American Journal of Hematology 41 :165-169 (1992)
lnefficacy of Intravenous Immunoglobulin in Patients With Low-Risk Thrombotic Thrombocytopenic Purpura/Hemolytic-Uremic Syndrome Guido Finazzi, Piero Bellavita, Anna Falanga, Piera Viero, and Tiziano Barbui Hematology Division and Transfusion Department, Ospedali Riuniti, Bergamo, Italy
Objective: To assess the efficacy of intravenous immunoglobulin (IVIG), in comparison with plasma exchange (PE), in the treatment of patients with thrombotic thrornbocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Design: Prospective, nonrandomizedcomparative study. Setting: Hematologydepartment in a general hospital. Patients: 17 consecutive adult patients, six of them pregnant, with diagnosis of TTP/ HUS. Three had a severity score at diagnosis s 4 and were treated with IVlG and 14 had a severity score of 25 and/or were pregnant and received PE. The response was evaluated after 5 days of therapy. Results: Complete remission was obtained in 0/3cases treated with WIG and 10114 (71%) with PE (Fisher’s exact test P = 0.05). Three patients died for widespread TTP-HUS, and four had persistent disease. Inthree of the four resistant patients, complete remission was obtained by further PE but not by further IVIG. The overall remission rate was 76% (13/17). Conclusions: Our study does not confirm the utility of IVlG in the management of TTP-HUS, as suggested by earlier single case reports. o 1992 Wiley-Liss, Inc. Key words: intravenous immunoglobulin, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, plasma exchange
INTRODUCTION
Thrombotic thrombocytopenic purpura (TTP) is a relatively rare syndrome of uncertain etiology, characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological dysfunction, and renal abnormalities. The clinical and pathological findings of TTP largely overlap with the hemolytic-uremic syndrome (HUS), and during the past decade it has become clear that TTP and HUS can be regarded as parts of a spectrum often designated TTP-HUS syndrome [ 1,2]. Plasma exchange (PE) has emerged as the treatment of choice for TTP-HUS, yielding 70-90% of complete response rates [3,4]. Other therapies, including plasma infusion, splenectomy , antidatelet agents, corticosteroids , and vincristine , have been effective in some cases, but their role and timing are not well defined [ 1J. Recent advances in understanding the pathogenesis of TTP-HUS have led to additional therapeutic proposals. Lian et al. showed that normal IgG can from inactivate a platelet-agglutinating factor TTP plasma [5,6], SO some investigators have introduced 0 1992 Wiley-Liss, Inc.
intravenous immunoglobulins (IVIG) in the management of some cases of TTP-HUS, mostly those refractory to PE. Favorable results have been described in some case reports [7-141, but not in others [15,16] and, since no prospective studies on consecutive series of patients are reported, the role of this therapy remains uncertain. We have previously described [ 171 the case of a young girl with a mild form of TTP-HUS who achieved a complete stable remission after IVIG. In the light of that observation, we decided to prospectively treat with IVIG all consecutive patients with a mild clinical presentation of TTP-HUS and to compare the remission rate with that observed in all other cases treated with plasmapheresis. In addition, we used IVIG as second-line treatment in
Received for publication September 16, 1991; accepted March 10, 1992. Address reprint requests to Dr. Guido Finazzi, Hematology Division, Ospedali Riuniti, Largo Barozzi 1, 24100 Bergamo, Italy.
166
Finazzi et al. TABLE 1. Severity Scoring of Patients With Thrombotic Thrombocytopenic Purpura* Score
Neurological
Renal
0
None
I
Confusion, lethargy
Cr 1.5-2.5 mgidl proteinuria
2
Seizure, coma, focal deficits
Cr >2.5 mg/dl dialysis
Platelets (/mms)
Hemoglobin (gidl)
> 100,000
>I2
20,00~100,000
9-12
50O U/ml; for neurological symp- therapy. toms, confusion, lethargy, behavioral changes, focal Second-line therapy. Patients with persistent TTPneurological deficits, convulsions, and coma; for im- HUS were given IVIG if previously treated with PE and paired renal function, a creatinine level of >1.5 mg/dl, vice versa. If they failed to recover after another 5 days, and proteinuria > 1 giday. additional therapy, including further PE and IVIG, was Thrombocytopenia and microangiopathic hemolytic carried out (for details, see Figs. 1, 2). anemia were considered sufficient for the diagnosis [ 181. Statistical analysis. The difference in remission rates Neurological abnormalities and renal impairment pro- between patients treated with IVIG or PE was assessed by vided supportive evidence but were not an absolute re- Fisher’s exact test. quirement [ 191. TTP-HUS was diagnosed in six pregnant women. In these patients, pre-eclampsia was ruled out because hy- RESULTS pertension and proteinuria were absent. In addition, no Clinical and Laboratory Findings improvement of the hematological parameters was obFrom 1986 to 1991, 17 consecutive patients with a served 24 hr after delivery, further confirming TTP-HUS diagnosis of TTP-HUS were admitted to our hospital and rather than pre-eclampsia [20]. No patient had a positive included in the study. There were 11 women and 6 men, Coombs’ test, consumptive coagulopathy , cancer, septiaged 22-65 years (median age 30 years). Six had TTPcemia, acute systemic lupus erythematosus, or malignant HUS in pregnancy, persisting 24 hr after delivery; one hypertension. male had chronic relapsing TTP-HUS. The main clinical and laboratory characteristics and the severity score of Severity Scoring the patients at diagnosis are shown in Table IT. Each patient was assigned a severity score based on four clinical and laboratory parameters at presentation: neurological impairment, renal impairment, platelet First-Line Therapy count, and hemoglobin level. Points were scored for each Three patients with a severity score of S 4 and without parameter corresponding to 0, no abnormality; 1, mild to concurrent factors (nos. 1-3 in Table 11) received IVIG. moderate abnormality; or 2, severe abnormality, as pro- The remaining 14 patients were given PE. After 5 days of posed by Rose and Eldor [21] and outlined in Table I. treatment, none of the patients treated with IVIG The severity score is the sum of all four parameters, with achieved a complete stable remission, compared with 10/14 (71%) treated with PE (Fisher’s exact test a range of &8 points. P = 0.05). Three patients with a high severity score Therapeutic Program treated with PE (nos. 15-17) died of widespread TTPFirst-line therapy. Patients with a severity score of HUS. Four patients, three treated with IVIG and one G4 received intravenous intact IgG molecules (Sandoz, (case no. 14) with PE, showed persistence of the disease
patients refractory to plasmapheresis. The results of this prospective investigation are reported here.
Intravenous Immunoglobulin in TTP/HUS
ASA
167
m
PDN 220
-
200
-
r 7000 1800
180-
2
1600
V
160-
--I
...-
140-
c
120-
1400 1200 1000 800
60
-='
'1
I
3
600
-
400
4020
200
-
0
0-
DAYS Fig. 1. Response of platelet count and LDH levels to different treatments in patient No. 3. Abbreviations
IgG PG12
PP ASA PDN
intravenous immunoglobulin prostacyclin plasmapheresis aspirin prednisone
after five days of therapy and were switched to the second-line therapy program. Second-Line Therapy Patient no. 1 , resistant to IVIG, showed a prompt response to PE. Patient no. 2, also resistant to IVIG, died suddenly soon after the first PE and after a CT scan with contrast media. Autoptic findings revealed massive pulmonary edema without apparent organ failure. A presumptive diagnosis of anaphylactic reaction to plasma and/or contrast media in a patient with TTP-HUS was established. Patient no. 3, resistant to IVIG, was also refractory to seven PE. Additional therapy with aspirin, 325 mg/day, prostacyclin, 4.6 ng/kg/min, further IVIG and two more was ineffective. Finally, complete stable remission was obtained with three additional PE 40 days after diagnosis (Fig. 1). The patient remains well 4 years later. Patient no. 14, initially resistant to plasma exchange, was also refractory to IVIG. She reached a first remission after three further PE. Subsequently, three relapses occurred; all responded to PE, but not to IVIG, until a complete stable remission was achieved 166 days after
diagnosis (Fig. 2). She remains well 3 years later. Overall, the remission rate in the 17 patients included in the study was 76% (13/17) (Table 111). DISCUSSION
Therapy with IVIG is of particular interest in the management of TTP-HUS in order to reduce the risk of infection related to PE. From a computer search using the Medline database, we found 13 published case reports of adults with TTP-HUS treated with IVIG [7-171. Complete stable remission was reported in nine cases, with a total remission rate of 69%. The main criticism in evaluating these case reports is that unexpected successes are much more likely to be reported than failures. To establish the efficacy of IVIG in the treatment of TTP-HUS, a prospective study in comparison with PE had to be done. However we considered unethical to design a randomized study of IVIG vs. PE. Thus, we decided to use IVIG to treat a selected group of consecutive patients in whom, according to our experience, the riskibenefit ratio of this therapy was expected to be more favourable, i.e., patients with a mild-moderate presentation of the disease.
Finaui et al.
168 IgG PP ASA
PDN 280
260 240
120 100
80
60 40
20
DAB
Fig. 2. Response of platelet count and LDH levels to different treatments in patient No. 14. Abbreviations for treatments as in Fig. 1. TABLE II. Clinical and Laboratory Characteristics of 17 Patients With TTP at Diagnosis Case No.
l3 2 3 4 5
6 7 8 9 10 II 12 13 14
15 16 17
AgelSex
Neurological
Renal
22iM 49lF 26lM 3 IIF 28lF 23lF 341F 31lM 36iF 29lF 29lF 22lM 62lF 27iF 65lM 441F 30lM
-
-
-
P P P
-
-
-
-
-
Focal deficits Focal deficits Focal deficits
-
-
P Cr 2.6 Cr 2.3 Dyalisis Cr 1.6 Cr 3.1 Cr 1.6 Cr 2.7
-
Coma Focal deficits Coma Coma Coma Coma
-
Platelets (irnm')
Hb (rngldl)
Severity score
70,000 64,000 37,000 53,000 3 1,000 83,000 2 1,000 45,000 45,000 19,000 65,000 46,000 15,000 17,000 24,000 19,000 10,000
8.9 8.6 8.0 9.9 8. I 7.0 7.5 8.5 7.8 8.0 7.3 8.0 9.5 5.8 7.0 8.1 1.5
3 4 4 3 3 3 5 5 5 5 5 6 I 7 7 7 8
Predisposing factors
Pregnancy Pregnancy Pregnancy
Pregnancy Pregnancy
Pregnancy
"Relapse of chronic relapsing thrombotic thrornbocytopenic purpura; P, proteinuria (>1 giday); Cr, creatinine.
Our results clearly show that IVIG is not a first-line therapy for TTP-HUS. In fact, no remission was observed, whereas PE yielded 71% of remissions. The difference was so striking that we stopped the study as soon as statistical significance was reached.
We also evaluated the efficacy of IVIG as second-line treatment in patients resistant to PE. The definition of resistance was a problem, since there is no agreement in the literature on the number of PE needed for complete recovery. Most patients respond to PE in the first days of
Intravenous Immunoglobulin in TTP/HUS TABLE 111. Response to Treatment of 17 Patients With lTP/HUS* Case No.
First-line treatment
Response
I 2 3 4 5 6 7 8 9
IVlG IVIG WIG PE PE PE PE PE PE PE PE PE PE PE PE PE PE
Resistance Resistance Resistance Remission Remission Remission Remission Remission Remission Remission Remission Remission Remission Resistance Dead Dead Dead
10
11 12 13 14
15 16 17
Second-line treatment
Response
PE PE See Fig. 1
Remission Dead Remission
See Fig. 2
Remission
*All patients received prednisone 2 mgikgiday. IVIG, intravenous immunoglobulin; PE, plasma exchange.
therapy but some can require up to 20-30 PE to reach a complete stable remission [22,23]. In the series of 17 patients reported by Blitzer et al. [18], the mean time to response was 3.8 days from the first PE and most patients (78%) responded within 5 days. Thus, we decided to evaluate the response to the firstline therapy after 5 days. Only one patient out of 14 treated with PE showed persistent disease. This patient did not respond to IVIG either but did reach remission after further PE. The same pattern of response was observed in three relapses of the disease until complete stable remission was achieved. Similarly, another patient, initially resistant to both IVIG and PE, was cured by further PE but not by further IVIG. In conclusion, this prospective study on a small consecutive series of patients failed to confirm previously anecdotal reports suggesting a potential efficacy of IVIG in the treatment of TTP-HUS. Further information on this setting could be gained more usefully from other prospective studies rather than from additional single case reports. REFERENCES 1. Byrnes JJ, Moake JL: Thrombotic thrombocytopenic purpura and haemolytic-uraemic syndrome: Evolving concepts of pathogenesis and therapy. Clin Haematol 15:413442, 1986. 2. Remuzzi G: HUS and TTP: variable expression of a single entity. Kidney Int 32:292-308, 1987.
169
3. Bell WR, Braine HG, Ness PM, Kickler TS: Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. N Engl J Med 325:398403, 1991. 4. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA, and the Canadian Apheresis Study Group: Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 325:393-397, 1991. 5. Lian ECY, Mui PTK, Siddiqui FA, Chiu AYY, Chiu LLS: Inhibition of platelet-aggregating activity in thrombotic thrombocytopenic purpura plasma by normal adult immunoglobulin G. J Clin Invest 73548555, 1984. 6. Siddiqui FA, Lian ECY: Platelet-agglutinating protein P37 from a thrombotic thrombocytopenic purpura plasma forms a complex with human immunoglobulin G. Blood 71:299-304, 1988. 7. Krishnamurhty M, Bellevue R, Lian E, Dosik M: Intravenous immunoglobulin in thrombotic thrombocytopenic purpura; a new mode of treatment. Blood 64:291, 1985 (abst). 8. Messmore HL, Yeshwant C, Remlinger K, Seghatchian MJ: Intravenous gamma globulin in refractory thrombotic thrombocytopenic purpura (TTP). Thromb Haemost 54:127, 1985 (abst). 9. Gilcher RO: Refractory TTP responding to I.V. gamma globulin. Blood 64:237, 1985 (abst). 10. Wong P, Itoh K, Yoshida S: Treatment of thrombotic thrombocytopenic purpura with intravenous gamma globulin. (Letter.) N Engl J Med 314:385-386, 1986. 11. Finn NG, Wang MD, Hong KJ: High-dose intravenous yakpa-immunoglobulin infusion in the treatment of thrombotic thrombocytopenic purpura. Arch Intern Med 147:2165-2167, 1987. 12. Staszewski H, Colbourn D, Donovan V, Ludnian H: Thrombotic thrombocytopenic purpura: Report of a case with a possible response to high-dose intravenous gammaglobulin. Acta Haeniatol 82:201-204, 1989. 13. Centurioni R, Leoni P: High-dose immunoglobulins in the treatment of thrombotic thrombocytopenictpurpura (TTP). (Letter.) Haematologica 75:19&197, 1990. 14. Castaman G, Rodeghiero F, Ruggeri M, Di Bona E, Dini E: Longlasting remission after high-dose intravenous immunoglobulins in a case of relapsing thrombotic thrombocytopenic purpura. Haematologica 7 6 3 1 1-5 12, 1991. 15. Chin D, Chyczij H, Etches W, Gordon P, King E: Treatment of thrombotic thrombocytopenic purpura with intravenous gammaglobulin. (Letter.) Transfusion 27:115-116, 1987. 16. Kelton JG, Moore JC, Murphy WG: Studies investigating platelet aggregation and release initiated by sera from patients with thrombotic thrombocytopenic purpura. Blood 69:924928, 1987. 17. Viero P, Cortelazzo S, Buelli M, Comotti B, Minetti B, Barbui T: Thrombotic thrombocytopenic purpura and high-dose immunoglobulin therapy. (Letter.) Ann Intern Med 104:282, 1986. 18. Blitzer JB, Granfortuna JM, Gottlieb AJ, et al: Thrombotic thrombocytopenic purpura: Treatment with plasmapheresis. Am J Haematol 24:329-339, 1987. 19. Kwaan HC: Clinicopathologic features of thrombotic thrombocytopenic purpura. Semin Haematol 24:71-81, 1987. 20. Weiner CP: Thrombotic microangiopathy in pregnancy and the postpartum period. Semin Haematol24: 119-129, 1987. 21. Rose M, Eldor A: High incidence of relapses in thrombotic thrombocytopenic purpura. Am J Med 83:437444, 1987. 22. Pisciotto P, Rosen D, Silver H, et al: Treatment of thrombotic thrombocytopenic purpura. Evaluation of plasma exchange and review of the literature. Vox Sang 45:185-196, 1983. 23. Joneau M, Cordonnier C, Vemant JP, Touzet C, Sobel A: How many plasma exchanges to cure thrombotic thronibocytopenic purpura? Scand J Haematol34:15-59, 1985.
lnefficacy of Intravenous Immunoglobulin in Patients With Low-Risk Thrombotic Thrombocytopenic Purpura/Hemolytic-Uremic Syndrome Guido Finazzi, Piero Bellavita, Anna Falanga, Piera Viero, and Tiziano Barbui Hematology Division and Transfusion Department, Ospedali Riuniti, Bergamo, Italy
Objective: To assess the efficacy of intravenous immunoglobulin (IVIG), in comparison with plasma exchange (PE), in the treatment of patients with thrombotic thrornbocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Design: Prospective, nonrandomizedcomparative study. Setting: Hematologydepartment in a general hospital. Patients: 17 consecutive adult patients, six of them pregnant, with diagnosis of TTP/ HUS. Three had a severity score at diagnosis s 4 and were treated with IVlG and 14 had a severity score of 25 and/or were pregnant and received PE. The response was evaluated after 5 days of therapy. Results: Complete remission was obtained in 0/3cases treated with WIG and 10114 (71%) with PE (Fisher’s exact test P = 0.05). Three patients died for widespread TTP-HUS, and four had persistent disease. Inthree of the four resistant patients, complete remission was obtained by further PE but not by further IVIG. The overall remission rate was 76% (13/17). Conclusions: Our study does not confirm the utility of IVlG in the management of TTP-HUS, as suggested by earlier single case reports. o 1992 Wiley-Liss, Inc. Key words: intravenous immunoglobulin, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, plasma exchange
INTRODUCTION
Thrombotic thrombocytopenic purpura (TTP) is a relatively rare syndrome of uncertain etiology, characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological dysfunction, and renal abnormalities. The clinical and pathological findings of TTP largely overlap with the hemolytic-uremic syndrome (HUS), and during the past decade it has become clear that TTP and HUS can be regarded as parts of a spectrum often designated TTP-HUS syndrome [ 1,2]. Plasma exchange (PE) has emerged as the treatment of choice for TTP-HUS, yielding 70-90% of complete response rates [3,4]. Other therapies, including plasma infusion, splenectomy , antidatelet agents, corticosteroids , and vincristine , have been effective in some cases, but their role and timing are not well defined [ 1J. Recent advances in understanding the pathogenesis of TTP-HUS have led to additional therapeutic proposals. Lian et al. showed that normal IgG can from inactivate a platelet-agglutinating factor TTP plasma [5,6], SO some investigators have introduced 0 1992 Wiley-Liss, Inc.
intravenous immunoglobulins (IVIG) in the management of some cases of TTP-HUS, mostly those refractory to PE. Favorable results have been described in some case reports [7-141, but not in others [15,16] and, since no prospective studies on consecutive series of patients are reported, the role of this therapy remains uncertain. We have previously described [ 171 the case of a young girl with a mild form of TTP-HUS who achieved a complete stable remission after IVIG. In the light of that observation, we decided to prospectively treat with IVIG all consecutive patients with a mild clinical presentation of TTP-HUS and to compare the remission rate with that observed in all other cases treated with plasmapheresis. In addition, we used IVIG as second-line treatment in
Received for publication September 16, 1991; accepted March 10, 1992. Address reprint requests to Dr. Guido Finazzi, Hematology Division, Ospedali Riuniti, Largo Barozzi 1, 24100 Bergamo, Italy.
166
Finazzi et al. TABLE 1. Severity Scoring of Patients With Thrombotic Thrombocytopenic Purpura* Score
Neurological
Renal
0
None
I
Confusion, lethargy
Cr 1.5-2.5 mgidl proteinuria
2
Seizure, coma, focal deficits
Cr >2.5 mg/dl dialysis
Platelets (/mms)
Hemoglobin (gidl)
> 100,000
>I2
20,00~100,000
9-12
50O U/ml; for neurological symp- therapy. toms, confusion, lethargy, behavioral changes, focal Second-line therapy. Patients with persistent TTPneurological deficits, convulsions, and coma; for im- HUS were given IVIG if previously treated with PE and paired renal function, a creatinine level of >1.5 mg/dl, vice versa. If they failed to recover after another 5 days, and proteinuria > 1 giday. additional therapy, including further PE and IVIG, was Thrombocytopenia and microangiopathic hemolytic carried out (for details, see Figs. 1, 2). anemia were considered sufficient for the diagnosis [ 181. Statistical analysis. The difference in remission rates Neurological abnormalities and renal impairment pro- between patients treated with IVIG or PE was assessed by vided supportive evidence but were not an absolute re- Fisher’s exact test. quirement [ 191. TTP-HUS was diagnosed in six pregnant women. In these patients, pre-eclampsia was ruled out because hy- RESULTS pertension and proteinuria were absent. In addition, no Clinical and Laboratory Findings improvement of the hematological parameters was obFrom 1986 to 1991, 17 consecutive patients with a served 24 hr after delivery, further confirming TTP-HUS diagnosis of TTP-HUS were admitted to our hospital and rather than pre-eclampsia [20]. No patient had a positive included in the study. There were 11 women and 6 men, Coombs’ test, consumptive coagulopathy , cancer, septiaged 22-65 years (median age 30 years). Six had TTPcemia, acute systemic lupus erythematosus, or malignant HUS in pregnancy, persisting 24 hr after delivery; one hypertension. male had chronic relapsing TTP-HUS. The main clinical and laboratory characteristics and the severity score of Severity Scoring the patients at diagnosis are shown in Table IT. Each patient was assigned a severity score based on four clinical and laboratory parameters at presentation: neurological impairment, renal impairment, platelet First-Line Therapy count, and hemoglobin level. Points were scored for each Three patients with a severity score of S 4 and without parameter corresponding to 0, no abnormality; 1, mild to concurrent factors (nos. 1-3 in Table 11) received IVIG. moderate abnormality; or 2, severe abnormality, as pro- The remaining 14 patients were given PE. After 5 days of posed by Rose and Eldor [21] and outlined in Table I. treatment, none of the patients treated with IVIG The severity score is the sum of all four parameters, with achieved a complete stable remission, compared with 10/14 (71%) treated with PE (Fisher’s exact test a range of &8 points. P = 0.05). Three patients with a high severity score Therapeutic Program treated with PE (nos. 15-17) died of widespread TTPFirst-line therapy. Patients with a severity score of HUS. Four patients, three treated with IVIG and one G4 received intravenous intact IgG molecules (Sandoz, (case no. 14) with PE, showed persistence of the disease
patients refractory to plasmapheresis. The results of this prospective investigation are reported here.
Intravenous Immunoglobulin in TTP/HUS
ASA
167
m
PDN 220
-
200
-
r 7000 1800
180-
2
1600
V
160-
--I
...-
140-
c
120-
1400 1200 1000 800
60
-='
'1
I
3
600
-
400
4020
200
-
0
0-
DAYS Fig. 1. Response of platelet count and LDH levels to different treatments in patient No. 3. Abbreviations
IgG PG12
PP ASA PDN
intravenous immunoglobulin prostacyclin plasmapheresis aspirin prednisone
after five days of therapy and were switched to the second-line therapy program. Second-Line Therapy Patient no. 1 , resistant to IVIG, showed a prompt response to PE. Patient no. 2, also resistant to IVIG, died suddenly soon after the first PE and after a CT scan with contrast media. Autoptic findings revealed massive pulmonary edema without apparent organ failure. A presumptive diagnosis of anaphylactic reaction to plasma and/or contrast media in a patient with TTP-HUS was established. Patient no. 3, resistant to IVIG, was also refractory to seven PE. Additional therapy with aspirin, 325 mg/day, prostacyclin, 4.6 ng/kg/min, further IVIG and two more was ineffective. Finally, complete stable remission was obtained with three additional PE 40 days after diagnosis (Fig. 1). The patient remains well 4 years later. Patient no. 14, initially resistant to plasma exchange, was also refractory to IVIG. She reached a first remission after three further PE. Subsequently, three relapses occurred; all responded to PE, but not to IVIG, until a complete stable remission was achieved 166 days after
diagnosis (Fig. 2). She remains well 3 years later. Overall, the remission rate in the 17 patients included in the study was 76% (13/17) (Table 111). DISCUSSION
Therapy with IVIG is of particular interest in the management of TTP-HUS in order to reduce the risk of infection related to PE. From a computer search using the Medline database, we found 13 published case reports of adults with TTP-HUS treated with IVIG [7-171. Complete stable remission was reported in nine cases, with a total remission rate of 69%. The main criticism in evaluating these case reports is that unexpected successes are much more likely to be reported than failures. To establish the efficacy of IVIG in the treatment of TTP-HUS, a prospective study in comparison with PE had to be done. However we considered unethical to design a randomized study of IVIG vs. PE. Thus, we decided to use IVIG to treat a selected group of consecutive patients in whom, according to our experience, the riskibenefit ratio of this therapy was expected to be more favourable, i.e., patients with a mild-moderate presentation of the disease.
Finaui et al.
168 IgG PP ASA
PDN 280
260 240
120 100
80
60 40
20
DAB
Fig. 2. Response of platelet count and LDH levels to different treatments in patient No. 14. Abbreviations for treatments as in Fig. 1. TABLE II. Clinical and Laboratory Characteristics of 17 Patients With TTP at Diagnosis Case No.
l3 2 3 4 5
6 7 8 9 10 II 12 13 14
15 16 17
AgelSex
Neurological
Renal
22iM 49lF 26lM 3 IIF 28lF 23lF 341F 31lM 36iF 29lF 29lF 22lM 62lF 27iF 65lM 441F 30lM
-
-
-
P P P
-
-
-
-
-
Focal deficits Focal deficits Focal deficits
-
-
P Cr 2.6 Cr 2.3 Dyalisis Cr 1.6 Cr 3.1 Cr 1.6 Cr 2.7
-
Coma Focal deficits Coma Coma Coma Coma
-
Platelets (irnm')
Hb (rngldl)
Severity score
70,000 64,000 37,000 53,000 3 1,000 83,000 2 1,000 45,000 45,000 19,000 65,000 46,000 15,000 17,000 24,000 19,000 10,000
8.9 8.6 8.0 9.9 8. I 7.0 7.5 8.5 7.8 8.0 7.3 8.0 9.5 5.8 7.0 8.1 1.5
3 4 4 3 3 3 5 5 5 5 5 6 I 7 7 7 8
Predisposing factors
Pregnancy Pregnancy Pregnancy
Pregnancy Pregnancy
Pregnancy
"Relapse of chronic relapsing thrombotic thrornbocytopenic purpura; P, proteinuria (>1 giday); Cr, creatinine.
Our results clearly show that IVIG is not a first-line therapy for TTP-HUS. In fact, no remission was observed, whereas PE yielded 71% of remissions. The difference was so striking that we stopped the study as soon as statistical significance was reached.
We also evaluated the efficacy of IVIG as second-line treatment in patients resistant to PE. The definition of resistance was a problem, since there is no agreement in the literature on the number of PE needed for complete recovery. Most patients respond to PE in the first days of
Intravenous Immunoglobulin in TTP/HUS TABLE 111. Response to Treatment of 17 Patients With lTP/HUS* Case No.
First-line treatment
Response
I 2 3 4 5 6 7 8 9
IVlG IVIG WIG PE PE PE PE PE PE PE PE PE PE PE PE PE PE
Resistance Resistance Resistance Remission Remission Remission Remission Remission Remission Remission Remission Remission Remission Resistance Dead Dead Dead
10
11 12 13 14
15 16 17
Second-line treatment
Response
PE PE See Fig. 1
Remission Dead Remission
See Fig. 2
Remission
*All patients received prednisone 2 mgikgiday. IVIG, intravenous immunoglobulin; PE, plasma exchange.
therapy but some can require up to 20-30 PE to reach a complete stable remission [22,23]. In the series of 17 patients reported by Blitzer et al. [18], the mean time to response was 3.8 days from the first PE and most patients (78%) responded within 5 days. Thus, we decided to evaluate the response to the firstline therapy after 5 days. Only one patient out of 14 treated with PE showed persistent disease. This patient did not respond to IVIG either but did reach remission after further PE. The same pattern of response was observed in three relapses of the disease until complete stable remission was achieved. Similarly, another patient, initially resistant to both IVIG and PE, was cured by further PE but not by further IVIG. In conclusion, this prospective study on a small consecutive series of patients failed to confirm previously anecdotal reports suggesting a potential efficacy of IVIG in the treatment of TTP-HUS. Further information on this setting could be gained more usefully from other prospective studies rather than from additional single case reports. REFERENCES 1. Byrnes JJ, Moake JL: Thrombotic thrombocytopenic purpura and haemolytic-uraemic syndrome: Evolving concepts of pathogenesis and therapy. Clin Haematol 15:413442, 1986. 2. Remuzzi G: HUS and TTP: variable expression of a single entity. Kidney Int 32:292-308, 1987.
169
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