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Keywords:

  • corticosteroid;
  • cytokine;
  • double-filtration plasmapheresis;
  • plasmapheresis;
  • toxic epidermal necrolysis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

Toxic epidermal necrolysis (TEN) is a life-threatening, drug-induced disorder characterized by severe epidermal injury. Although there is no standard therapeutic intervention in TEN, plasmapheresis (PP) is being used increasingly to treat extremely ill TEN patients. In addition to conventional PP, double-filtration PP (DFPP) has been recently used for severe and refractory TEN. In this review, we focus on the clinical usefulness of PP by both demonstrating three cases of TEN refractory to conventional therapies, who were successfully treated with conventional PP or DFPP, and evaluating its therapeutic efficiency. We also provide evidence to suggest the mechanisms of action of PP by investigating the correlation between disease intensity and serum cytokine levels before and after treatment with PP or DFPP in these patients with TEN. At present, PP is a much more effective option for treatment of severe and/or recalcitrant TEN than any other treatment, such as pulsed corticosteroids and i.v. immunoglobulin.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

Toxic epidermal necrolysis (TEN) is a rare life-threatening, drug-induced disorder characterized by extensive, full-thickness, epidermal necrosis and mucous membrane involvement. The mortality rate is approximately 30%, most deaths being due to systemic infection.1,2 The most important prognostic factors are age and the extent of skin detachment related to body surface area: a severity-of-illness score for TEN (SCORTEN) has been recently validated to verify the predictive mortality in patients with TEN.3

Because drug-specific T cells are generally thought to play an important role in initiating the death of epidermal cells at the early stage of TEN, high doses of systemic corticosteroids, i.v. immunoglobulins (IVIG) and immunosuppressive drugs such as cyclophosphamide or cyclosporine have been used in the treatment of TEN with variable success.4–6 The potential benefit of any specific treatment, however, has not been established, because none of these treatments have been evaluated in a prospective randomized trial. Thus, their use remains highly controversial and there is no standard intervention. Owing to concern of increased risk of infections and gastrointestinal bleeding, and masking of early signs of sepsis, many physicians consider that protracted use of high-dose corticosteroids should be avoided in TEN. Therefore, there is a continuing search for another safe and effective option for treatment of TEN refractory to conventional treatment modalities. In this regard, dramatic and rapid improvement of clinical symptoms has been reported to occur in severe and refractory TEN patients treated with plasmapheresis (PP).7,8 In addition to conventional PP, double-filtration PP (DFPP), in which high molecular proteins including inflammatory cytokines can be selectively removed, has been recently used for severe and refractory TEN in limited studies.9 However, only anecdotal experience is available to guide the choice of which methods should be used for TEN. In this review, we focus on the clinical usefulness of PP, by both demonstrating three cases with TEN refractory to conventional therapies, who were successfully treated with conventional PP or DFPP, and comparing the therapeutic efficacy. We also provide evidence to indicate that depletion of pro-inflammatory cytokines is one of the mechanisms whereby PP is efficacious in TEN, by demonstrating our results of serum cytokine levels in these patients before and after treatment. Based on these findings, we discuss novel intervention strategies for TEN.

Pp As An Intervention Strategy For Ten

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

In PP, whole blood is withdrawn, plasma separated from the cellular constituents is discarded and the cellular constituents are reinfused back into the patient, together with albumin or pooled plasma.2 PP has been thought to be a safe intervention in the more severe form of TEN and can be used as an adjunct treatment modality in selected patients, because pathogenic, non-dialyzable factors such as pro-inflammatory cytokines, autoantibodies, immune complexes and other unknown toxic substances can theoretically be removed from the circulation. PP consists of conventional PP (plasma exchange), DFPP, cryofiltration and immunoadsorption. Since Gerard et al.10 reported the successful use of PP in the treatment of TEN, 100 patients with TEN have been report-edly treated with PP: 85 patients with conventional PP and the remaining 15 patients with DFPP.11–18 In view of the reported observation that patients receiving PP had more extensive skin detachment (mean, 58.8%) than those receiving other treatment, the mortality rate (17%) is thought to be reduced by PP. Seventeen patients died of sepsis, disseminated intravascular coagulation and anamnestic malignancy and heart failure;8 however, they were not necessarily elderly patients who have been shown to be associated with a poor prognosis.

In DFPP, two membrane filters with different pore sizes are used to selectively remove high molecular weight proteins including pro-inflammatory cytokines and pathogenic immune complexes. The pore size of the filter employed for DFPP is theoretically sufficient to remove high molecular weight proteins larger than albumin (69 kDa) while those smaller than albumin are retained in the circulation. Therefore, because tumor necrosis factor (TNF)-α has a molecular weight of 51 kDa, the DFPP procedure cannot theoretically remove TNF-α and other unwanted inflammatory substances including interferon (IFN)-γ (50 kDa), interleukin (IL)-1β (17 kDa), IL-6 (19–26 kDa) and soluble Fas ligand (sFasL) (26 kDa). Indeed, our studies showed that serum levels of pro-inflammatory cytokines were dramatically increased after treatment with DFPP or the next day, as described later. Nevertheless, because these cytokines could exist in a larger size due to binding to proteins and multimer forms in the circulation, some forms of these substances would be depleted even by the DFPP procedure. In terms of clearance efficiency, the DFPP procedure is unlikely to fulfill the purpose of selective depletion of unwanted inflammatory substances which had accumulated in patients (Fig. 1). In addition, even though selective depletion of these substances were sufficiently efficacious by choosing appropriate filters with the pore size that allow selective depletion of these substances, the rebound of cytokine synthesis typically observed in case 1, as described later, would be an obstacle to progress and the strategy to overcome the rebound synthesis would be needed.

image

Figure 1.  Selective depletion of high molecular weight proteins larger than albumin (69 kDa) including coagulation factors, which depends on the pore size of the filter employed for double-filtration plasmapheresis (DFPP).

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Methods For Pp

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

Conventional PP is performed by the use of a plasma separator filter (Plasmaflo OP-05W; Asahikasei-Kuraray-Medical, Tokyo, Japan). On each exchange, 2 L of plasma is usually removed; the total volume of plasma removed is 4.0–6.0 L corresponding to 40 mL/kg of bodyweight. The replacement fluid consists of 2 L of fresh frozen plasma (FFP) to supply lost plasma including coagulation factors. The replacement fluid and original blood cell component are reconstituted and returned to the patient. Vascular access is obtained through the antecubital or femoral vein with a double-lumen Quinton catheter (Teflex Medical Japan, Tokyo, Japan).

In contrast, DFPP is performed with the use of Plasmaflo (OP-08W; Asahikasei-Kuraray-Medical) as the primary separation filter and Evaflax (2A20; Asahikasei-Kuraray-Medical) as the secondary separation filter; the second filter is used to selectively remove high molecular weight proteins including inflammatory cytokines. On each exchange, 1.8 L of plasma is processed; the total volume of plasma is processed is 3.6 L. The blood and plasma flow are approximately 100 mL/min. The processed plasma, replacement solution and original blood cell components are reconstituted and returned to the patient through the antecubital or femoral vein; usually 250–500 mL of a 5–20% human albumin solution are used as the replacement solution to supply the loss of albumin (Fig. 2). The treatment lasts for 3–4 h and approximately 2.5 L of plasma are removed from each patient. A second treatment session is usually initiated 7 days after the first treatment if necessary.

image

Figure 2.  Diagrammatic representation of the arrangement of conventional plasmapheresis (PP) and double-filtration PP (DFPP). FFP, fresh frozen plasma.

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Our Treatment Protocol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

Patients usually receive one session consisting of two plasma exchanges, on 2 consecutive days. In our cases, medications taken before, during and after PP consisted of oral prednisolone, 50 mg/day. If a patient developed new lesions or skin and mucous membrane lesions did not resolve, the patient received the second session of two plasma exchanges at intervals of 1 week. Concomitant prednisolone was not tapered until the lesions had resolved and no new lesions had appeared for 3 days.

Case Presentation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

To demonstrate a promising effect of PP as a safe and effective therapeutic option in the severe form of TEN refractory to conventional treatment modalities, three cases are shown together with one control case treated with pulsed corticosteroids.

Case 1

A 69-year-old woman with asthma was treated with montelukast sodium, codeine phosphate and prednisolone, 40 mg/day on an as-needed basis. Her medical and family history was unremarkable and she had not taken any other medication. A generalized skin eruption occurred 2 weeks after starting these therapies. She was admitted to our hospital with the generalized eruptions accompanied by high fever, conjunctivitis and painful hemorrhagic oral erosions. On admission, the trunk and limbs displayed widespread dull red macules and atypical target lesions. The eruption evolved into large areas of blistering with extensive epidermal necrosis. On hospital day 2, more than 70% loss of epidermis over the skin surface was noted, with severe conjunctival and oral involvement. Despite treatment with oral prednisolone (50 mg/day), the lesions rapidly extended over the entire body. In view of her age and acutely deteriorated condition (Fig. 3a), she was treated with DFPP for 2 days. Although the progression of blistering had stopped (Fig. 3b), re-epithelization was delayed as compared with that in cases 2 and 3. Nevertheless, the patient’s condition began to improve 7 days after DFPP. The prednisolone dosage was gradually tapered over 4 week.

image

Figure 3.  Clinical appearance 1 day before double-filtration plasmapheresis (a) and 1 day after double-filtration plasmapheresis (b) in case 1.

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Case 2

A 39-year-old woman was referred from another hospital where she had been admitted with a presumptive diagnosis of TEN and treated with pulsed corticosteroids (i.v. methylprednisolone at a daily dose of 1 g for 3 days) and IVIG (15 g/day for 3 days) without benefit. Despite these treatments, she developed dusky red patches, bullae and sloughing of the skin which rapidly extended over the trunk and limbs to involve more than 40% of her skin surface. Ophthalmological examination showed acute conjunctivitis with corneal erosions. She was admitted to our hospital on day 9 of the illness. On admission she had tender oral ulcers and hemorrhagic crusts on her lips. Four days later, the eruption intensified and re-epithelization was delayed despite oral prednisolone at 50 mg/day. Conventional PP was started as a last attempt to arrest the progression of her lesions. After 2 days, the progression of blistering with extensive epidermal necrosis had stopped and rapid re-epithelization occurred. Despite a course complicated by sepsis due to Gram-negative bacillus, she rapidly recovered within 7 days and is alive and well.

Case 3

A 48-year-old woman was referred to the Department of Medicine in our hospital because of high fever, severe cough and difficulty in breathing. On the day of admission, the diagnosis of Mycoplasma pneumoniae respiratory infection was made and therapy was then started with pulsed corticosteroids (i.v. methylprednisolone at a daily dose of 1 g for 3 days), together with ciprofloxacin, ceftriaxone and azithromycin. Intermittent positive-pressure breathing was also immediately initiated. Treatment included maintenance i.v. fluid replacement and antipyretics. After starting pulsed corticosteroids, her respiratory status rapidly improved. During the period of 10 days after pulsed corticosteroids, there was a complete absence of any skin and mucosal lesion. Three days after tapering her methylprednisolone to 80 mg/day, she developed slightly edematous, symmetrical erythema on the trunk that spontaneously resolved within 2 days. The patient was placed on a gradually reducing dose of prednisolone: a 3–5 day-tapered course of prednisolone (40, 30, 20 mg/day). When prednisolone was tapered to 15 mg/day, erythematous macules and plaques recurred, initially over the trunk, with a high-grade fever. Despite apparent signs of deterioration of her erythema, oral prednisolone continued to be tapered. As a result, the erythematous macules rapidly increased in number and progressed to involve the entire body. She was eventually referred to us and the diagnosis of TEN was made. She developed numerous targetoid lesions over the entire body with bullous lesions. On admission to our department, her respiratory status remained stable and the pneumonia had cleared radiologically. Ophthalmologic investigation documented a bilateral mild conjunctivitis. Touching her skin lesions caused painful sloughing and bleeding. Although her prednisolone dose was increased to 50 mg/day, the low fever persisted and epidermal detachment of more than 80% of the body surface with widespread macules was noted. On the 8th hospital day, conventional PP was initiated. The fever resolved within 24 h and within 3 days skin lesions had sufficiently improved; the patient received one session of two exchanges over 7 days. On day 16, she made an excellent recovery with almost resolution of the skin lesions (Fig. 4). Although culture and direct molecular detection by polymerase chain reaction were unavailable, results of serological studies of this patient disclosed a significant rise in M. pneumoniae PA and CF antibodies and positive immunoglobulin (Ig)M antibody, consistent with an active Mycoplasma infection. She remained free of symptoms for 6 months without any treatment.

image

Figure 4.  Clinical appearance 2 days before conventional plasmapheresis (PP) (a) and 2 days after conventional PP (b) in case 3.

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Case 4

A 48-year old woman with ulcerative colitis presented with 4 days’ history of fever and a rash that began on her breast and then spread to the extremities and face. She had been treated with salazosulfapyridine. One day before admission, she experienced high fever, generalized erythematous raised atypical targets and small blisters in the center of these lesions. On physical examination, she had bilateral corneal erosions, eroded lips with overlying hemorrhagic crust and oral ulceration with overlying white exudates. These lesions progressed over 2 days to become a widespread, confluent erythema, with a positive Nikolsky’s sign. She was treated with pulsed corticosteroids. Over the next few days, her condition slightly improved but new erythematous lesions occurred. The patient was again treated with pulsed corticosteroids. The skin lesions improved, showing re-epithelization and never progressed to extensive full thickness skin detachment. Later, the dosage of prednisolone was gradually tapered and the remainder of her hospital course was uneventful.

These four patients underwent serial laboratory measurements and blood samples were obtained just before the first PP and after the last PP (cases 1–3), or before and after pulsed corticosteroids (case 4). Serial blood samples were immediately centrifuged and sera were stored at −80°C. All samples were tested simultaneously for IL-6, -8, -10 and TNF-α levels using cytometric bead arrays (CBA; BD Biosciences, San Diego, CA, USA) according to manufacture’s protocol.

Correlation Between Disease Intensity And Serum Cytokine Levels

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

Cases 2 and 3 showed a striking clinical response to conventional PP; both were able to return to normal lifestyle 2 weeks after PP, although case 2 had an episode of sepsis due to a double lumen catheter-related line infection. Case 1 improved gradually for up to 2 weeks. Thus, case 1 showed much less striking benefit from the treatment; initial improvement was delayed and the short-lived rebound of the skin lesions was found. The most rapid and remarkable improvement was observed in cases 2 and 3, although they had the most extensive disease. In contrast, cases 1 and 4 treated with DFPP and pulsed corticosteroids, respectively, showed a relatively delayed improvement with occasional formation of new lesions; these lesions had healed completely just 8 weeks after treatment. Oral prednisolone could be tapered more slowly in cases 1 and 4, than that in cases 2 and 3.

During PP treatment, blood counts and coagulant factors were measured. There was no remarkable changes in white blood cell and platelet numbers, coagulation factors and other clinical variables in cases 2 and 3, before and after conventional PP, although the C-reactive protein level after the PP showed a slight reduction. In contrast, a dramatic increase in white blood cell numbers was noted after DFPP in case 1. The fibrinogen levels dropped to 5% of the initial value and it took 3 days to return to normal levels. IgG, A and M levels fell to approximately a fourth of pretreatment concentrations but showed a slower recovery due to their resynthesis (Table 1).

Table 1.   Laboratory findings before and after treatment
 Case 1 (DFPP) before [RIGHTWARDS ARROW] afterCase 2 (PP) before [RIGHTWARDS ARROW] afterCase 3 (PP) before [RIGHTWARDS ARROW] afterCase 4 (mPSL) before [RIGHTWARDS ARROW] after
  1. WBC, white blood cell; PT, prothrombin time; APTT, activated partial thromboplastin time; TP, total protein; Alb, albumin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein; IgG, immunoglobulin G; DFPP, double-filtration plasmapheresis; PP, plasmapheresis; mPSL, methylprednisolone.

WBC5.116.18.26.912.714.911.911.9
PT10017.095.099.094.085.0  
APTT32.5168.833.732.636.338.0  
TP5.73.46.46.55.25.36.16.0
Alb2.62.83.03.32.53.22.82.7
AST531546309143724
ALT11126433715115064
CRP3.20.82.51.91.60.513.43.1
IgG148039316161298104887114351549

As shown in Figure 5, the serum levels of IL-6, -8 and TNF-α were significantly increased before PP in these patients as compared with those in healthy controls. Conventional PP had a dramatic beneficial effect at reducing these pro-inflammatory cytokine levels in cases 2 and 3, while the unexpected increase in TNF-α and IL-8 levels was observed in case 1 after DFPP. This increase positively correlated with an increase in white blood cell number. In contrast, in case 4 treated with pulsed corticosteroids, a significant decrease in TNF-α levels was noted, but its level remained high, as compared with that in healthy controls. Cases 1, 3 and 4 had elevated levels of IL-10 after DFPP, conventional PP and pulsed corticosteroid therapy, respectively. Although there was no statistically significant correlation between IL-10 levels and the extent of clinical improvement, the IL-10 levels tended to increase coincident with clinical resolution.

image

Figure 5.  Alteration of serum cytokine levels before and after plasmapheresis (PP) or pulsed corticosteroids. DFPP, double-filtration plasmapheresis; IL, interleukin; TNF, tumor necrosis factor.

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Comparison Between Conventional Pp And Dfpp

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

Although observational studies and case series support the use of either conventional PP or DFPP as the treatment of severe and refractory TEN, no attempts have been made to compare the efficacy of DFPP with that of conventional PP. Based on our results presented here, conventional PP appears to be more efficacious in TEN than DFPP. Treatment with conventional PP is beneficial during the first 2 weeks, but the benefit is likely to be greatest when treatment is given early. Thus, conventional PP can replace DFPP as the preferred treatment for severe TEN. However, concern has also been expressed for many years that FFP used as the replacement solution in conventional PP is a blood product and poses a risk of contamination with infectious organisms despite testing and antiseptic measures to kill or filter them. A catheter-related line infection is a more common complication than is generally realized. However, the risk of a catheter-related line infection in conventional PP is comparable to that in DFPP. Indeed, case 2 developed sepsis despite its remarkable efficacy, after conventional PP. This type of infection was not observed in other cases. The major disadvantage, and the primary reason why DFPP has not been employed in a widespread manner in TEN, are that many pro-inflammatory cytokines responsible for the development of TEN cannot be sufficiently depleted by DFPP because their molecular weights are smaller than the pore size of membrane filters used for DFPP; this is in sharp contrast to pemphigus vulgaris, in which the removal of pemphigus antibodies by DFPP is a reasonable therapeutic approach.19,20 Therefore, pro-inflammatory cytokines sufficiently removed by DFPP include monocyte colony-stimulating factor (M-CSF) but not IL-1, IL-6 and TNF-α. In support of this possibility, Kodama et al.21 reported that serum levels of IFN-γ, TNF-α, IL-1β, IL-6, and GM-CSF did not decrease after DFPP was started while G-CSF and M-CSF gradually decreased. Indeed, after the DFPP treatment in case 1, no decrease in any cytokine level was discovered, while slight clinical improvement were found. On the contrary, the highest levels of IL-8 and TNF-α occurred immediately after the DFPP, suggesting the rebound production or release of these cytokines. In view of the fact that either IL-8 or TNF-α can be secreted by neutrophils that accumulate in the circulation after DFPP, the unexpected increase in these cytokine levels might reflect ongoing in vivo activation of neutrophils during the process of DFPP. Interestingly, similar, although less remarkable, increase in leukocytes have been reported to occur immediately after blood transfusion but not after plasma infusion.22

Because it has been shown that direct contact of blood mononuclear cells with the filter membrane and adherence of platelet to the membrane leads to not only cytokine production but also complement activation,23 the unexpected increase in white blood cell number after DFPP would result from serum complement activation. Given the ability of neutrophils to respond to these cytokines, the unexpected increase in these cytokine levels after the DFPP appears to result from an in vivo positive feedback mediated by the rebound synthesis of these cytokines by activated neutrophils. Alternatively, macrophages would be the major source of these cytokines. However, because these cytokine levels eventually decreased 2 days after the DFPP in patients with bullous pemphigoid (unpubl. data, T. Shiohara, 2010), the rebound of cytokine production would be short-lived. The rebound in cytokine levels after DFPP, but not conventional PP, indicates that the use of FFP during the process of conventional PP would serve to prevent neutrophil or macrophages from secreting more cytokines. Because, in DFPP, original blood cell components initially separated are reconstituted with the processed plasma and replacement solution and returned to the circulation, this process may stimulate neutrophils and macrophages to additionally release these cytokines. Thus, the rebound of cytokine production after DFPP is likely to be the reason why its onset of action is usually delayed after the DFPP and why DFPP is less efficacious in TEN than conventional PP. These results explain why the therapeutic efficacy of DFPP is not high as compared with conventional PP, although theoretically it can selectively reduce toxic substances from the circulation.

Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

Our results indicate that either conventional PP or DFPP modulates the balance between inflammatory and anti-inflammatory cytokines, because the IL-6 levels decreased while the IL-10 level increased after PP except for case 2. Because our patients received 50 mg/day prednisolone during the period of PP (cases 1–3), we cannot exclude the possibility that the combination therapy of PP and prednisolone is key in modulating the cytokine balance in favor of the relative IL-10 dominance. In patients treated with conventional PP, the concomitant use of prednisolone together with FFP may serve to prevent the rebound of cytokine production that occurs normally after DFPP. The additional benefit of conventional PP with the use of FFP as the replacement solution is that there is no significant change in leukocyte populations and coagulation factors while efficiently reducing the levels of inflammatory cytokines.

The rebound of pro-inflammatory cytokine production associated with increased white blood cell counts we observed immediately after DFPP may explain some of the less significant effects of DFPP than those of conventional PP, although DFPP may benefit selected patients with TEN. Because our study indicates that dosage of oral prednisolone was able to rapidly be tapered after conventional PP, we suggest that conventional PP may be an effective adjunct treatment modality in severe and refractory TEN by rapidly reducing inflammatory cytokines without inducing their rebound production. Nevertheless, a mere comparison of treatment efficacy in this study is problematic and might be misleading because only a small number of patients were treated and there were differences in the age of the patients and in the severity of the reactions when the treatment started. According to our data, decreases in pro-inflammatory cytokine levels and increases in IL-10 levels would be a promising marker to identify individuals responding to PP, although this finding will have to be confirmed in larger cohorts. To predict the therapeutic improvement, monitoring of serum cytokine levels may be useful and allow case-by-case therapeutic management. Because extreme caution on procedural complication such as line infection is needed, this method should only be used as a last resort in patients with TEN refractory to conventional treatments.

Other Combination Therapy With pp

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

Plasmapheresis is usually used for TEN patients refractory to high doses of corticosteroids. Several immunosuppressive agents are also used to treat these TEN patients; they include cyclosporine, tacrolimus, and anti-TNF-α antibodies or soluble TNF receptors to neutralize TNF-α. These agents have been shown to be effective in the treatment of TEN patients.6,24 Although adding PP to these drugs would also decrease disease severity, there is little available information on this combination therapy.

A tyrosine kinase inhibitor, such as imatinib (Gleevec; Novartis Pharmaceuticals, Basel, Swiss), which is used clinically for patients with chronic myeloid leukemia, would also be effective in reducing inflammation of TEN by reducing TNF-α production.25 Because this kinase inhibitor has been shown to reduce TNF-α production by human monocytes in response to lipopolysaccharide but not suppress production of an anti-inflammatory cytokine IL-10, it is likely that TEN patients may benefit from this tyrosine kinase inhibitor. Statins can be also used to reduce inflammation in patients with TEN as an adjunct treatment added to PP, because of their widespread use and long-term safety record.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

In Japan, PP is now only used as a last resort in TEN patients who are not responding to the standard therapy, high doses of corticosteroids. It remains unknown, therefore, whether PP alone could prevent severe inflammation in TEN. Although the risk of transmission of endogenous unknown viruses to the patients through FFP have not been totally eliminated, it appears that PP has found a place in the treatment of TEN. Another drawback of PP is a catheter-related line infection that could be treated with antibiotics. Nevertheless, the benefits of PP outweigh these risks: PP appears be a much more effective option for treatment of severe and/or recalcitrant TEN than any other treatments, such as pulsed corticosteroids and IVIG, although the exact mode of action remains unknown. Our data raise the possibility that serum cytokine levels, such as TNF-a, IL-6 and IL-10, before and after PP can serve as predicting markers for its therapeutic efficacy, a hypothesis that requires further testing.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References

This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology (to T. S.) and the Health and Labor Science Research Grants (Research on Intractable Disease) from the Ministry of Health, Labor and Welfare of Japan (to T. S.).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pp As An Intervention Strategy For Ten
  5. Methods For Pp
  6. Our Treatment Protocol
  7. Case Presentation
  8. Correlation Between Disease Intensity And Serum Cytokine Levels
  9. Comparison Between Conventional Pp And Dfpp
  10. Effects Of Concomitant Use Of Corticosteroids On Efficacy Of Pp
  11. Other Combination Therapy With pp
  12. Conclusions
  13. Acknowledgments
  14. References
  • 1
    Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drug. N Engl J Med 1994; 331: 12721285.
  • 2
    Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol 2007; 56: 181200.
  • 3
    Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115: 149153.
  • 4
    Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mochenhaupt M. Effect of treatments on the motality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 2008; 58: 3340.
  • 5
    Bachot N, Revus J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 2003; 139: 3336.
  • 6
    Mochenhaupt M. Severe drug-induced skin reactions: clinical pattern, diagnosis and therapy. J Dtsch Dermatol Ges 2009; 7: 142160.
  • 7
    Egan CA, Grant WJ, Morris SE, Saffle JR, Zone JJ. Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol 1999; 40: 458461.
  • 8
    Gerasimos B, Natse T, Christidou F et al. Plasma exchange in patients with toxic epidermal necrolysis. Ther Apher 2002; 6: 225228.
  • 9
    Yamada H, Takamori K, Yaguchi H, Ogawa H. A study of the efficacy of plasmapheresis for the treatment of drug induced toxic epidermal necrolysis. Ther Apher 1998; 2: 153156.
  • 10
    Gerard A, Schooneman F, Roche G et al. Lyell’s syndrome: treatment by plasma exchange. Plasma Ther Transfus Technol 1984; 5: 259260.
  • 11
    Wada N, Yamada H, Ozawa Y, Masuda T. A case of drug indused toxic epidermal necrolysis successfully treated with double filtration plasmapheresis. Jpn J Clin Dermatol 1997; 51: 517520 (in Japanese).
  • 12
    Takimoto R, Takamori K. Plasmapheresis in toxic epidermal necrolysis. Jpn J Clin Dermatol 2002; 56: 103105 (in Japanese).
  • 13
    Nakata K, Hirasawa H, Oda S et al. Two cases of toxic epidermal necrolysis treated with plasma exchange. J Jpn Assoc Acute Med 2003; 14: 273278 (in Japanese).
  • 14
    Mizutani K, Hashimoto T, Tamada Y, Matsumoto Y. A case of toxic epidermal necrolysis successfully treated with plasma exchange. Jpn J Clin Dermatol 2004; 58: 539541 (in Japanese).
  • 15
    Lissia M, Figus A, Rubino C. Intravenous immunogloblins and plasmapheresis combined treatment in patients with severe toxic epidermal necrolysis: preliminary report. Br J Plast Surg 2005; 58: 504510.
  • 16
    Nakata K, Hirasawa H, Oda S, Shiga H. Toxic epidermal necrolysis. Jpn J Acute Med 2004; 28: 11611164 (in Japanese).
  • 17
    Takimoto R, Takamori K. Drug induced toxic epidermal necrolysis. Jpn J Clin Med 2004; 62: 515518 (in Japanese).
  • 18
    Okuyama Y, Yamada H, Ikeda S. Plasmapheresis for the treatment of toxic epidermal necrolysis. Jpn J Apher 2008; 27: 139144 (in Japanese).
  • 19
    Turner MS, Sutton D, Sauder DN. The use of plasmapheresis and immunosuppression in the treatment of pemphigus vulgaris. J Am Acad Dermatol 2000; 43: 10581064.
  • 20
    Martin LK, Murrell DF. Treatment of pemphigus. The need for more evidence. Arch Dermatol 2008; 144: 100101.
  • 21
    Kodama K, Kuno H, Koide M, Matsuo T. Virus-associated haemophagocytic syndrome responsive to steroid pulse therapy and double-filtration plasmapheresis. Clin Lab Haemotol 2000; 22: 179181.
  • 22
    Fenwick JC, Cameron M, Naiman SC et al. Blood transfusion as a cause of leucocytosis in critically ill patient. Lancet 1994; 344: 855856.
  • 23
    Craddock PR, Fehr J, Dalmasso AP et al. Hemodialysis leucopenia. J Clin Invest 1977; 59: 879888.
  • 24
    Hanger RE, Hunziker T, Buettiker U et al. Rapid resolution of toxic epidermal necrolysis with anti-TNF-alpha treatment. J Allergy Clin Immunol 2005; 116: 923924.
  • 25
    Paniagua RT, Sharpe O, Ho PP et al. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest 2006; 116: 26332642.