Introduction

The arrival of immunoadsorption (IA), also termed immunoapheresis, about 20 years ago [25] allowed the selective removal of Ig and immune complexes from patients’ circulation. IA has been successfully used in patients with systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, dilated cardiomyopathy, antibody-mediated graft rejection, Guillain–Barré syndrome, ABO-incompatible kidney transplantation, rheumatoid arthritis, idiopathic thrombocytopenic purpura, and hemophilia with inhibitors [12, 13, 15, 17, 24, 28, 37, 46, 49]. In the latter three disorders, IA has been approved by the US American Food and Drug Administration. IA depletes Ig irrespective of its specificity. Specific adsorbers have been developed for autoantibodies to the β1-adrenergic receptor in dilated cardiomyopathy (Coraffin®, Fresenius Medical Care), C1q in systemic lupus erythematosus (Miro®, Fresenius Medical Care), and to ABO blood group antigens [21, 29, 51, 74].

IA also comprises cytapheresis. In cytapheresis, leukocytes are depleted by filtration, a procedure termed leukocytapheresis, or granulocytes and monocytes/macrophages are removed using cellulose acetate beads (Adacolumn®, Jimro, Gunma, Japan). Cytapheresis is particularly employed in inflammatory bowel disease, but has also been applied in rheumatoid arthritis and systemic lupus erythematosus [39, 54, 55, 70].

In dermatology, IA has been increasingly used in patients with autoimmune bullous diseases. In addition, patients with psoriasis have been successfully subjected to cytapheresis [34] and most, recently, in patients with severe atopic dermatitis and very high serum IgE levels, SCORAD could be halved following 10 IA procedures (TheraSorb®, Miltenyi, Bergisch Gladbach) [27].

The novel therapeutic principle was particularly attractive for autoimmune bullous disorders since the pathogenic relevance of autoantibodies has been clearly established in most of them, including pemphigus [1, 2, 4, 56], bullous pemphigoid [23, 32, 42, 57, 67], anti-laminin 332 mucous membrane pemphigoid [31], and epidermolysis bullosa acquisita [66, 68, 69, 77]. In the present review, the application of IA in autoimmune blistering diseases is discussed.

Autoimmune bullous diseases

Autoimmune bullous diseases are a heterogeneous group of disorders that can be subdivided according to the level of split formation into intraepidermally blistering pemphigus diseases and subepidermal bullous disorders, latter including pemphigoid diseases, epidermolysis bullosa acquisita, and dermatitis herpetiformis. In the pemphigus group (pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus), autoantibodies recognize desmoglein 1 and 3, while in paraneoplastic pemphigus, additional proteins of the plakin family are bound [5, 75]. In the pemphigoid group (bullous pemphigoid, linear IgA disease, pemphigoid gestationis, mucous membrane pemphigoid), type XVII collagen (BP180), BP230, laminin 332, and α6β4 integrin are targeted. Autoantibodies in patients with epidermolysis bullosa acquisita react with type VII collagen in anchoring fibrils. In dermatitis herpetiformis, immune complexes containing IgA and epidermal transglutaminase are deposited in the upper dermis [61].

Within the group of autoimmune bullous skin diseases, in Central Europe and the USA, the most common are bullous pemphigoid and mucous membrane pemphigoid [6, 30, 36]. In other geographic regions, such as Iran and Israel, pemphigus is about 10 times more frequent as compared to Central Europe and the USA [9, 48], and in Africa, linear IgA disease is the second most common immunobullous disease, the most frequent being bullous pemphigoid [40].

In the majority of autoimmune bullous disorders, disease activity can be sufficiently controlled by systemic corticosteroids in combination with further immunosuppressants/immunomodulants, such as dapsone, doxycycline, methotrexate, azathioprine, or mycophenolate mofetil. However, adverse events of these therapeutic agents may significantly increase both morbidity and mortality [8]. In pemphigus, mucous membrane pemphigoid, and epidermolysis bullosa acquisita, treatment is challenging and only in a minority of patients, conventional immunosuppressive therapy induces clinical remission. Until recently, only cyclophosphamide and high-dose intravenous Ig had been available as potent second-line therapies. Meanwhile, IA and the monoclonal anti-CD20 antibody rituximab, which may also be used in combination, have been established as further therapeutic options.

Plasmapheresis

Before the introduction of IA, plasmapheresis was the sole therapeutic intervention that allowed the immediate decrease in pathogenic autoantibodies. In 1978, plasmapheresis was first employed in pemphigus [10]. Following promising reports on its successful application in pemphigus [52, 53, 71–73], the controlled prospective multicenter trial by Guillaume et al. was a major drawback for this treatment principle. In 34 pemphigus patients, treatment with prednisolone (tapering doses of 0.5 mg/kg/day with dose increases up to 2 mg/kg/day when required) was compared with the application of ten plasmapheresis procedures within 4 weeks in combination with the same prednisolone protocol. Although no differences were observed in clinical efficacy and cumulative prednisolone dose, in four patients of the plasmapheresis arm, a fatal sepsis occurred [18].

When compared with plasmapheresis, IA has several advantages: IA (1) more selectively removes Ig, (2) does not require the substitution of plasma components such as fresh-frozen plasma or human albumin (Fig. 1), (3) allows the processing of the two- to threefold plasma volume per treatment session, and (4) it is associated with a lower rate of adverse events, such as infections and allergic reactions [7]. When IA is available, it may thus preferentially be applied to selectively deplete Ig.

Fig. 1
figure 1

Schematic diagram of plasmapheresis and immunoadsorption (IA). In both plasmapheresis (a) and IA (b), patient plasma is generated from the patients’ blood by filtration or centrifugation. In plasmapheresis, the plasma is discarded and needs to be replaced by human albumin or fresh-frozen plasma (a). In contrast, in IA, the plasma is passed over a column that is loaded with an immunoglobulin (Ig)-specific ligand that binds the patient’s Ig. The Ig-depleted plasma is then re-infused after supplementation with the previously separated patient cells (b). Single-use IA columns are exhausted after being charged with Ig from 2–3 l of plasma, whereas in regenerable systems, a pair of adsorber columns is used. While one column is loaded with plasma, in the other, antibodies are eluted by a sudden pH change allowing for a continuous apheresis process

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Immunoadsorption

Immunoadsorption systems differ with respect to ligands, matrix, volume of the columns, affinity to certain Ig classes and reusability. As an adsorber matrix, usually, sepharose is used, but cellulose and polyvinyl alcohol is also applied (Table 1). In single-use devices, phenylalanine, tryptophan, dextran sulfate, and hydrophobic amino acids serve as ligands. Adsorbers capable of being regenerated contain the ligands protein A, the synthetic peptide PGAM146, or sheep antibodies-directed against human Ig (Table 1). No differences in IgG depletion rates between the protein A-based and the anti-human Ig-based reusable systems have been observed [38].

Table 1 Commercially available adsorber for removal of immunoglobulin
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In the first step of IA, plasma and cellular components are separated by plasma filtration or centrifugation (Fig. 1). Single-use adsorbers are subjected to the patient plasma until their capacity is utilized. In reusable systems, a pair of adsorber columns is used. While one column is loaded with plasma, the other is regenerated, i.e. the antibodies are flushed away, allowing for a continuous apheresis process. The three commercially available reusable adsorbers allow for up to 20 treatment sessions for the same patient.

Autoantibody levels can be lowered by 75% by a single IA procedure with a reusable system as exemplified by desmoglein-specific antibodies in patients with pemphigus for the initial 3 IA procedures (Fig. 2a). After three IA on three consecutive days, autoantibody levels can be decreased by about 95% (Fig. 2a). In contrast, a tryptophan adsorber achieves a 30% reduction [35]. In addition to its lower capacity, the latter has the side effect of a significant drop in fibrinogen levels. More importantly, a single IA procedure is less effective because autoantibodies re-diffuse from the tissue to the circulation and 24 h after the first IA, 40% of the initial levels are reached again (Fig. 2a). Interestingly, irrespective of the treatment protocol and adjuvant immunosuppression, lowering serum anti-desmoglein autoantibody levels by IA appeared to be sustainable. After 1 month of the first IA, autoantibody levels were decreased by nearly 80%, after 6 months, a reduction by 90% was observed. After 12 months, average reduction was still 90% as compared to the pre-IA anti-desmoglein levels with 30% of pemphigus patients in whom autoantibody levels were negative (Fig. 2b).

Fig. 2
figure 2

Autoantibody levels during immunoadsorption (IA). Autoantibody levels during the initial 3-day-treatment cycle (a). Ten patients with severe and/or refractory pemphigus were subjected to 3 IA on three consecutive days using regenerable systems (Immunosorba®, TheraSorb®). Levels of anti-desmoglein (Dsg) antibodies were determined by ELISA (MBL, Nagoya, Japan). Autoantibody levels prior to the first IA were normalized to 100 and levels of subsequent analyses are given in percent of the initial levels (light blue squares). Autoantibody levels were measured directly before and directly after the individual IA. Negative ELISA values are indicated by magenta squares. Mean anti-desmoglein autoantibody levels (black line) ± standard deviation as well as median levels (dotted line) are indicated. After the first IA, autoantibody levels decreased by 76%. Owing to re-diffusion from the tissue, autoantibody levels increased again to 40% of the initial values on the next day. This observation necessitates the serial application of IA on consecutive days. After the third IA autoantibody levels were reduced by 96% compared with pre-IA levels. Autoantibody levels during a follow-up period of 12 months after the initial treatment cycle (b). The long-term effect of IA on the circulating autoantibody levels is visualized. Data are retrieved from 22 previously reported pemphigus patients treated according to protocol 1, 2 and 5 [58, 63, 64]. Anti-desmoglein antibody levels were determined by ELISA (MBL). Autoantibody levels prior to initiation of IA were normalized to 100 and levels of subsequent analyses are given in percent of the initial levels (light blue squares). Negative ELISA values are indicated by magenta squares. Mean anti-desmoglein autoantibody levels (black line) ± standard deviation as well as median levels (dotted line) are indicated. After 1 month of the first IA, autoantibody levels decreased by an average of 79% and 5 months later, by 91% compared with the initial levels. After 12 months, autoantibody levels remained low and were reduced to 11% of the pre-IA levels

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Immunoadsorption in pemphigus

As soon as IA became available, this novel procedure has extensively been exploited in immunobullous diseases (Table 2). In 1998, IA was applied for the first time in these disorders, e.g. in a patient with paraneoplastic pemphigus [62]. In this patient, following the surgical removal of his retroclavicular myofibroblastic tumour, ten IA (Therasorb®) were performed over 4 weeks in conjunction with low-dose oral prednisolone that resulted in a complete remission defined as healing of all lesions and no further immunosuppression required [62]. Definitions of the clinical responses are given in Table 2.

Table 2 Immunoadsorption in autoimmune bullous skin diseases: concomitant immunosuppression, clinical response and adverse events
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To date, 48 pemphigus patients, 40 with pemphigus vulgaris, 7 with pemphigus foliaceus, and 1 with paraneoplastic pemphigus have been subjected to IA. In 38 patients, reusable systems were applied [11, 14, 19, 35, 45, 47, 58, 62–64] (Table 2). Assessing the real value of IA in immunobullous disorders is difficult, because no prospective controlled study has been performed yet. Indeed, all data are based on case reports and five case series of up to nine patients. In addition, different adsorbers and treatment protocols were applied. Below, the six reported treatment protocols are presented, the last one being currently applied in our patients with severe and/or refractory pemphigus.

Protocol 1

In a first protocol, repeated IA (Immunosorba®) was used in five refractory pemphigus patients in combination with tapering doses of methylprednisolone (initially, 0.5 mg/kg per day) and a single i.v. pulse of dexamethasone (100 mg on days 4–6) and cyclophosphamide (500 mg on day 4). IA was performed 19 times in each patient: on three consecutive days in the first week (days 1–3) and then four times in weekly, 2-weekly, 3-weekly, and 4-weekly intervals, respectively [58]. In all patients, after 12 weeks, autoantibody levels had decreased to <20% compared with pre-IA levels. Healing of all lesions was noted after 3–21 weeks [58]. After a follow-up period of 8–10 years, however, only one patient is still in clinical remission without relapse (unpublished data).

Protocol 2

In this approach, the same IA protocol was used in nine patients with pemphigus vulgaris. Unlike in the previous protocol, however, higher doses of methylprednisolone were given (initially 2.0 mg/kg per day) in conjunction with azathioprine (50–250 mg per day) or mycophenolate mofetil (2 g per day). The i.v. pulse with dexamethasone and cyclophosphamide was omitted in this protocol. In eight patients, rapid clinical remissions were induced [63]. At present, after follow-up periods between 6 and 7 years, five patients have remained in clinical remission without relapses; one patient died after all lesions had healed 2 years after initiation of IA, one patient suffered from a severe relapse, and one patient was lost for follow-up (unpublished data). While the second protocol resulted in better long-term responses, the fourfold higher corticosteroid doses and addition of azathioprine or mycophenolate mofetil may have contributed to an increased risk of severe adverse events.

Protocol 3

This protocol applied a single-use absorber system (IM TR350®). Six patients with refractory and three with acute severe pemphigus were treated on days 1 and 3, followed by i.v. prednisolone (1.5 mg/kg) on the same days. On day 4, methylprednisolone (0.5 mg/kg per day) in combination with additional immunosuppressants, including azathioprine, mycophenolate mofetil, and cyclophosphamide were initiated [35]. When compared with the long-term protocol with reusable systems [58, 63], markedly less reduction in serum autoantibodies and shorter durations of clinical improvement were noted [35].

Protocol 4

This approach included the application of the reusable Globaffin® adsorber in four refractory patients with pemphigus vulgaris and in two with pemphigus foliaceus. IA was performed on four consecutive days followed by IVIG (10 g) and in some patients, i.v. cyclophosphamide (750 mg/m2), on the fifth day. This procedure was repeated 4 weekly until all lesions had healed. Adjuvant immunosuppression consisted of prednisolone (1.0–2.0 mg/kg per day) and azathioprine (1.5–2.5 mg/kg per day)/mycophenolate mofetil (2–3 g per day). A rapid decline in serum autoantibodies was observed and most lesions cleared within a few weeks. During the follow-up period of 2 years, clinical remissions occurred in three patients while still on immunosuppressants. In the three others, partial remissions were induced [11].

Recently, six additional patients with pemphigus vulgaris, resistant to systemic corticosteroids combined with azathioprine or mycophenolate mofetil, were subjected to the same IA schedule [47]. IVIG and cyclophosphamide were omitted in these patients. In three patients, a clinical remission (defined as healing of all lesions, but further immunosuppression required) was achieved. The remaining three patients experienced partial remissions and were subsequently treated with rituximab [47].

Protocol 5

To have the patients benefit from both the rapid clinical response seen with IA and the striking long-term effect of rituximab [41, 59, 60], protocol 2 was modified as followed: IA (Immunosorba®) was performed on days 1, 2, 3, 8, 15, 22, 29, and then in 2-, 3-, and 4-weekly intervals as described [58, 63]; four rituximab infusions (375 mg/m2) were administered on days 9, 16, 23, and 30, a schedule that was adopted from patients with B-cell non-Hodgkin lymphoma. Concomitantly, patients received tapering doses of oral prednisolone (2.0 mg/kg per day) plus azathioprine (2.5 mg/kg per day) or mycophenolate mofetil (2 g per day) [64]. Seven patients with severe pemphigus, six of them with treatment-resistant disease, were included. Within 1 month, in four patients, no new lesions appeared and in three patients, partial remissions were obtained. After 1 year, one patient had achieved complete remission, four were in clinical remission, and two had reached partial remission [64]. In all patients, serum autoantibodies decreased strikingly. Four patients suffered from severe adverse events, including Staphylococcus aureus sepsis, P. carinii pneumonia, herpes zoster infection, pulmonary embolism, and deep venous thrombosis [64]. To date, after follow-up periods of 3 to more than 4 years, one patient is in complete remission, two in clinical, and one in partial remission. In three patients, relapses occurred between 14, 30, and 34 months after initiation of this regimen (unpublished data).

Following the same protocol, another patient with pemphigus vulgaris has been treated with excellent outcome (Table 2). His lesions cleared 8 weeks after the first IA and currently, he is in complete remission while circulating and tissue-bound autoantibodies have become undetectable [61].

Current protocol

Based on these data, the strength of IA in pemphigus seemed to rely on the rapid induction of clinical remission by swift reduction of circulation autoantibodies during the first weeks of treatment rather then the influence of long-term outcome. To maximize this effect, we currently perform IA on three consecutive days (referred to as 1 cycle) followed by additional cycles 3 weeks later and then 4 weekly until lesions have healed for 90% and serum autoantibodies have dropped to 10% of original levels (Fig. 3). Rituximab is applied twice at a dose of 1 g on days 4 and 25. This schedule was based on the one for rheumatoid arthritis for which rituximab had meanwhile been licensed. Unlike the rituximab protocol for rheumatoid arthritis in pemphigus, the second IA cycle and the second rituximab infusion were performed 3 weeks after the initial infusion to avoid reducing rituximab levels by subsequent IA. To decrease the rate of severe side effects encountered in Protocol 5 (see below), oral prednisolone was replaced by i.v. dexamethasone pulses (100 mg on 3 consecutive days) applied in conjunction with each IA. As in previous protocols, azathioprine or mycophenolate are also given (Fig. 3). Until now, 15 patients have been subjected to this protocol. Rapid clinical responses were seen (Fig. 4) while only two severe adverse events have occurred [65].

Fig. 3
figure 3

Novel treatment protocol for patients with severe and/or refractory autoimmune bullous diseases combining the rapid clinical response following immunoadsorption (IA) and the excellent long-term effect of rituximab. IA (red arrows) is performed on three consecutive days representing one treatment cycle. IA cycles are repeated after 3 weeks and then 4 weekly until lesions have healed to about 90% and serum autoantibodies have dropped by about 90%. Rituximab (green arrows) is applied twice at a dose of 1 g on days 4 and 25. In addition, i.v. dexamethasone pulses (100 mg on 3 consecutive days; blue arrows) are administered in prolonging intervals of initially 3, and later of up to 8 weeks together with daily azathioprine (2.5 mg/kg per day with normal TPMT) or mycophenolate mofetil (2 g per day)

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Fig. 4
figure 4

Clinical response in a patient with refractory pemphigus vulgaris treated with immunoadsorption (IA), rituximab, i.v. dexamethasone pulses, and azathioprine. Multiple erosions on the palate before (a) and healing of all lesions after 18 IA (6 treatment cycles of 3 IA) and 5 months after initiation of the combination regimen including protein A immunoadsorption, rituximab, i.v. dexamethasone pulses and azathioprine (b). For further details of the treatment protocol refer to the section current protocol and Fig. 3

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IA treatment of three additional patients with refractory pemphigus vulgaris has been reported [14, 19, 45]. Among them, one patient received monthly IA for almost 2 years [14]. Further details are presented in Table 2.

IA in pemphigoid diseases and epidermolysis bullosa acquisita

Immunoadsorption has also been successfully performed in four refractory patients with bullous pemphigoid, three with epidermolysis bullosa acquisita, and one patient with pemphigoid gestationis and anti-p200 pemphigoid, respectively (Table 2).

In 2 patients with bullous pemphigoid and high-serum levels of anti-BP180 autoantibodies (312 and 10,226 U/ml) who were unresponsive to methylprednisolone (0.5 mg/kg per day) plus dapsone (1.5 mg/kg per day) and methylprednisolone (1.5 mg/kg per day) plus azathioprine (2.0 mg/kg per day), respectively, two single IA on consecutive days using the tryptophan-linked matrix IM TR350® resulted in dramatic clinical responses within 2 weeks after initiation of IA and sharp decreases of circulating autoantibodies [20]. The other two patients with bullous pemphigoid were treated with four and six IA by the use of dextran sulphate conjugated cellulose columns (Selesorb®) during a 2-week period. Skin lesions improved considerably and serum autoantibodies decreased [22].

In one relapsed patient with the inflammatory variant of epidermolysis bullosa acquisita, IA (Immunosorba®) was performed following Protocol 2 with some modifications [63]. After 26 months and 37 IA that were performed in finally monthly intervals, clinical remission was achieved while prednisolone could be reduced to 4 mg per day [33]. In two patients with the mechanobullous variant of epidermolysis bullosa acquisita, 2 IA (Globaffin®) were combined with rituximab and mycophenolate mofetil leading to partial remissions [43].

In an 18-year-old woman with pemphigoid gestationis, 6 IA (Therasorb®) applied between the 30th and 34th week of gestation in conjunction with prednisolone (0.6 mg/kg per day) controlled her disease. She had previously been unresponsive to methylprednisolone (1.0 mg/kg per day). In parallel with the clinical response anti-BP180 autoantibodies decreased by 70% and the prednisolone dose could be reduced to 0.3 mg/kg per day [76].

Very recently, we have described a 70-year-old male patient with anti-p200 pemphigoid in whom 2 IA with IM TR-350® combined with oral doxycycline 200 mg per day and topical clobetasol propionate 0.05% twice daily resulted in a clinical response within 2 weeks without adverse events [26]. This treatment regimen was chosen due to the severity of skin lesions, relatively high autoantibody levels, and an active duodenal ulcer accompanied with hematochezia refraining us from employing systemic corticosteroids. Eighteen weeks later, 2 weeks after the discontinuation of doxycycline, a severe relapse occurred. Interestingly, the relapse was associated with autoantibodies to both the p200 antigen and BP180 [26].

Adverse events

Of the 14 pemphigus patients treated in Protocol 1 and Protocol 2, only two severe adverse events were noted, including a deep venous thrombosis and a perforating diverticulitis [58, 63]. In Protocol 5, that combined high-dose oral prednisolone with IA, rituximab, and azathioprine/mycophenolate mofetil, four of seven patients suffered from severe adverse events [64] (Table 2). In our current protocol (Fig. 3), high-dose oral prednisolone was replaced by i.v. dexamethasone pulses and only two severe adverse events were noted in 15 pemphigus patients [65]. The relatively high rate of severe unwanted events in Protocol 5 [64] may be related to prolonged administration of high dose of oral prednisolone.

Excluding the patients treated in Protocol 5, in only 6 of the remaining 50 patients with immunobullous disorders treated with IA, severe adverse events were observed. Of all adverse events, only four appear to be directly related to IA: a single episode of hypotension and bradycardia as well as a grade III anaphylactic reaction during the IA procedure and Staphylococcus aureus sepsis after infection of the central venous catheter in two patients (Table 2). In addition, venous access was sometimes difficult and temporary paraesthesia of hands and lips that rapidly resolved after administration of calcium did occur. The relatively low incidence of adverse events seen in autoimmune blistering diseases is in line with data from the Swedish Apheresis Group that reported adverse events in <1% of procedures [44].

Recommendations

Below, recommendations for the use of IA in the treatment of autoimmune bullous diseases that have been published following a consensus meeting of German, Austrian, and Swiss physicians experienced in IA are summarized [78].

(Contra-) indications

Immunoadsorption may be performed as first-line treatment in pemphigus or epidermolysis bullosa acquisita patients with acute and severe disease [defined as involvement of (1) >30% of the body surface or (2) >25% of oral or genital mucous membranes or (3) conjunctiva or (4) esophagus]. In patients with other autoimmune blistering disorders, IA should be reserved for refractory patients with disease courses of more than 3 months and at least two adequate immunosuppressive therapies (Fig. 5). IA may not be performed in patients with known hypersensitivity to column material, severe cardiovascular disease, extreme bleeding tendency during anticoagulation, treatment with ACE inhibitors (discontinue drugs at least 72 h before IA), and children under 15 kg of body weight.

Fig. 5
figure 5

Algorithm for the use of immunoadsorption in autoimmune bullous skin disorders as recommended by a Consensus meeting of German, Austrian, and Swiss physicians experienced in this therapy [78]

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In all patients, the diagnosis needs to be based on characteristic clinical findings, direct immunofluorescence microscopy and/or the detection of typical serum autoantibodies. IA should be performed in centers experienced in extracorporal circulation on an in-patient basis. It is advisable to obtain written informed consent of the patients. Owing to the higher rate of infections in patients with central venous catheters a peripheral venous access may be chosen whenever possible [78].

Treatment protocol

An induction phase comprises three to four IA procedures on consecutive days with high-affinity adsorbers (e.g. Immunosorba®, Globaffin®, Therasorb®) or in selected cases, two consecutive treatments with low-affinity columns (e.g. IM TR350®, IM PH350®, Selesorb®). Subsequent treatments depend on the clinical activity and may consist of weekly single IA or monthly IA on three or four consecutive days. To document efficacy of IA autoantibody levels should be monitored before and after each IA. Adjuvant immunosuppression is obligatory and tapering doses of prednisolone (1.0–2.0 mg/kg per day) combined with azathioprine (2.5 mg/kg per day with normal TPMT) or mycophenolate mofetil (usually 2 g per day) are standard regimens. The application of i.v. cyclophosphamide pulses (500–750 mg/m2) or rituximab is also possible [78].

Perspectives

Regarding all available data, IA appears to be a rational, effective, and relatively safe adjuvant therapy for severe and/or treatment-resistant autoimmune bullous disorders. IA allows the rapid reduction of serum autoantibodies which is reflected by rapid clinical responses. In our experience, the rapid clinical effect following IA obtained in most of these patients is, for the time being, ideally complemented with the B-cell depleting agent rituximab. The combination of IA and rituximab has also been successfully applied in demyelinating polyneuropathy and is currently increasingly used in ABO-incompatible organ transplantations [16, 50].

A major drawback in the treatment of autoimmune bullous disorders has always been the rarity of high-quality prospective controlled studies. Prospective controlled trials in pemphigus have recently been published for the use of IVIG [3] and initiated for rituximab (www.clinicaltrial.gov). Most recently, support for a multicenter prospective controlled trial to explore the value of IA in pemphigus has been granted by the German Research Foundation. In this trial, 82 pemphigus patients will either receive tapering doses of prednisolone 1.0 mg/kg/day p.o plus azathioprine/mycophenolate mofetil or the same regimen in combination with IA. Two to four IA cycles of four IA on consecutive days are scheduled with a 3-week interval. This trial may also open the avenue for the development of adsorbers specific for the relevant target antigens.