio of CD19+/CD27− naïve B cells to CD19+/CD27+ memory B cells [37].
Short-lived plasma cells rather than long-lived plasma cells are more dependent on C20+ memory B cells for replenishment. Thus, rituximab has a greater effect on the eventual depletion of short-lived plasma cells rather than long-lived plasma cells which can remain in circulation for an indefinite period of time. This may in part explain the more significant decrease in serum IgG autoantibodies relative to total immunoglobulin levels, as IgG autoantibodies appear to be produced more often by short-lived plasma cells [38–40]. In fact, following treatment with rituximab, IgG to common pathogens and recall antigens does not decrease [38, 41]. This can in part be explained by rituximab-mediated increases in B-cell-activating factor (BAFF) expression, which is associated with increased pathogen-specific IgG such as anti-Epstein-Barr-virus IgG and anti-varicella-zoster-virus IgG, but not autoantibodies in pemphigus [42]. Following repopulation with CD19+ B cells, BAFF levels return to normal IgG. In a few reported cases of bullous pemphigoid patients treated with rituximab, early relapse was associated with lower peak serum levels of BAFF [43].
10.4.2 Mechanism of B-Cell Destruction
The mechanism by which rituximab-induced B-cell depletion occurs is complex and occurs by a combination of several mechanisms: antibody-dependent cell-mediated cytotoxicity (ADCC), complement-mediated lysis, and direct apoptosis. The degree to which each of these processes results in cell death is, however, somewhat disease specific, thus making comparison to lymphoma and other autoimmune disease more challenging.
Antibody-dependent cell-mediated cytotoxicity (ADCC) occurs when monocytes and macrophages are recruited via Fc and FcyR interaction [44, 45]. This interaction subsequently leads to the release of cytotoxic cytokines, proteases, and reactive oxygen species [46]. This process is primarily mediated by NK cells [47, 48]. NK cells function in a primarily IL-2-dependent manner and are enhanced following treatment with rituximab [49, 50]. FCγRIII (CD16) is the major Fc receptor involved in ADCC which leads to binding to the Fc portion of the antibody, subsequently resulting in the release of IFN-γ. FCγRIIB (CD32) is a potent regulator of ADCC, enhancing the internalization of rituximab. In follicular lymphoma, FCγRIIB predicts a poor response to rituximab [51]. Likewise, mice deficient in FCγRIIB demonstrated an increased ability to undergo ADCC [52]. Though less clear, pure blockage of the Fc receptor may additionally account for some of the short-term responses seen with rituximab [53].
Rituximab is able to bind to C1q inducing complement-mediated cell lysis [54] via the formation of reactive oxygen species [55]. In fact, in mice deficient in C1q, rituximab loses its efficacy against lymphoma cells [56]. Increases in C3b breakdown products additionally lead to increased rituximab-mediated cell death of CD20+ cells [57]. Rituximab also causes redistribution of CD20 into Triton x-100-insoluble lipid rafts which cluster and enhance complement binding [58, 59]. In contrast, increased complement defense molecules such as CD55 and CD59 have been associated with resistance to treatment in lymphoma [60]. Likewise, in vivo studies of complement-deficient mice have demonstrated reduced anti-CD20 activity [61, 62]. In chronic lymphocytic leukemia, rituximab depletes complement, which in turn reduces its therapeutic function until fresh frozen plasma is given, restoring the complement pool [63]. As complement involvement plays a critical role in the acantholysis seen in pemphigus, it is unclear whether the effect of rituximab on this pathway plays a role in clinical response [64].
Rituximab can also influence apoptosis directly by causing cross-linking of CD20 and the monoclonal antibodies [65]. A caspase-independent mechanism of rituximab-induced cell death has also been described [66]. Rituximab’s ability to directly induce apoptosis, however, appears to be marginal in comparison to other mechanisms [67].
10.4.3 Cellular Immunity
While immunobullous disorders may appear to be primarily a disorder of humoral immunity, T cells are in fact a critical component of the pathogenesis and maintenance of autoimmunity [9, 68–70]. Plasma cells appear to receive signaling from CD4+ T cells and antigen-presenting cells, which may dictate their longevity [71, 72]. In patients with PV, treatment with rituximab led to a decrease in Dsg3-specific CD4+ T cells, though the total quantity of CD4+ cells as well as the quantities of cytokines that they produce do not appear to change significantly [36, 73]. Interestingly, however, tetanus toxoid-reactive CD4+ T cells did not change following rituximab, thus demonstrating a role of B-cell-mediated regulation of autoreactive T-cell activation [33]. Likewise, rituximab was found to have an effect on regulatory T cells [74] and monocyte-derived macrophages [75] in SLE and rheumatoid arthritis, respectively. In idiopathic thrombocytopenic purpura, patients who received rituximab experienced a restoration in Th1/Th2 ratio with an increase in the number of Treg cells [76, 77]. Similar findings have been noted in SLE, yet not RA [74, 78, 79]. Rituximab also leads to a decrease in the expression of CD40 and CD80 on B cells which affects T-cell activation [80].
A small subset of T cells (1.6 %) expresses CD20 and exists in the normal population. These cells are split with 45 % expressing CD8 and 55 % expressing CD4. In RA, these cells constitutively express IL-1B and TNF-α and are depleted following treatment with rituximab. It is unclear whether these cells play a clinically meaningful role in other disease states such as in immunobullous disorders [81].
10.4.4 Mechanisms of Treatment Resistance
Multiple potential mechanisms for treatment resistance have been explored. Resistance can occur through the formation of anti-chimeric antibodies, as the murine sequences of the chimeric IgG1 can contain immunogenic sequences. Interestingly, these anti-drug antibodies were more often observed in rituximab used for the treatment of autoimmune disease rather than lymphoma. The inhibitory effect of these anti-drug antibodies has been demonstrated to interfere with the ability of rituximab to bind to B cells in vitro [82] as well as decreased clinical response to treatment [83]. These anti-drug antibodies have also been associated with the development of serum-like sickness and infusion reactions.
Fc receptor polymorphisms additionally appear to provide a means for treatment resistance by decreasing the affinity of receptor binding to IgG. The FcγRIIIa polymorphism and FcγRIIa polymorphism correlated with a decreased response to rituximab treatment in lymphoma [84]. In SLE, the FcγRIIIa polymorphism was additionally found to be predictive of decreased treatment efficacy, with a tenfold increase in rituximab serum level necessary to achieve comparable B-cell depletion. This failure may be in part due to the observation that NK cells with the FcγRIIIa polymorphism require a significantly greater concentration of rituximab in order to induce the same level ADCC [85]. While these polymorphisms have known effects in other disease processes, it is unclear what effect they have in immunobullous disorders. For example, while a spliced mRNA transcript of CD20 (D393-CD20) has been associated with resistance to rituximab in lymphoma patients, this transcript was not found to be associated with failure to respond to rituximab therapy in patients with pemphigus [86].
Lastly, the inability of rituximab to effectively remove B cells occupying the bone marrow compartment may make rituximab ineffective in certain patients with central memory cells [87]. This is consistent with our finding that an increase in the duration of disease was associated with a decrease in the percentage of patients experiencing complete response versus partial response [88].
10.4.5 Clinical Studies
10.4.5.1 Pemphigus Vulgaris and Foliaceus
Large-scale clinical trials have been conducted demonstrating the clinical efficacy of rituximab in PF and PV [32, 89–93]. Approximately 60–80 % of PV and PF patients treated with rituximab experienced complete remissions [94, 95]. Most studies have used either the lymphoma protocol (375 mg/m2 × 4 weeks) or the rheumatology protocol (1,000 mg weekly × 2 weeks). In a review of 272 patients, Zakka et al. found a lower response rate with a higher mortality rate, yet a low rate of infection and relapse in patients treated with the lymphoma protocol in contrast to the rheumatology protocol [95]. Variations of these protocols have been described, with some groups halving the dosages in the original two protocols. In our analysis of patients responding to a single cycle of rituximab (those patients achieving either partial or complete remission following treatment), patients treated with the standard lymphoma protocol appeared to demonstrate an increase in the time until relapse. We additionally found the half rheumatology protocol (500 mg weekly × 2 weeks) to be the least efficacious, with a shorter time until relapse and fewer patients experiencing complete response [88]. Likewise, Kanwar et al. in a prospective blinded study comparing the full rheumatology protocol to the half rheumatology protocol demonstrated improved outcomes with the regular-dosed rheumatology protocol versus the half-dosed protocol [96]. Nevertheless, treatment preferences vary widely between physicians, and there remains significant controversy regarding protocol selection [97].
Despite its effectiveness, rituximab does not necessarily appear to alter the long-term relapse rate without maintenance therapy in comparison to conventional immunosuppressive therapy [35]. Nevertheless, certain therapeutic options exist to increase the length of time until relapse such as immunoadsorption [88] or the use of minimal maintenance therapy. In cases of relapse, however, Cianchini et al. demonstrated that repeated cycles of rituximab sufficiently mitigated clinical relapses without necessitating the use of concomitant immunosuppression [92].
10.4.5.2 Paraneoplastic Pemphigus
Paraneoplastic pemphigus carries a far worse prognosis than either PV or PF, as treatment must ultimately be directed against the underlying malignancy. In particular, patients presenting with erythema multiforme-like lesions with histologic keratinocyte necrosis carry an even worse prognosis [98]. Paraneoplastic pemphigus most commonly occurs secondary to lymphoproliferative disorders, particularly non-Hodgkin lymphoma [99]. Thus at times, rituximab may be indicated to treat the malignancy. Paraneoplastic pemphigus like PF and PV is, however, still an IgG-mediated disease with numerous autoantibodies present. Antibodies against envoplakin and periplakin are, however, the most sensitive and specific markers in a clinically suggestive setting [100]. The effect of the rituximab may thus be twofold by targeting the lymphoproliferative disease process while also leading to the destruction of B cells that may develop into IgG autoantibody-secreting plasma cells. Yet, clinical improvement in paraneoplastic pemphigus following treatment with rituximab has been mixed, with most case reports demonstrating only a marginal improvement [99]. A particularly interesting case is that presented by Schadlow et al. that described a patient with long-standing B-cell lymphoma who did not experience clinical improvement with rituximab [101]. This is both surprising and suggestive that perhaps the length of time with the primary malignancy may have an effect on the paraneoplastic pemphigus and its susceptibility to rituximab. Nevertheless, paraneoplastic pemphigus is a complex disease process that does not follow the similar pathogenic steps seen in other immunobullous disorders.
10.4.5.3 Other Autoimmune Blistering Diseases
Compared to PV, there have been far fewer studies and reported cases evaluating the efficacy of rituximab in bullous pemphigoid. In a 2013 review of 16 previously reported cases of BP patients treated with rituximab, Shetty et al. found that 69 % of patients experienced complete remission [102]. While this is comparable to the percentage of patients who experience complete remission in PV, this small sample size of reported cases prevents further analysis into factors associated with superior outcomes.
Several larger studies have examined the efficacy of rituximab in the treatment of mucous membrane pemphigoid. 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 [103, 104]. Nevertheless, the significant relapse rate necessitating further cycles in a short period of time remains a concern [104, 105].
A handful of reports have described successful clinical outcomes in patients with epidermolysis bullosa acquisita treated with rituximab [106–114]. As the disease remains extremely rare with an estimated incidence of 0.2 per million per year [115], it is unlikely that larger studies will be possible. Nevertheless, despite the limited reports, treatment outcomes of epidermolysis bullosa acquisita appear comparable to that of other immunobullous disorders.
10.4.6 Safety
The relative risks associated with chronic steroid suppression and nonbiologic immunosuppressive medications must be weighed against the risks associated with rituximab. In a review of 153 pemphigus patients treated with rituximab, 7 % developed serious infections with 1.3 % fatalities [94]. In comparison, a large study in SLE demonstrated a 9.5 % risk of serious infection [116]. While this number may be of concern, patients treated with corticosteroids demonstrated an 8 % incidence of mild to severe infections, while 21 % those receiving corticosteroids plus mycophenolate mofetil developed an infection [117]. While the severity of the infections must be taken into account, rituximab does not lead to many of the chronic medical conditions to which corticosteroids lead. Interestingly, many of the rituximab patients who developed an infection also received high-dose corticosteroids and other forms of immunosuppression. Of the mucous membrane pemphigoid patients treated with rituximab, only those experiencing severe infectious complications were on concomitant immunosuppressants and high-dose corticosteroids [103]. It thus remains challenging to truly compare the risks of rituximab monotherapy or rituximab with concomitant low-dose corticosteroids with traditional immunosuppression.
The concomitant use of IVIG has not only demonstrated efficacy in treating immunobullous disorders but has also been suggested as a useful adjuvant to rituximab in decreasing the incidence of infections [93, 118]. While IVIG in theory repletes serum IgG during 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 from mild infusion reactions to severe reactions such as aseptic meningitis [119].
References
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Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J. Bullous pemphigoid and pemphigus vulgaris–incidence and mortality in the UK: population based cohort study. BMJ. 2008;337:a180.PubMedCentralPubMed
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Beutner EH, Jordon RE. Demonstration of skin antibodies in sera of pemphigus vulgaris patients by indirect immunofluorescent staining. Proc Soc Exp Biol Med. 1964;117:505–10.PubMed
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