sign in sign up
<<
Home , Dermatitis herpetiformis

Review Article

GOAP Dermatological Diseases Treated with Therapeutic Apheresis Rolf Bambauer1 and Ralf Schiel2

1Formerly Institute for Blood Purification, 66424 Homburg, Germany 2Inselklinik Heringsdorf GmbH, 17424 Seeheilbad Heringsdorf, Germany

*Correspondence: Rolf Bambauer, Frankenstrasse 4, 6424 Homburg, Germany, Tel: 0049/(0)6841/68500; Fax: 0049/(0)6841/68561; E-mail: [email protected] Abstract In dermatological diseases, TA is increasingly applied as support treatment for severe and/or refractory autoimmune bullous diseases. These diseases are -mediated against structural proteins of the skin and/or mucous membranes. Autoimmune blistering diseases have a high morbidity and mortality. These diseases include among others vulgaris, and bullous phemphigoid. Drug-induced pemphigus and other forms, such as herpetiformis, herpes gestationis, , pyoderma gangrenosum, epidermal necrolysis, Behcęt disease, vulgaris, Henoch- Schönlein purpura, and porhyria cutanea tarda, are mentioned, too. Pathogenetical aspects are demonstrated in these diseases, in which they are clarified. TA has been shown to effectively remove the from blood and lead to rapid clinical improvement. Keywords: Therapeutic apheresis, Immunoadsorption, Extracorporeal photopheresis, Dermatologic diseases, Immunologic origin

Introduction thrombocytes - that occurs when membrane hollow fiber are used is less than that occurring when centrifugation Therapeutic Apheresis (TA) has successfully used is used for cell separation [1]. in various -mediated diseases. Since the pathogenetic relevance of autoantibodies could defined TA methods, such as therapeutic plasma exchange in various diseases, disease-specific adsorbers have been (TPE), and semi- or selective plasma exchange methods, developed for example, in dilated cardiomyopathy (β1- such as immunoadsorption (IA), were discussed by adrenergic receptors), in systemic erythematosus Bambauer et al. [5]. Adsorptive cytapheresis mentioned (C1q), and in grouping ABO blood group antigens [1-4]. in previous studies is a therapeutic procedure in which Besides the selective removal of immunoglobulins from blood from the patient is passed through a medical a patient’s blood, the adsorbers also remove immune device that contains a column or filter that selectively complexes, etc. Some dermatologic immune-mediated adsorbs activated monocytes and granulocytes and the diseases respond to TA. In this review, the indications remaining part of the blood is returned to the patient of TA in autoimmune blistering diseases and atopic [6]. Extracorporeal photopheresis (ECP) is a procedure dermatitis are discussed. in which buffy coat, separated from patient’s blood, is Methods and Results treated extracorporeally with a photoactive compound (e.g. psoralens) and exposed to ultraviolet A light and The advantages of this method are a complete subsequently reinfused to the patient during the same separation of the corpuscular components from the treatment [6]. The guidelines on the use of TA provided plasma and higher efficacy due to increased blood by the Apheresis Applications Committee (AAC) of the flow rate. Furthermore, cell damage - especially to American Society for Apheresis (ASFA) has discussed in Goap Dermatol, 1(1): 35-45 (2019) 35 previous studies [6,7]. therapeutic options include , gold, and systemic . They are often used in combination with Dermatologic immune-mediated diseases represent other immunosuppressant agents, such as azathioprine, a heterogeneous group of disorders associated with methotrexate, and cyclophosphamide. Newer therapeutic circulating autoantibodies against distinct adhesion modalities, such as TPE, ECP, mycophenolate mofetil, molecules of the skin and/or mucosa. According to the chlorambucil, dexamethasone-cyclophosphamide, IVIG level of split formation, the disorders can classified as therapy, anti-CD20 monoclonal antibody (rituximab), intraepidermal blistering pemphigus, such as pemphigus have also been investigated [7]. vulgaris (PV), , and , and as subepidermal blistering The rationale for using TPE in the treatment of diseases, such as (BP), pemphigoid PV based on the presence of circulating pathogenic gestations, and dermatitis herpetiformis [7]. autoantibodies. TPE was used in patients in all age groups (13-80 years old). The duration of disease prior The incidence of autoimmune blistering skin diseases to using TPE ranged between 1 month and 25 years. The for example in Germany has doubled during in the last 10 goal of TPE was to reduce the level of autoantibodies years, to about 25 new cases per million humans per year, with subsequent improvement in clinical symptoms. because of improved diagnostic techniques as well as the The decline in autoantibody titers, antikeratinocyte cell age of the population [8]. The incidence of pemphigus surface antibodies, and anti-desmoglein-3 correlated in Europe is one to two cases per million humans per with clinical response in a number of patients [7]. Many year, and 80% of pemphigus patients have PV [9]. BP is patients have treated successful clinical results of TPE, IA the most common type of subepidermal autoimmune and ECP in the treatment of PV [11-16]. blistering skin disease in Europe, with an incidence of about 13 cases per million humans per year. The other The antiepidermal antibodies, which usually belong common types are mucous membrane pemphigoid and to the IgG category, can be easily eliminated with TPE. pemphigoid gestationis [10]. The standard of diagnostic Many authors have reported successful clinical results testing for autoimmune blistering skin diseases is direct of TPE in the treatment of PV [17-21]. Standard therapy (IF) microscopy to demonstrate the for PV based on a combined administration of high-dose presence of tissue-bound autoantibodies and/or of C3 in glucocorticoids and immunosuppressive drugs. Other patients’ skin or mucous membranes. therapy strategies include TPE, steroid pulse therapy, IVIG, various immunosuppressive agents (e.g. azathioprine, (PV) is a severe, chronic disease of cyclophosphamide, cyclosporin, mycophenolate mofetil, the skin and mucous membranes, has poor prognosis and and mizoribine), and rituximab [18]. In the most intractable acantholytic and erosion, and is characterized by cases, a combination of these adjuvant treatments may the presence of antibodies against epidermal intercellular be used [17]. substances. PV is a classic example of autoantibody- induced immune dermatosis, which can be recurrent or IA has successfully applied in patients with severe relapsing [1]. Both genders are equally affected with the and high total serum IgE levels [13]. mean age of onset in the sixth and seventh decade of During the last few years, various IA systems and life, and the patients present with skin lesions that occur immunosuppressive protocols have been used to reduce typically as flaccid blisters [7]. The blisters can be located the circulating autoantibodies [8]. IA must be combined on the entire body surface as well as on the mucous with immunosuppressant treatment. The membranes of the mouth. PV is characterized by the rates and side effects are low and comparable with those deposition of an autoantibody on the cell of the other extracorporeal circulations [20]. surface. The titers of IgG4 antikeratinocyte antibodies can be correlated with disease activity. The levels of autoantibody have been noted to rebound in the reported patient within 1-2 weeks PV was associated with a high morbidity and mortality. after discontinuation of treatment, which necessitates Introduction of corticosteroids reduced the mortality continuation of immunosuppression [7]. In the guidelines rate from 70% to 100% to a mean of 30% [7]. However, for the use of TA by the AAC of the ASFA, PV has category long-term administration of high doses of corticosteroids III for TPE, IA, and ECP with a recommendation of grade can be associated with severe side effects. Other (RG) 2B and 2C, respectively (Table 1) [7,8]. The rational

Goap Dermatol, 1(1): 35-45 (2019) 36 approach should include monitoring of autoantibody rational discontinuation criteria should be similar as titers and clinical symptoms. For ECP, the treatments those for TPE [7]. were continued until clinical response was noted. The Table 1: TA in dermatological diseases with immunolgic origin (Category I: accepted for TA as first-line therapy; Category II accepted for TA as second-line therapy; Category III: not accepted for TA, decision should be individualized; Category IV: not accepted for TA IMB approval is desirable if TA is undertaken (6, 7).

Dermatological Apheresis Application Committee of the ASFA [6,7] diseases treated with TA to date [1] TA Treated TA modality Category Recommenda- Treated Replacement Frequency modality with TA tion grade Volume Solution (TPV) Intraepidermal Human- Daily or blistering PV albumin every Other Pemphigus TPE, + TPE, IA, ECP III 2B, 2C 1-1.5 electrolyte day vulgaris IA + solution Subepidermal blistering BP Bullous TPE, + ------pemphigoid IA + D-penicil- TPE, + ------lin-amine-induced IA + pemphigus Cutaneous T cell TPE + Human- Daily or lymphoma (CTCL) albumin every Other -erythrodermic ECP, I 1B 1-1.5 electrolyte day -non-erythrodermic ECP III 2C solution Dermatitis TPE + ------herpetiformis Herpes TPE + ------gestationes Progressive TPE + TPE, III 2C 1-1.5 Human- Daily or scleroderma ECP III 2B albumin every Other Dermatomyositis TPE + TPE, IV 2A electrolyte day IA IV 2A solution Pyoderma TPE + ------gangrenosum Epidermal TPE + TPE III 2B 1-1.5 Human- Daily or necrolysis (Lyell albumin elec- every Other syndrome) trolyte day solution Behcęt disease TPE + ------Psoriasis vulgaris TPE + TPE, III 2C adsorptive III 2C Cytapheresis, Human- Daily or Lymphocyt- III 2C 1-1.5 albumin every Other Apheresis, electrolyte day ECP IV 2B solution Henoch-Schönlein TPE + TPE III 2C purpura Porphyria cutanea TPE + ------tarda Goap Dermatol, 1(1): 35-45 (2019) 37 Bullous pemphigoid (BP) is another form of induced [27]. subepidermal blistering pemphigus; BP is a rare BP. BP frequently involves a premonitory stage with pruritic In drug-induced pemphigus, it was demonstrated urticarial and eczematous lesions followed by that autoantibodies have the same antigenic specificity, the classical bullous stage with tense blisters, erosions, on a molecular level, as autoantibodies from other and crusts [8]. BP is a chronic dermatosis often associated pemphigus patients [28]. The chance of acquiring with acute exacerbations, with the formation of bullae pemphigus after penicillamine intake of least 6 months is blisters usually on the inflamed skin, subepidermal 7%. Subsequently, more have been reported formation, and antibodies against the epidermal basal to evoke pemphigus, such as penicillin, ampicillin, membrane. The pathophysiology is regarded as being a rifampicin, pyrazolon derivatives, a combination of consequence of the combined effect of antigen, antibody, aspirin and indomethacin, and a combination of propanol complement, and inflammatory cells, whereby lysosomal and mepbromate [29]. Drugs at risk for pemphigus are enzymes actually destroy the basal membrane zone and sulfhydryl (SH) group-containing drugs, known as thiol induce subepidermal blistering [20]. It is still unclear drugs (i.e., captopril). Drug-induced pemphigus and drug- whether or ultraviolet rays can provoke BP. It triggered pemphigus are considered separate entities [30]. is also possible that destruction of the basal membrane In drug-triggered pemphigus, the drug only stimulates a zone with release of basal membrane antigens can cause predisposition to develop active . a direct immunological response in predisposed people. It appears that penicillamine- and SH-containing drugs Thus, BP can also occur in combination with other actually induce pemphigus, whereas other drugs only autoimmune disorders. trigger a disimmune mechanism previously programmed and ready to be set off [30]. Drug-triggered pemphigus is The course of this pemphigus disorder is not as dramatic known to be refractory to therapy if the offending drug is as other forms of the disease, with good response to not stopped immediately [31]. high-potency corticosteroids, which are usually combined with dapsone, doxycycline, methotrexate, or azathioprine Only case reports of D-penicillamine-induced [8]. BP has an annual incidence of about 13-42 new pemphigus treated successfully with TA were reported. cases per 1 million in central Europe and the United It is generally recommended to combine TA with Kingdom [10,21]. Only a few cases have been treated immunosuppression [32]. IA is the most specific with TPE up to now (Table 1). Because the pathogenic therapeutic option, in which only the pathogenic IgG is relevance of autoantibodies was clearly demonstrated in depleted in the patient’s plasma. IgG autoantibodies are the majority of autoimmune bullous diseases, removal adsorbed on antihuman IgG affinity agarose column. of autoantibodies, therefore, appears to be a rational Resynthesis of IgG autoantibodies was inhibited by therapeutic approach for these patients. IA has been postapheresis IVIG; therefore, the additional effect shown to effective lower the antibody levels and leads to of IA is difficult to observe since IVIG has also a rapid clinical responses in patients with immuno bullous immunomodulatory potency [8]. A combination of IA disorders [22]. Meanwhile, IA and rituximab have been and rituximab showed rapid and long-lasting response established as additional therapeutic options [23-25]. of concomitant immunosuppressive medication [33]. Rituximab is almost given as an adjuvant drug, i.e., D-Penicillamine-induced pemphigus, steroid-resistant in addition to another type of immunosuppressive pemphigus, is a foliaceustype disease with high lethality treatment. Complications of rituximab in patients with and mortality rate, which can occur as a side effect in autoimmune blistering skin diseases include infections, long-term penicillamine therapy, which is a particular deep venous thrombosis of the lower limbs, pulmonary indication for TPE [26,27] (Table 1). The mechanism by embolism, longterm hypogammaglobulinemia, and which this drug induces acantholysis of the neutropenia with an overall mortality of 4% [33]. The has still not been clarified. Most investigators suspect indications, contraindications, and dosage of rituximab that immunological processes similar to those in PV are treatment for autoimmune blistering skin diseases involved. The final step in anti-Dsg-induced acantholysis and the criteria for discontinuing rituximab have been is the response of the keratinocyte to autoantibodies established [34]. binding via downstream signaling events and eventual keratin filament retraction and apoptosis, as many and its leukemic variant, Sézary signaling pathways have been implicated in anti-Dsg- syndrome (SS), are the most common types of cutaneous

Goap Dermatol, 1(1): 35-45 (2019) 38 T-cell lymphoma (CTCL) whose pathogenesis remains of TPE in progressive scleroderma and dermatomyositis elusive [6] (Table 1). CTCL is incurable. Therapy is aimed is still disputed (Table 1). at alleviating symptoms, improving skin manifestations, controlling extra cutaneous complications, and Pyoderma gangrenosum (PG) is a rare, polyetiological minimizing immunosuppression [8]. Chemotherapy is syndrome based on a pathological immune reaction. recommended for aggressive SS, with alemtuzumab and In over 40% of cases, this disease occurs together with stem cell transplantation being considered for refractory colitis ulcerosa. In the vessel walls of vasculitic lesions, disease. granular IgG, C3, complement, and IgM deposits have been observed [40]. PG is a non-infectious neutrophilic In CTCL ECP is indicated. ECP involves the collection dermatosis that usually starts with sterile pustules that of circulating malignant CD4+ T cells, ex vivo treatment rapidly progress to painful ulcers of variable depth and with 8-methoxypsoralen and UVA light and reinfusion of size with undermined violaceous borders. In 17%-74% of the cells. The therapeutic effect appears to be mediated cases, PG is associated with an underlying disease, most by in vivo stimulation of antitumor immunity through the commonly inflammatory bowel disease, rheumatological interactions of irradiated, apoptotic lymphoma cells with or hematological disease, or malignancy. Diagnosis of PG antigen-presenting dendritic cells [8]. ECP in combination is based on a history of underlying disease, typical clinical with other non-chemotherapy agents can be considered presentation and histopathology, and exclusion of other as a salvage approach for nonresponsive or relapsed diseases that would lead to a similar appearance [41]. PG patients or those with early-stage disease. The advantage is characterized by painful, enlarging necrotic ulcers with of ECP is the relative lack of immune suppression and bluish undermined borders surrounded by an advancing reduced risk of infections [8]. zone of erythema; its clinical variants include ulcerative or ECP should be planned for a minimum of 6 months. classic, pustular, bullous or typical, vegetative, peristomal, When maximal response is achieved, it can be reduced and drug-induced. Subcorneal pustular dermatosis is to once every 6-12 weeks. If there is evidence of disease an uncommon relapsing symmetric pustular eruption progression after 6 months of ECP alone, combination that involves flexural and intertriginous areas; it can therapy should be considered. If there is minimal or no be idiopathic or associated with cancer, infections, response after 3 months of combination therapy, ECP medications, and systemic diseases [42]. Because the should be discontinued [7]. incidence of PG is low, no prospective randomized controlled trials and only a few studies with case numbers TPE is in combination with immunosuppression have been published [42,43]. probably successful due to the pathogenesis of severe cases of dermatitis herpetiformis and herpes gestationis The treatment with corticosteroids and cyclosporin [35,36]. Herpes gestationis or pemphigoid gestationis is an is documented for disseminated as well as for localized autoimmune subepidermal blistering disease that occurs disease and should be considered as first-line therapy. In in women in the second or third trimesters of pregnancy cases that do not respond to this treatment, alternative or even puerperium. It is a rare skin disease, the incidence therapeutic procedures (e.g. systemic corticosteroids of which has been estimated of approximately one case and mycophenolate mofetil; mycophenolate mofetil in every 40,000-60,000 pregnancies [36]. In patients and cyclosporin; tacrolimus; infliximab, or TPE) are who are resistant to corticosteroids, other treatments recommended [43]. Despite recent advances in therapy, have been tested including immunosuppressant drugs, the prognosis of PG remains unpredictable. such as cyclosporin, azathioprine, and tacrolimus and TPE. In contrast, dermatitis herpetiformis produces anti- Drug-induced toxic epidermal necrolysis (TEN), also desmoglein-3 autoantibodies and could be a variant of known as Lyell’s syndrome, is a life-threatening drug PV with unique clinical and histological features [37]. reaction characterized by extensive destruction of the epidermis and mucosal epithelia. The eyes are typically Scleroderma or systemic sclerosis is a rare, generalized involved in TEN. The disease has a high mortality rate. autoimmune disease. Scleroderma is characterized by TEN and the Stevens-Johnson syndrome (SJS) are vascular abnormalities, fibrosis, inflammatory changes, closely related, although their severity and outcome and late-stage /obliterative vasculopathy. are different. The SJS and TEN are rare but present Localized scleroderma forms show a longitudinal or severe skin manifestation. They are estimated to occur circumscribed skin involvement [38,39]. The effectiveness in one to three people per million per year in Europe

Goap Dermatol, 1(1): 35-45 (2019) 39 and the United States [44]. They are characterized by debated, is not clear. Although TPE has been successful a low incidence but high mortality, and drugs are most in individual cases [55]. In recent years, there have been commonly implicated in 80% of TEN cases. TEN is the most reports on the successful treatment with implementation severe form of drug induced skin reaction and is defined of cyclosporin A, tacrolimus, or infliximab, etc. as epidermal detachment of .30% of total body surface area (TBSA). SJS presents with epidermaldetachment of Psoriasis vulgaris is a common autoimmune chronic 10% of TBSA, whereas involvement of 10%-30% of TBSA inflammatory skin disease that affects approximately is defined as SJS/TEN overlap [45]. Etiological, clinical, 2% of the world’s population. Fundamental for its and histological characteristics help to distinguish TEN immunopathogenic mechanism is the secretion of from severe forms of . The current type 1 (Th 1) cytokines by T cells and their activation understanding of the pathomechanism of TEN suggests [56]. Cytokines are intercellular molecules that have an that are key initiator cells. It is probable important role in the development and maintenance of that combined deleterious effects on keratinocyte of cutaneous [57]. The indication for TPE in both are the cytokine. Tumor necrosis factor (TNF)-α and psoriasis vulgaris is also based on the presumption of oxidative stress induce a combination of apoptotic and immunopathogenesis. The pathogenesis of psoriasis is necrotic events [46]. still for the most part unclear; however, autoantibodies, circulating immune complexes, and cytokines are thought In Lyell’s syndrome, the acute phase can be very to be responsible for triggering flairs of the disease or a successfully treated by TPE. The allergic or toxin-induced new attack [1]. skin necrolysis is usually triggered by a drug acting like a hapten [47]. Lyell’s syndrome is fortunately very rare Valbonesi et al reported lasting improvement in seven but has a high mortality rate, approximately 50%, and out of eight psoriasis patients who had been treated with thus, early administration of TPE is justified. TPE is a TPE [58]. Jorstad et al. treated eight patients with psoriasis safe intervention in severely ill TEN patients and may with skin scales and seven with disabling psoriatic arthritis reduce the mortality in this severe disease [48] (Table with cascade filtration for 2 weeks [59]. There was a large 1). Other authors found that using IVIG in association drop in the levels of circulating immune complexes due with TPE might be effective in patients with severe TEN to treatment, and the removal of circulating immune [49-51]. The application of monoclonal antibody to complex (CIC) was followed by reduced inflammatory TNF-α (infliximab) was also successful [52]. However, activity in skin lesions and joints as evaluated by pain, prospective multicenter trials are needed to further morning stiffness, grip strength, plaque score, and define its usefulness. Psoriasis Area Severity Index (PASI) index. However, there was no correlation between the level of CIC, disease Behcęt disease, a multisystemic inflammatory activity, or treatment response. TPE may be beneficial in disorder, presents with the involvement of muco- patients with psoriatic arthropathy and not responding cutaneous, occular, vascular, central nervous and to conventional therapy [59]. Other authors reported gastrointestinal systems. It is an idiopathic, chronic, their results with treatment of extracorporeal photo and recurrent disease characterized by exacerbation chemotherapy and lymphocytapheresis. However, the alternating with plasma of quiescence, episodic pan skin lesions did not respond to photopheresis [56,59,60] uveitis, and aggressive no granulomatous occlusive (Table 1). However, blocking TNF-α by infliximab or of the arteries and veins of any size with etanercept has shown particular promise, especially in explosive ocular inflammatory attacks that primarily the management of psoriasis. However, further studies affect the retinal and anterior segment vasculature of to address its mechanism of action and potential long- the eye [53]. Central nervous system involvement, most term side effects are needed. often due to necrotizing vasculitis, may be the most protean manifestation of the disease, leading to death. The frequency of ocular manifestations is 70%-85% in Henoch-Schönlein purpura (HSP) is a systemic these patients. The underlying mechanism of this disease vasculitis that affects vessels of small size. The vascular in all organ systems is an occlusive vasculitis [1]. Ethnic purpura is usually confined to the lower limbs and is diversity can influence the progression severity and associated, at varying degrees, with joint, gastrointestinal, clinical manifestation [54]. The effect of TPE in Behcęt and renal involvement. It is a systemic disease where disease, where immuno-pathogenesis is also being antigen-antibody (IgA) complexes activate the alternate

Goap Dermatol, 1(1): 35-45 (2019) 40 complement pathway, resulting in inflammation and erythroid-specific 5-aminolevulinate synthase [66]. small-vessel vasculitis [61]. Protoporphyrin accumulates in the maturing red blood cells during hematopoiesis. When red blood cells enter HSP is defined as the presence of two or more of the circulation, free protoporphyrin diffuses across the the following criteria: age of disease onset (20 years red blood cell membrane and binds to plasma proteins. or younger), palpable purpura, acute , The liver extracts protoporphyrin from the plasma, most and granulocytic infiltration in the walls of arterioles or of which is excreted unchanged into the bile, with the venuoles [62]. Focusing on the pathogenic role of IgA remainder being metabolized (by liver ferrochelatase) to immune complexes in HSP as a small-vessel vasculitis hem. Some protoporphyrin is subsequently reabsorbed with predominant IgA vascular deposits. All patients during enterohepatic circulation [67]. TPE as a treatment develop palpable purpura. In the skin, these deposits for PCT is reported by many authors, but no controlled lead to subepidermal hemorrhage and small-vessel studies are available. necrotizing vasculitis producing the purpura [7]. IgG autoantibodies directed at mesangial antigens may Other dermatological diseases, such as necrotic play a role in pathogenesis. In other organs, necrotizing xanthogranuloma and scleromyxedema, are not vasculitis leads to organ dysfunction or hemorrhage. mentioned due to the oncological treatment or the Nonetheless, the precise role of IgA or antibodies in the lack of clinical data. All mentioned TA methods are still pathogenesis of the disease remains unclear. technically complicated and very expensive. The costs of the mentioned TA methods vary widelyin Germany; for In the guidelines for the use of TPE by the AAC of example, the costs for TEP are between 830 and 1,620€, the ASFA, the crescentic form and severe extra renal for IA between 2,040 and 2,240€, and for ECP between manifestations of the HSP are classified as category III 1,600 and 2,700€ per treatment [68]. It is the responsibility with the recommendation being grade 2C for TPE [7] of the manufacturers to develop simpler and less costly (Table 1). Prospective randomized clinical studies proving techniques. treatment efficacy are still lacking [63]. Spontaneous recovery even in patients with severe clinical and Physicians are committed to helping all patients histological presentation and of late evolution to chronic entrusted to them to the best of their knowledge, and kidney disease in patients with mild initial symptoms this means that medical treatment - and particularly renders it difficult for treatment protocols [64]. the apheresis processes - must become affordable. This demand represents a great challenge to physicians, (PCT), a genetic enzyme defect, politicians, health organizations, and above all to the was also considered as being a treatable condition with manufacturers. Industry constantly justifies the high possible indication for TPE [1]. PCT is a metabolic disorder costs with the extensive research and development of the hem biosynthesis caused by decreased activity of required. All those involved in the health-care system uroporphyrinogen decarboxylase. PCT is manifest by must intensify their cooperation in this respect. fragility, erosions, bullae, milia, and scars on sun-exposed Conclusion skin. Excess porphyrins in the skin interact with light of approximately 400-nm-wave length radiant energy, TA has been successfully used in varies antibody- forming reactive oxygen species. PCT is categorized as mediated diseases. PV is a classic example of antibody- familial, acquired, or toxic. Factors that may induce clinical induced immune dermatosis. TPE or IA and ECP are expression of PCT in susceptible individuals include indicated in patients with severe symptoms who either alcohol, estrogen, iron, polyalogenated compounds, received high doses of conventional agents and/or had and viral infections. PCT is associated with an increased an aggressive and rapidly progressive disease. BP is incidence of the hemochromatosis gene [65]. another rare form of subepidermal blistering pemphigus. BP is not as dramatic as other autoimmune diseases with Recent advances in the pathogenesis are the good response of conventional therapy. TPE and IA in identification of the iron overload-induced inhibitor combination with immunosuppression are indicated in of hepatic uroporphyrin decarboxylase activity that BP and d-penicillamine-induced pemphigus only in severe causes the most common porphyria, PCT, and the cases. Chemotherapy and stem cell transplantation are identification of an X-linked form of erythropoietic indicated for more aggressive forms of CTCL. Following porphyria due to gain of-function mutations in the recommendations of the AAC of the ASFA, CTCL has

Goap Dermatol, 1(1): 35-45 (2019) 41 category I and grade 1B for ECP. The advantage of ECP is on the use of Therapeutic Apheresis in Clinical the relative lack of immune suspension and reduced risk Practice-Evidences-Based Approach from the of infection. Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher. In severe cases of progressive scleroderma, 2016;31:149-338. PMID: https://www.ncbi.nlm.nih. dermatomyositis, TEN, psoriasis vulgaris, and HST, TPE gov/pubmed/27322218 or IA can be successful. In these diseases, and in those 7. Padmanabhan A, Connelly-Smith L, Aqui N, et al. patients who do not respond to this therapy, the first- Guidelines on the Use of Therapeutic Apheresis in line therapy is immunosuppression. Other immuno- Clinical Practice - Evidence-Based Approach from suppressants, biologics, or TA could act as second-line the Writing Committee Of the American Society therapy. TA is only indicated in severe cases of Behcęt for Apheresis: The Eigth Special Issue. J Clin Apher. disease, PG, dermatitis herpetiformis, and herpes 2019;34:171-354. DOI: https://doi.org/10.1002/ gestations as second-line therapy. In the guidelines of jca.21705 AAC of the ASFA, the last four mentioned diseases are 8. Meyersburg D, Schmitt E, Kasperkiewicz M, et al. not discussed. However, for all mentioned diseases, the Immunoadsorption in dermatology. Ther Apher Dial. quotient relevant for cost-effectivity assessment [cost 2012;16(4):311-320. PMID: https://www.ncbi.nlm.nih. of treatment - cost saved]: [improvement in life quality] gov/pubmed/22817118 must be discussed and calculated exactly by all the persons involved. 9. Hahn-Ristic K, Rzany B, Amagai M, et al. Increased incidence of pemphigus vulgaris in southern References Europeans living in Germany compared with native Germans. J Eur Acad Dermatol Venereol. Bambauer R, Latza R, Schiel R. Therapeutic Plasma 1. 2002;16:68-71. PMID: https://www.ncbi.nlm.nih.gov/ Exchange and Selective Plasma Separation Methods. pubmed/11952295 Fundamental Technologies, Pathology and Clinical Results. 4th ed. Lengerich: Pabst Science Publishers; 2013. 10. Langan SM, Smeeth L, Hubbard R, et al. Bullous https://www.researchgate.net/ pemphigoid and pemphigus vulgaris-incidence and publication/276014929_Rolf_Bambauer_Reinhard_ mortality in the UK: population based on cohort Latza_Ralf_Schiel_Therapeutic_Plasma_Exchange_ study. BMJ. 2008;337:a180. PMID: https://www.ncbi. and_Selective_Plasma_Separation_Methods_ nlm.nih.gov/pubmed/18614511 Fundamental_Technologies_Pathology_and_Clinical_ 11. Fine JD, Appell ML, Green LK, et al. Pemphigus vulgaris. Results_Fourth_Editon_Pabst_Science_Publish Combined treatment with intravenous corticosteroid 2. Wallukat G, Reinke P, Dörffel WV, et al. Removal pulse therapy, plasmapheresis, and azathioprine. of autoantibodies in dilated cardiomyopathy by Arch Dermatol. 1988;124:236-239. PMID: https://www. immunoadsorption. Int J Cardiol. 1996;54:191. PMID: ncbi.nlm.nih.gov/pubmed/3277542 https://www.ncbi.nlm.nih.gov/pubmed/8803685 12. Ruocco E, Baroni A, Wolf R, et al. Life-threatening 3. Hiepe F, Pfüller B, Wolbart K, et al. C1q: a bullous dermatosis: pemphigus vulgaris. Clin multifunctional ligand for a new immunoadsorption Dermatol. 2009;23:223-226. PMID: https://www.ncbi. treatment. Ther Apher. 1999;3:246-251. PMID: https:// nlm.nih.gov/pubmed/15896536 www.ncbi.nlm.nih.gov/pubmed/10427623 13. Kumar R, Jindal A, Kaur A, et al. Therapeutic Plasma 4. Kumlien G, Ullström L, Losvall A, Persson LG, Tydén Exchange - A New Dawn in the Treatment of G. Clinical experience with a new apheresis filter has Pemphigus Vulgaris. Ind J Dermatol. 2015;60(4):419. specifically depletes ABO blood group antibodies. PMID: https://www.ncbi.nlm.nih.gov/pmc/articles/ Transfusion. 2006;46:1568-1575. PMID: https://www. PMC4533556/ ncbi.nlm.nih.gov/pubmed/16965585 14. Tselmin S, Julius U, Bornstein SR, et al. Low rate of 5. Bambauer R, Schiel R, Lehmann B, Bambauer C. infectious complications following immunoadsorption Therapeutic aphaeresis. Technical aspects. ARPN therapy without regular substitution of intravenous J Sci Technol. 2012;2:399-421. DOI: https://doi. immunoglobulins. Ateroscler Supplem. 2017;30:278- org/10.4137%2FCMT.S14112 282. PMID: https://www.ncbi.nlm.nih.gov/ pubmed/29096850 6. Schwarz J, Padmanabhan A, Aqui N, et al. Guidelines 15. Mazzoni A, Giampietrro C, Bianco I, et al. Extracorporeal Goap Dermatol, 1(1): 35-45 (2019) 42 photophersis and liver transplantation: Our rituximab: a protocol without initial high dose or experience and preliminary data. Transf Apher Sci. pulse steroid medication. J Eur Acad Dermatol Venereol. 2017;56:515-519. PMID: https://www.ncbi.nlm.nih. 2014;28(6):771-780. PMID: https://www.ncbi.nlm.nih. gov/pubmed/28774829 gov/pubmed/23651052 16. Edelson R, Wu Y, Schneiderman J. American Council 26. Matkaleck RM, Boilin PL. Penicillamine-induced on ECP (ACE): Why now? Consensus Conference pemphigus foliaceus. Arch Dermatol. 1981;117:56. Report. J Clin Apher. 2018;33:464-468. PMID: https:// DOI: 10.1001/archderm.1981.01650030034016 www.ncbi.nlm.nih.gov/pubmed/29575114 27. Culton DA, Qian Y, Li N, et al. Advances in pemphigus 17. Odamaki S, Hori Y, Nakai S, et al. A Solution Kinetics and its endemic pemphigus foliaceus (Fogo selvagam) simulation method for Conventional and Selective phenotype: a paradigm of human . J Plasma Exchange Using a Complete Mixed Reactor Autoimmun. 2008;31(4):311-324. PMID: https://www. Model. Ther Apher Dial. 2018;23(3):266-270. PMID: ncbi.nlm.nih.gov/pubmed/18838249 https://www.ncbi.nlm.nih.gov/pubmed/31026124 28. Penas PF, Buezo GF, Carvajal I, et al. D-penicillamine- 18. Hashimoto T. Treatment strategies for pemphigus induced pemphigus foliaceus with autoantibodies to vulgaris in Japan. Exp Opin Pharmacother. desmoglein-1 in a patient with mixed connective tissue 2008;9:1519. PMID: https://www.ncbi.nlm.nih.gov/ disease. J Am Acad Dermatol. 1997;37:121-123. PMID: pubmed/18518782 https://www.ncbi.nlm.nih.gov/pubmed/9216536/ 19. Behzad M, Möbs C, Kneisel A, et al. Combined treatment 29. Mueller S, Stanley JR. Pemphigus: pemphigus vulgaris with immunoadsorption and rituximab leads to fast and pemphigus foliaceus. In: Wojnarowska F, and prolonged clinical remissions in difficult to treat Briggaman RA, eds. Management of Blistering Diseases. pemphigus. Br J Dermatol. 2012;166:844-852. PMID: 1st ed. London: Chapmann and Hall Medical; 1990:43. https://www.ncbi.nlm.nih.gov/pubmed/22092243 30. Brenner S, Wolf R, Ruocco V. Drug-induced pemphigus. 20. Kasperkiewicz M, Shimanovich I, Meier M, et al. I. A surveyA, et al. D-penicillamine-induced pemphigus: Treatment of severe pemphigus with a combination changes in anti-32-2B immunostaining patterns. Ann of immunoadsorption, rituximab, pulsed Dermatol Vénéréol. 2013;140(3-9):531-4. dexamethasone and azathioprine/mycophenolate 31. Khaehoggi M, Macher I, Perinaud A, et al. mofetil: a pilot study of 23 patients. Br J Dermatol. D-penicillinamine-induced pemphigus: changes in 2012;166:154-160. PMID: https://www.ncbi.nlm.nih. anti-32-2B immunostaining patterns. Ann Dermatol gov/pubmed/21910700 Vénéréol. 2013;140(3-9):531-534. PMID: https://www. 21. Ludwig RJ. Clinical presentation, pathogenesis, ncbi.nlm.nih.gov/pubmed/24034638 diagnosis, and treatment of epidermolysis bullosa 32. Bambauer R, Latza R, Burgard D, Schiel R. Auto- acquisita. ISRN Dermatol. 2013;2018: 812029. PMID: immune Disoders treated with Therapeutic Apheresis. https://www.ncbi.nlm.nih.gov/pubmed/23956869 Immunol Res Ther J. 2017;1(1):111-131. 22. Bertram F, Bröcker EB, Zillikens D, Schmidt E. 33. Schmidt E, Zillikens D. Immunoadsorption in Prospective analysis of the incidence of autoimmune dermatology. Arch Dermatol Res. 2010;302:241- bullous disorders in Lower Franconia, Germany. J 253. PMID: https://www.ncbi.nlm.nih.gov/ Dtsch Dermatol Ges. 2009;7:434-440. PMID: https:// pubmed/20049466 www.ncbi.nlm.nih.gov/pubmed/19170813 34. Hertl M, Zillikens D, Borradori L, et al. 23. Bambauer R, Burgard D, Schiel R. Therapeutic Recommendations for the use of rutiximab (anti- Apheresis in Dermatological Diseases. Clin Med Ins. CD20 antibody) in the treatment of autoimmune 2015;7:53-62. DOI: https://doi.org/10.4137%2FCMT. bullous skin diseases. J Dtsch Dermatol Ges. S14112 2008;6:366-373. PMID: https://www.ncbi.nlm.nih. 24. Kasperkiewicz M, Schmidt E. Current treatment gov/pubmed/18201220 of autoimmune blistering diseases. Curr Drug Disc 35. Hörgensen EH, Clemmensen O, Anagnostaki L. Herpes Technol. 2009;6:270-280. PMID: https://www.ncbi. gestationis. Acta Obstet Gynecol Scan. 1987;66:175. nlm.nih.gov/pubmed/20025595 36. Ruiz-Villaverde R, Sánchez-Cano D, Ramirez-Tortosa 25. Kolesnik M, Becker E, Reinhold D, et al. Treatment CL. Pemphigoid gestationes: therapeutic response to of severe autoimmune blistering skin diseases with pre- and postpartum immunoglobulin therapy. Actas combination of protein A immunoadsorption and Goap Dermatol, 1(1): 35-45 (2019) 43 Dermosifiliogr. 2011;102:735-737. PMID: https://www. Drug Safety. 2010;33:189-212. PMID: https://www. ncbi.nlm.nih.gov/pubmed/21531361 ncbi.nlm.nih.gov/pubmed/20158284 37. Kubo A, Amagai M, Hashimoto T, et al. Herpetiform 48. Harr T, French LE. Toxic epidermal necrolysis pemphigus showing reactivity with pemphigus and Stevens-Johnson syndrome. Orpha J Rare Dis. vulgaris antigen (desmoglein 3). Br J Dermatol. 2010;5(1):39. PMID: https://www.ncbi.nlm.nih.gov/ 1997;137:109-113. PMID: https://www.ncbi.nlm.nih. pmc/articles/PMC3018455/ gov/pubmed/9274636 49. Koštál M, Bláha M, Lánská M, et al. Beneficial effect of 38. Laszio C, Cecilia V. Clinical features of scleroderma- plasma exchange in the treatment of toxic epidermal like disorders: a challenge for the rheumatologist. necrolysis: a series of four cases. J Clin Apher. Curr Rheumatol Rev. 2006;2:369-379. DOI: https://doi. 2012;27:215-220. PMID: https://www.ncbi.nlm.nih. org/10.2174/157339706778699850 gov/pubmed/22407895 39. Harris ES, Meiselman HJ, Moriatry PM, et al. 50. Lissa M, Figus A, Rubino C. Intravenous Therapeutic plasma exchange for the treatment Immunoglobulins and plasmapheresis combined of systemic sclerosis: A comprehensive review and treatment in patients with severe toxic epidermal analysis. J Sclerod Rel Dis. 2018;3(2):132-152. PMID: necrolysis: preliminary reports. JPRAS. 2005:58:504- https://doi.org/10.1177%2F2397198318758606 510. PMID: https://www.ncbi.nlm.nih.gov/ 40. Wolff K, Stingl G. Pyoderma gangrenosum. Pyod pubmed/15897036 Gangr. 1989;112:1328. 51. Krajewski A, Mazurek MJ, Mlynska-Krajewska E, et 41. Wollina U. Clinical management of pyoderma al. Toxic Epidermal Necrolysis Therapy with TPE and gangrenosum. Am J Clin Dermatol. 2002;3(3):149- IVIG - 10 Years of Experience of the Burns Treatment 158. PMID: https://www.ncbi.nlm.nih.gov/ Center. J Burn Care Res. 2019;40(5):652-665. PMID: pubmed/11978136 https://www.ncbi.nlm.nih.gov/pubmed/31032516 42. Attar S, Spangehl MJ, Casey WJ, et al. Pyoderma 52. Lissa M, Mulas P, Bulla A, et al. Toxic epidermal gangrenosum complicating bilateral total knee necrolysis (Lyell’s disease). Burns. 2010;36(2):152- arthroplasty. Orthopedics. 2010;33(6):441. PMID: 163. PMID: https://www.ncbi.nlm.nih.gov/ https://www.ncbi.nlm.nih.gov/pubmed/20806762 pubmed/19766401 43. Reichrath J, Bens G, Bonowitz A, et al. Treatment 53. Evereklioglu C. Current concepts in the etiology recommendations for pyoderma gangrenosum: and treatment of Behcet disease. Surv Ophthalmol. an evidence-based review of the literature based 2005;50(4):297-350. PMID: https://www.ncbi.nlm.nih. on more than 350 patients. J Am Acad Dermatol. gov/pubmed/15967189 2005;53:273. PMID: https://www.ncbi.nlm.nih.gov/ 54. Direskeneli H. Autoimmunity vs autoinflammation pubmed/16021123 in Behcet’s disease: do we oversimplify a complex 44. Fritsch PO, Sidoroff A. Drug-induced Stevens-Johnson disorder? Rheumatology. 2006;45:1461-1465. PMID: syndrome/toxic epidermal necrolysis. Am J Clin https://www.ncbi.nlm.nih.gov/pubmed/16998234 Dermatol. 2000;1(6):349-360. PMID: https://www. 55. Mumcu G, Inanc N, Yavuz S, et al. The role of infectious ncbi.nlm.nih.gov/pubmed/11702611 agents in the pathogenesis, clinical manifestations 45. Kim HI, Kim SW, Park GY, et al. Causes and outcomes and treatment strategies in Behcet disease. Clin Exp of Stevens-Johnson syndrome and toxic epidermal Rheumatol. 2007;25:S27-S33. PMID: https://www. necrolysis in 82 adult patients. Kor J Intern Med. ncbi.nlm.nih.gov/pubmed/17949548 2012;27(2):203-210. PMID: https://www.ncbi.nlm.nih. 56. Liumbruno GM, Centoni PE, Molfettini P, et al. gov/pubmed/22707893 Lymphocytopheresis in the treatment of psoriasis 46. Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal vulgaris. J Clin Apher. 2006;21:158. necrolysis. J Am Aca Dermatol. 2007;56(2):181- 57. Williams JDL, Griffiths CEM. Cytokine blocking agents 200. PMID: https://www.ncbi.nlm.nih.gov/ in dermatology. Clin Exper Dermatol. 2002;27(7):585- pubmed/17224365 590. PMID: https://www.ncbi.nlm.nih.gov/ 47. Paquet P, Piéard GE. New insights in toxic epidermal pubmed/12464154 necrolysis (Lyell’s syndrome). Clinical considerations, 58. Valbonesi M, Garelli S, Montani F, et al. Short- pathophysiology and target treatments revisited. term effects of plasma exchange treatment of

Goap Dermatol, 1(1): 35-45 (2019) 44 psoriasis: preliminary clinical and immuno-chemical ncbi.nlm.nih.gov/pubmed/21393485 investigations. Plasma Ther Transfus Technol. 65. Bleasel NR, Varigos GA. Porphyria cutanea tarda. Austr 1982;3:177. J Dermatol. 2000;41:197-206. PMID: https://www.ncbi. 59. Jorstad S, Bergh K, Iversen OJ. Effects of cascade nlm.nih.gov/pubmed/11105361 apheresis in patients with psoriasis and psoriatic 66. Balwani M, Desnick R. The porphyrias: advances arthropathy. Blood Purif. 1998;16:37-42. PMID: in diagnosis and treatment. Blood. 2012;120:4496- https://www.ncbi.nlm.nih.gov/pubmed/9513761 4504. PMID: https://www.ncbi.nlm.nih.gov/ 60. Wilfert H, Hönigsmann H, Steiner G, et al. Treatment pubmed/22791288 of psoriatic arthritis by extracorporeal photo 67. Anstey AV, Hit RJ. Liver disease in erythropoietic chemotherapy. Br J Dermatol. 1990;122:225-232. PMID: protoporphyria: insights and implications for https://www.ncbi.nlm.nih.gov/pubmed/2152448 management. Postgrad Med J. 2007;83:739-748. PMID: 61. Sohagia AB, Guptha Gunturu S, Tong TR, Hertan https://www.ncbi.nlm.nih.gov/pubmed/18057171 HI. Henoch-Schönlein Purpura - a case report and 68. Kribben A, Lütkes P, Müller H. Cost calculations for review of the literature. Gastroenterol Res Prat. dialysis and other therapy methods. Das Krankenhaus. 2010;2010:597648. PMID: https://www.ncbi.nlm.nih. 2004;5:356-363. gov/pubmed/20508739 62. Rech J, Fuchs F, Kallert S, et al. Plasmapheresis therapy in an elderly patient with rapidly progressive Henoch-Schönlein purpura with disseminated organ involvement. Clin Rheumatol. 2007;26:112-114. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16429242 63. Chartapsiak W, Opastiraku SL, Willis NS, et al. Prevention and treatment of renal disease in Hennoch-Schönlein purpura: a systemic review. Arch Dis Child. 2009;94:132-137. PMID: https://www.ncbi. nlm.nih.gov/pubmed/18701559 64. Davin JC. Henoch-Schönlein purpura nephritis: pathophysiology, treatment and future strategy. Clin J Am Soc Nephrol. 2011;6:679-689. PMID: https://www.

Copyright: © Bambauer et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Goap Dermatol, 1(1): 35-45 (2019) 45