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To cite this article: Ekarat Rattarittamrong, Prot Eiamprapai, Adisak Tantiworawit, Thanawat
Rattanathammethee, Sasinee Hantrakool, Chatree Chai-Adisaksopha & Lalita Norasetthada
(2016): Clinical characteristics and long-term outcomes of warm-type autoimmune hemolytic
anemia, Hematology, DOI: 10.1080/10245332.2016.1138621
Article views: 11
Download by: [Orta Dogu Teknik Universitesi] Date: 12 April 2016, At: 17:45
Clinical characteristics and long-term
outcomes of warm-type autoimmune
hemolytic anemia
Ekarat Rattarittamrong 1, Prot Eiamprapai2, Adisak Tantiworawit 1, Thanawat
Rattanathammethee 1, Sasinee Hantrakool 1, Chatree Chai-Adisaksopha 1, Lalita
Norasetthada 1
1
Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang
Mai, Thailand, 2Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai,
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Thailand
Objectives: To study the clinical manifestations, outcomes, and survival of warm-type autoimmune hemolytic
anemia (AIHA) patients.
Methods: This study was a retrospective single-center study from 2002 to 2013. Clinical data of AIHA patients
were reviewed and analyzed.
Results: One hundred and one patients were included, of whom 77% were female with a median age of 43
years. Primary AIHA was found in 61% of the patients. The secondary causes were systemic lupus
erythematosus (SLE) (64%), solid malignancies (13%), lymphomas (10%), drugs (8%), and infections
(5%). Most patients (96%) responded to steroids, which were not different between primary and
secondary AIHA. Second-line treatments were required in 33 patients (33%). The indications were steroid
dependence (58%), relapse (30%), and others (12%). The most common second-line treatment was
cyclophosphamide (52%). The response rate for second-line treatments was 93%. Relapse occurred in 50
patients (50%) in which 58% occurred more than 3 years after diagnosis. The SLE patients relapsed and
received second-line therapy more than the non-SLE group (P < 0.001). At the median 53-month follow-
up, the overall survival (OS) was 84%. The independent risk factors for OS were age more than 50 years
and malignancy. Sepsis was the most common cause of death.
Discussion and conclusion: AIHA has a good prognosis and long-term survival especially in young patients
without malignancy. Most patients have responded initially to steroids and have a high response rate to
second-line therapy. Carefully adjusted and rapid taper of immunosuppressant is necessary to avoid
sepsis complications.
Keywords: Autoimmune hemolytic anemia (AIHA), Warm-type autoimmune hemolytic anemia, Primary autoimmune hemolytic anemia, Secondary
autoimmune hemolytic anemia
Owing to the rarity of this disease, limited numbers survival (EFS) was defined as time since diagnosis to
of studies regarding clinical manifestations, etiologies, relapse or death. All cases that were lost to follow-up
second-line treatment, and long-term outcomes were or were referred to other hospitals were searched in
available.10–12 One study from Thailand in 1977 the civil registration of Thailand to identify survival
showed that Thai AIHA patients were younger with status and cause of death.
female predominance and had less incidence of cold-
type AIHA compared with Caucasians.10 Statistical analysis
In this study, the authors present the clinical presen- Demographic data and laboratory data were presented
tation, secondary causes, and long-term treatment out- as descriptive statistics including frequency, percen-
comes of warm-type AIHA at Chiang Mai University tage, mean, median, and range. Comparison between
Hospital, Thailand. two groups was performed by the Chi-square or
Fisher’s exact test depending on the type of variables
Research objectives with statistical significance at P-value less than 0.05.
This study examined clinical manifestations, second- The survival analysis was determined by the Kaplan-
ary causes, both first-line and second-line therapies, Meier curve and log-rank test with P-value less than
response rate, relapsed rate, and survival of warm- 0.05 to determine statistical significance. The factors
type AIHA patients. that affected the outcomes were analyzed with multi-
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Rattarittamrong et al. Characteristics and outcomes of AIHA
Table 1 Baseline characteristics of warm-type AIHA Table 2 Clinical outcomes of warm-type AIHA patients
patients
Clinical outcomes N = 101
Baseline characteristics N = 101
Steroid responsiveness (two patients excluded who did not
Sex receive steroids)
Female 78 (77.2%) Overall 95/99 (96.0%)
Age (years) Primary AIHA 60/62 (96.8%)
Median (range) 43 (15–83) Secondary AIHA 35/37 (94.6%)
Age group Second-line treatment 33 (32.7%)
Less than 50 years 64 (63.4%) Indication
More than 50 years 37 (36.6%) Steroid dependence 19/33 (57.6%)
Hemoglobin (g/dl) Relapse 10/33 (30.3%)
Median (range) 5.3 (2–10) Other indications 4/33 (12.1%)
Causes Type
Primary 62 (61.4%) Cyclophosphamide 17/33 (51.5%)
Secondary 39 (38.6%) Azathioprine 7/33 (21.2%)
- SLE 25/39 (64.1%) Cyclosporine 2/33 (6.1%)
- Solid cancer* 5/39 (12.8%) Splenectomy 2/33 (6.1%)
- NHL 4/39 (10.3%) Danazol 2/33 (6.1%)
- Drugs** 3/39 (7.7%) Azathioprine + cyclophosphamide 1/33 (3.0%)
- Others*** 2/39 (5.1%) Azathioprine + IVIG 1/33 (3.0%)
Secondary causes according to sex: female MMF 1/33 (3.0%)
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Rattarittamrong et al. Characteristics and outcomes of AIHA
Relapse
Relapse of AIHA occurred in 50 patients (49.5%).
Most of the relapse events appeared after 3 years in
29 patients (58%) with the median time to relapse of
36 months as shown in Table 2. Thirty-one primary
AIHA patients (50%) and 19 secondary AIHA
patients (48.7%) experienced relapse, which showed
no statistical difference (P = 0.9). Almost all except
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Rattarittamrong et al. Characteristics and outcomes of AIHA
The EFS at the median follow-up time was 48% (51%) after long-term follow-up.6 The studies from
with a median EFS of 33 months and median Asian countries had lower incidence of secondary
relapse-free survival of 46 months (95% CI cause AIHA from cancer compared with European
25.64–66.36). From multivariate analysis, only age countries.6 In light of these data, it is possible that
more than 50 years had an impact on EFS (P = the median age was lower, and more common SLE
0.009; HR 2.08 (1.21–2.57)). There was no signifi- as secondary cause of AIHA.2,6 A large cohort
cantly different EFS between primary and secondary study in England since 1981 revealed that drug-
AIHA (P = 0.236), sex (P = 0.864), and the presence induced immune hemolytic anemia (DIIHA) was
of malignancy (P = 0.121). the most common cause (47%), while other com-
monly associated diseases were CLL (14%), solid
Discussion cancer (8%), and NHL (6%).15 In contrast to the
During the 12-year study period from 2002 to 2013, current study, SLE was reported to be associated
the majority of warm-type AIHA patients were with warm-type AIHA in only 1.5% and secondary
female (77%) with median age of 43 years. Most of causes were found more common than primary
the patients (63.3%) were diagnosed when they were AIHA with a ratio of approximately 3:2.15 Almost
50 years of age. Especially secondary AIHA from all except one DIIHA patients in that study were
SLE which was more commonly found in young from methyldopa, whereas three DIIHA in the
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females, 68% of this group had an age that was less current study were associated with ceftazidime, iso-
than 30 years. The baseline characteristics were com- niazid, and telmisartan. Although the first two
parable to the study by Baek et al. that showed a drugs were reported as DIIHA,16,17 telmisartan was
median age of 48 years and female predominance.12 not previously documented.17–19
However, this Korean study had more female predo- AIHA had very good responses (96%) to corticos-
minance (94%) compared with our study (77%). This teroids as an initial treatment, which were in accord-
could be explained by more SLE as a secondary ance with the previous studies.2,6,12 The result of the
cause of AIHA (56 and 25%).12 present study was in agreement with data obtained
Primary AIHA was found slightly more often than by Genty et al. that initial response for both primary
secondary AIHA with a ratio of 3:2. The most and secondary warm-type AIHA was not different.6
common cause of secondary AIHA was SLE (64%), The responses were slightly higher than the Italiano
which occurred predominately in females. As a Malattie e Matologiche dell’Adulto (Italian Group
result, physicians should look for the possibility of for Adult Hematologic Diseases) (GIMEMA) Study
SLE in young women with AIHA. Moreover, AIHA that showed overall response rate of 82% in primary
is a common manifestation of SLE which accounted warm-type AIHA with a complete response rate
for 6%13 and continues to be one of the diagnostic cri- (Hb > 12 g/dl) of 50% and a partial response rate
teria of SLE according to the Systemic Lupus (Hb > 10 g/dl) of 32%.2 Our study used the response
International Collaborating Clinics Classification cri- criteria at Hb > 10 g/dl. The slightly different
teria.14 In the study from Korea, about half of patients response rate could be explained by different response
were found to have SLE after warm-type AIHA was criteria between studies. Moreover, the response and
diagnosed with the median time of 8 months.12 The relapse criteria of our study used only cut-off value
risk factors of SLE conversion were younger age (less of hemoglobin rather than both cut-off value and
than 60 years) and positive anti-nuclear antibody.12 hemoglobin-level change from baseline compared
AIHA was associated not only with thrombocytopenia with other studies.2,12
and lymphopenia, but also with other organ involve- Second-line therapies were used in both primary and
ment including proteinuria, urinary cellular casts, sei- secondary AIHA. The indication to start second-line
zures, pericarditis, and pleuritis with a younger age of treatment was steroid dependence more than relapse.
disease onset.13 The rate of using second-line treatment in secondary
Secondary causes of warm-type AIHA varied AIHA was higher than primary AIHA, but it was
among many studies at different times and not statistically different. SLE was the most common
region.2,6,9,15 In agreement with our present study, cause of secondary AIHA, which was prescribed on
SLE was the most common cause in a Korean study second-line drug as high as 64%. This could be
in 2011, which found five from seven patients with explained by the fact that SLE patients had a high
secondary AIHA.12 SLE was also found as a probability rate of relapse by disease nature and
common cause of secondary AIHA in a French might also receive second-line treatment due to other
study in 2002, which was equal to NHL (both 14 organ involvement.
out of 83 cases).6 In that study, the diagnosis of Commonly used second-line therapies in the present
AIHA preceded NHL up to 66 months and lead to study were immunosuppressive drugs including cyclo-
a slightly greater frequency of secondary AIHA phosphamide and azathioprine, although there were
Hematology 2016 5
Rattarittamrong et al. Characteristics and outcomes of AIHA
limited numbers of studies to support the efficacy.9 provided overall clinical features, causes, and out-
However, the overall response rate from second-line comes of warm-type AIHA patients in Thailand.
treatments in the current study was higher at 93%
than the 40–60% response rate of immunosuppressive Conclusion
drugs from the literature.8 High response rate in our AIHA has a good prognosis and long-term survival
study may be due to a high prevalence of steroid especially in young patients without secondary malig-
dependence and other indications for SLE, which nancy. Most patients have responded initially to steroid
trended to response more than the relapse and treatment and have a high response rate to second-line
steroid refractory group. Only two patients underwent therapy. The most common cause of death was sepsis,
splenectomy, which was accepted as effective second- which was related to treatment side effects.
line therapy for AIHA,7–9 since this is an invasive pro-
cedure and has some risks such as overwhelming infec- Disclaimer statements
tions. Rituximab has good activity in refractory severe Contributors E.R. wrote and revised the paper; P.E. col-
AIHA with a response rate of 77%20 and is also rec- lected and summarized clinical data, and wrote the
ommended as second-line treatment.7–9 In the paper; A.T. designed the research, obtained researched
GIMEMA study, rituximab both standard dose grant, analyzed data, and wrote the paper; and T.R.,
(375 mg/m2 per week for 4 weeks) and fixed low S.H., C.C., and L.N. revised the manuscript.
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Rattarittamrong et al. Characteristics and outcomes of AIHA
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15 Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: Jarque I, Caballero D, et al. Rituximab is an effective and safe
an 18-year study of 865 cases referred to a regional therapeutic alternative in adults with refractory and severe auto-
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2023–7. 21 Zupanska B, Sylwestrowicz T, Pawelski S. The results of pro-
16 Robinson MG, Foadi M. Hemolytic anemia with positive longed treatment of autoimmune haemolyticanaemia.
Coombs’ test. Association with isoniazid therapy. JAMA. Haematologia. 1981;14(4):425–33.
1969;208(4):656–8. 22 Valent P, Lechner K. Diagnosis and treatment of autoimmune
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