# Comorbidities of Idiopathic Thrombocytopenic Purpura: A

Authors: M. A. Feudjo-Tepie; G. Le Roux; K. J. Beach; D. Bennett; N. J. Robinson
Journal: Advances in Hematology
 (2009)

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## Abstract

A person experiencing more than one medical condition may have ambiguous clinical
presentation. ITP is a serious autoimmune disease with little epidemiological evidence on its
burden, risk factors, and comorbidities. Using the United Kingdom
general practice research database, we conducted a 14 years population-based
case control-type study to explore medical conditions more likely to cooccur with
ITP and their temporal relationship in association with ITP. ITP patients were matched
to non-ITP on practice, age, gender, and follow-up period. Potential comorbidities
were represented by patients’ medical information at the preferred
term level of the MedDRA international classification. As well as death
(OR=60.0; 95% CI [4.47–806.0]) and known clinical signs and symptoms
of ITP, ITP is associated with considerable number of medical conditions.
The association between ITP and some of these conditions is apparent both
before and after ITP diagnosis. Specific targeted studies can now be setup to reexamine
observed associations.


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## Body

## 1. Introduction

Idiopathic thrombocytopenic purpura
(ITP) is a serious acquired autoimmune disorder characterized by a low platelet
count (thrombocytopenia) and mucocutaneous bleeding [1]. It is commonly assumed
that ITP results from autoantibodies causing accelerated platelet destruction.
Recent data suggest that autoantibodies may also inhibit platelet production
[2]. The diagnosis of ITP is complex and is very often
based on the exclusion of other causes of thrombocytopenia [3–6].ITP is traditionally divided
into acute and chronic forms, based on the duration of thrombocytopenia (i.e.,
less than 6 months for acute and more than 6 months for chronic) [5]. ITP is generally acute in young children and
typically, occurs a few days to a few weeks after an infection (e.g., varicella
zoster virus). ITP in children is thought
to be a benign and self-limiting disorder with an excellent prognosis. In
contrast, ITP in adults is primarily
chronic, and the onset is often asymptomatic. The disease is more prevalent
in females than males [4].There is relatively little
epidemiological evidence on disease burden and risk factors; prevalence in
adults and children may range from 9.6 to 189 per 100 000 person [7–9]. Frederiksen
and Schmidt  [7] estimated incidence of 2.7 per 100 000 person per year in Denmark. Our recent estimation of
the prevalence of chronic ITP in the United State using a large U.S. claim database gave 20.3 per 100 000 person [10].The coexistence in an individual with two
(or more) medical conditions is commonly referred to as comorbidity. More
specifically, Feinstein [11] defines comorbidity as “any distinct additional
clinical entity, that has existed or that may occur during the clinical course
of a patient who has the index disease under study.” A person experiencing more
than one condition may present with an ambiguous clinical presentation [12]. Thus,
knowledge of disease comorbidities can provide a better understanding of
disease burden as well as inform diagnosis and treatment decisions. For example,
the investigation of idiopathic normal pressure hydrocephalus (INPH) comorbidities confirmed the early suspicions
of INPH as a multi-aetiological clinical
entity possibly overlapping physiologically with cerebrovascular and Alzheimer
diseases [13]. Disease comorbidities also have consistently been shown to be
important prognostic factors of a number of health conditions including cancer,
independent of the tumour stage [14–18]. Colinet et al. [19] suggested
that comorbidities may explain in part the variability in survival observed from
stage I nonsmall cell lung cancer. So, the importance of comorbidity studies is
well acknowledged in the literature and their use well documented.However,
evidence on ITP specific comorbidities is sparse. Indeed, apart from the known symptoms of
the disease (i.e., bleeding, petechia, purpura, etc), to our knowledge, there
is little empirical evidence in the literature on the association, or lack of
it, between ITP and other medical
conditions. Knowledge of ITP specific comorbidities, that is those frequently occurring with ITP, may provide
a better understanding of ITP disease
progression, ITP disease burden,
and could inform treatment decisions. Their knowledge might lead to preventive
measures, early diagnoses, and better disease management. Comorbidities of ITP can also help put into context potential safety
signals and improve clinical trial design and planning. Hence, using “real world”
evidence, this study aims to reduce the knowledge gap. More specifically,
using a large UK
healthcare database, the paper describes the basic characteristics of an ITP population and identifies other medical
conditions more likely to cooccur or to be diagnosed with ITP. Furthermore, comparing the ITP cohort to a matched non-ITP cohort, the study investigates potential temporal relationship in the
association between identified comorbidities and ITP.


## 2. Material and Method

### 2.1. Data Source

The study population includes
patients registered on UK’s
general practice research database (GPRD) during the period 1990–2004. The GPRD has been described elsewhere [20, 21] and has previously been
used to study comorbidities of newly diagnosed COPD and asthma [22] among other
things. Briefly, the GPRD contains
detailed information on diagnoses, prescribing, GP investigations, outcomes,
and hospital referrals, together with basic demographic information for about 6
million patients from more than 370 representative general practices throughout
the UK.
The database is population-based and representative of the age, sex, and
geographic regions of the UK [21]. Data quality is monitored continuously by the UK Medicines and Healthcare
products Regulatory Agency (MHRA), and practices that fail to maintain the
required standards are removed. The completeness and accuracy of the recording  of medical information have been validated [23–26]. This study was approved by the scientific ethical and advisory
group for the GPRD.


### 2.2. Study Design and Case Definition

A case control study-type approach was utilized. ITP patients (cases) were identified using READ or
OXMIS codes (contact authors for details). Patients with less than 1 year of follow-up before
or after the first diagnosis of ITP were excluded. For each ITP case
up to five, non-ITP patients
(controls) were matched on practice, age, gender, and follow-up
period. The index date of a case was the first ITP diagnosis date, while that of a control was the index date of his/her matched ITP case. Potential controls also had to have at
least one medical record or a recorded prescription in the database within one year
before or one year after the ITP diagnosis date.Potential comorbidities were all medical conditions listed in the GPRD of
the cases and/or controls at preferred term level (PTL) of the medical dictionary
for regulatory activities (MedDRA) hierarchical classification, over the period
of a year before and a year after index date. Additionally, seven selected grouped
medical conditions of a priori interest were defined and considered: myocardial
infarction, breast cancer, chronic renal failure, hepatitis, liver damage,
systemic lupus, and thromboembolic events.Because the
period 1 year before and 1 year after the index date can lead to bias due to differential medical screening between
cases and controls [27], the relative frequency of comorbidity between case and
controls was further assessed by considering a longer follow-up period. Hence, over the period of 5 years
before and 5 years after the index date, trends in risks and risk ratios of
identified comorbidities were explored. However, in this latter analysis, in
order to reduce the list of
considered medical conditions to a manageable size, identified conditions at
the preferred term level were grouped in a clinical meaningful way by a
clinical epidemiologist with a good knowledge of the UK
health system. This pooling of
medical conditions into more aggregate groups (hereafter 26 grouped medical
conditions) also increases the power of any comparison between cases and
controls with respect to the frequency occurrence of any potential comorbidity.
Indeed, because in this analysis we were only interested in the first
occurrence of potential comorbidities, over the course of the follow-up period,
small sample size was an issue. This is the case, particularly for rare
conditions.


### 2.3. Statistical Analysis

Age and gender characteristics of
ITP patients together with the
number of controls per case were described using frequency tables. For each comorbidity,
the frequency of its occurrence in cases was compared to that in controls using
odds ratios calculated by conditional logistic regression [28]. All medical conditions
with odds ratios greater than or equal to 2 and statistically significant at the
0.1% level were selected, ranked by odds ratios and reported. The sensitivity
of our chosen significance
level of 0.1% to the risk of false positives due to multiple testing was assessed
using false discovery rate procedure (FDR) [29].Trends for each comorbidity over the 10-year period were
explored using annual incidence rates (calculated as the number of events over
person-years at risk) and rate ratios (with 95% confidence intervals) between
ITP and non-ITP patients. Confidence intervals were calculated using the
Clayton and Hills formula [30]. To complement the analysis of annual incidence
rates, a cumulative risk
analysis [31] over the 5-year post index period for each of the comorbidities
is performed using log rank test. All analyses are performed using SAS version
9.1.


## 2.1. Data Source

The study population includes
patients registered on UK’s
general practice research database (GPRD) during the period 1990–2004. The GPRD has been described elsewhere [20, 21] and has previously been
used to study comorbidities of newly diagnosed COPD and asthma [22] among other
things. Briefly, the GPRD contains
detailed information on diagnoses, prescribing, GP investigations, outcomes,
and hospital referrals, together with basic demographic information for about 6
million patients from more than 370 representative general practices throughout
the UK.
The database is population-based and representative of the age, sex, and
geographic regions of the UK [21]. Data quality is monitored continuously by the UK Medicines and Healthcare
products Regulatory Agency (MHRA), and practices that fail to maintain the
required standards are removed. The completeness and accuracy of the recording  of medical information have been validated [23–26]. This study was approved by the scientific ethical and advisory
group for the GPRD.


## 2.2. Study Design and Case Definition

A case control study-type approach was utilized. ITP patients (cases) were identified using READ or
OXMIS codes (contact authors for details). Patients with less than 1 year of follow-up before
or after the first diagnosis of ITP were excluded. For each ITP case
up to five, non-ITP patients
(controls) were matched on practice, age, gender, and follow-up
period. The index date of a case was the first ITP diagnosis date, while that of a control was the index date of his/her matched ITP case. Potential controls also had to have at
least one medical record or a recorded prescription in the database within one year
before or one year after the ITP diagnosis date.Potential comorbidities were all medical conditions listed in the GPRD of
the cases and/or controls at preferred term level (PTL) of the medical dictionary
for regulatory activities (MedDRA) hierarchical classification, over the period
of a year before and a year after index date. Additionally, seven selected grouped
medical conditions of a priori interest were defined and considered: myocardial
infarction, breast cancer, chronic renal failure, hepatitis, liver damage,
systemic lupus, and thromboembolic events.Because the
period 1 year before and 1 year after the index date can lead to bias due to differential medical screening between
cases and controls [27], the relative frequency of comorbidity between case and
controls was further assessed by considering a longer follow-up period. Hence, over the period of 5 years
before and 5 years after the index date, trends in risks and risk ratios of
identified comorbidities were explored. However, in this latter analysis, in
order to reduce the list of
considered medical conditions to a manageable size, identified conditions at
the preferred term level were grouped in a clinical meaningful way by a
clinical epidemiologist with a good knowledge of the UK
health system. This pooling of
medical conditions into more aggregate groups (hereafter 26 grouped medical
conditions) also increases the power of any comparison between cases and
controls with respect to the frequency occurrence of any potential comorbidity.
Indeed, because in this analysis we were only interested in the first
occurrence of potential comorbidities, over the course of the follow-up period,
small sample size was an issue. This is the case, particularly for rare
conditions.


## 2.3. Statistical Analysis

Age and gender characteristics of
ITP patients together with the
number of controls per case were described using frequency tables. For each comorbidity,
the frequency of its occurrence in cases was compared to that in controls using
odds ratios calculated by conditional logistic regression [28]. All medical conditions
with odds ratios greater than or equal to 2 and statistically significant at the
0.1% level were selected, ranked by odds ratios and reported. The sensitivity
of our chosen significance
level of 0.1% to the risk of false positives due to multiple testing was assessed
using false discovery rate procedure (FDR) [29].Trends for each comorbidity over the 10-year period were
explored using annual incidence rates (calculated as the number of events over
person-years at risk) and rate ratios (with 95% confidence intervals) between
ITP and non-ITP patients. Confidence intervals were calculated using the
Clayton and Hills formula [30]. To complement the analysis of annual incidence
rates, a cumulative risk
analysis [31] over the 5-year post index period for each of the comorbidities
is performed using log rank test. All analyses are performed using SAS version
9.1.


## 3. Results

### 3.1. Description of Cases and Controls

A total of 1033 incident physician-diagnosed ITP cases during the period
1990–2004 were
identified, 578 (56.0%) of whom were females. Table1 presents the distribution
of these patients by age, group, and gender. Approximately, 50% are 50 or over.
Mean age was 46 in females and 44 years in males. Following matching, 883 cases
(85.5%) had at least one matched control, and these 883 cases were used in
further analyses. A total of 3700 controls were selected, and Table 2 presents
the distribution of number of controls per case, 69% of cases had 4 or 5
controls.Table 1
ITP patients by age and gender.
Age (years)GenderTotal N (%*)Femalen (%*)Malen (%*)0–1594 (16.3)131 (28.8)225 (21.7)16–49208 (36.0)95 (20.9)303 (29.3)50 +276 (47.7)229 (50.3)505 (49.9)Total578 (100.0)455 (100.0)1033 (100.0)P*roportions are column proportions.Table 2
Distribution of number of controls per case.
Number of controls per caseFrequency (cases)PercentCumulative percent015014.514.521646.2020.722393.7824.493686.5831.07420619.951.02550649.0100.00ITP patients and their matched controls had a
total 2366 unique medical conditions at the PTL of the MedDRA classification. Figure1 and Table 3  show medical conditions with an odds ratio (OR)
greater than 2 and significant at the 0.1% level. Conditions are sorted in
descending order of OR. Clinical signs or symptoms known to characterize ITP are strongly associated with ITP (i.e., purpura, OR=146; bruise, OR=57; neutropenia,
OR=29; etc.). There is a strong association between ITP and death (OR=60.0; 95% CI [4.47–806.0]). It is also
important to note that more than 90 conditions are associated with ITP in this analysis despite our use of stringent
criteria (i.e., an odds ratio greater than 2 and statistically significant at a
0.1% level). The use of the false discovery rate
procedure to control for the increasing risk of false positives due to multiple
testing indicates that setting the significance level of each individual test at
0.35% would have guaranteed a targeted overall 5% level. So, our choice of 0.1%
as a significance level is on the cautious side with respect to expected false
positives. As noted above, all of these significant conditions were
grouped into 26 broader conditions as shown in Table 4.Table 3
Comorbidities significantly associated with
ITP in the period or 2 years around diagnosis date.
POdds ratioCLPreferred term namePOdds ratioCLPreferred term name<.0001146.0023.48907.97Purpura.00093.301.308.36Breast cancer female NOS<.0001146.0023.48907.97Purpura NOS.00093.301.308.36Condition aggravated<.000160.004.47805.56Death.00083.181.317.75Haemoptysis<.000160.004.47805.56Death NOS.00083.181.317.75Confusion<.000157.3319.85165.60Increased tendency to bruise<.00013.171.586.35Diabetes mellitus noninsulin-dependent.000929.002.11398.24Neutropenia<.00013.171.586.35Diabetes mellitus noninsulin-dependent<.000121.503.34138.56Whole blood transfusion<.00013.141.655.99Prostatism<.000117.3110.8427.65Ecchymosis.00012.941.436.06Left ventricular failure<.000115.639.9724.49Contusion.00082.921.286.69Respiratory disorder.000612.501.8882.96Chills.00082.921.286.69Respiratory disorder NOS.000612.501.8882.96Rigors.00042.811.335.95Analgesic effect<.000111.002.3351.99Chemoprophylaxis NOS<.00012.731.514.93Vaginal haemorrhage<.000111.002.3351.99Prophylactic chemotherapy.00052.711.305.62Dermatitis diaper<.00019.502.4536.79Haematemesis.00072.691.265.71Phlebitis NOS<.00018.434.0717.46White blood cell disorder<.00012.671.444.94Oral candidiasis<.00018.434.0717.46White blood cell disorder NOS.00022.651.355.21Postoperative analgesia<.00017.572.6921.33Pneumonia<.00012.611.544.42Iron deficiency
anaemia<.00017.572.6921.33Pneumonia NOS<.00012.591.584.27Anaemia<.00017.002.0423.98Blister<.00012.591.584.27Anaemia NOS<.00017.001.7727.74Dry mouth<.00012.591.454.65Osteoporosis<.00016.902.8916.50Leg ulcer (exc
varicose)<.00012.591.454.65Osteoporosis NOS<.00016.902.8916.50Leg ulcer (excl
varicose)<.00012.581.424.67Dry eye NEC<.00016.824.0511.49Epistaxis<.00012.581.424.67Dry eye NOS.00096.001.4924.12Dementia<.00012.571.454.56Keratoconjunctivitis
sicca.00096.001.4924.12Dementia NOS.00052.501.264.94Lethargy.00096.001.4924.12Decubitus ulcer<.00012.441.474.07General symptom.00096.001.4924.12Pressure sore<.00012.441.474.07General symptom
NOS.00045.601.6019.56Venesection<.00012.441.533.89Rectal haemorrhage.00045.601.6019.56Venipuncture.00042.371.274.44Mouth ulceration<.00015.552.3912.89Peripheral
swelling.00042.311.264.23Cardiac failure
congestive<.00015.532.8010.90Eczema
gravitational.00082.301.214.38Cerebrovascular
accident<.00015.532.8010.90Stasis dermatitis<.00012.271.603.22Oedema peripheral<.00015.502.2713.33Acute myocardial
infarction.00082.241.214.16Gastro-oesophageal
reflux disease.00055.401.5418.92Intermittent claudication.00082.241.214.16Gastro-oesophageal
reflux disease<.00015.001.9512.80Abdominal pain
lower<.00012.211.583.10Viral infection.00035.001.5815.82Hip arthroplasty<.00012.211.583.10Viral infection
NOS<.00014.712.2110.06Myocardial
infarction<.00012.211.702.87Rash<.00014.242.397.52Feeling abnormal<.00012.211.702.87Rash NOS<.00013.952.117.41Skin ulcer<.00012.151.313.52Menorrhagia<0.00013.711.718.07Dry eye<.00012.131.383.29Diabetes mellitus.00063.671.399.66Folliculitis<.00012.131.383.29Diabetes mellitus
NOS<.00013.641.677.92Acarodermatitis.00042.121.233.65Haematuria<.00013.641.677.92Scabies
infestation<0.00012.121.363.30Haemorrhoids<.00013.601.439.04Angina unstable<.00012.081.333.26Prophylaxis<.00013.352.235.03Malaise<.00012.081.333.26Prophylaxis NOS.00093.301.308.36Oral pain.00022.021.243.29Atrial
fibrillationTable 4
Comorbidities at the PTL of the MedDRA classification and their 26 grouping.
Grouped conditionsMedical conditions at preferred term levelBleedingEcchymosis, haemoptysis, conjunctival haemorrhage, menorrhagia, rectal haemorrhage, gastrointestinal haemorrhageNOS*, haematuria, epistaxis, haematemesisPulmonaryRespiratory disorder, respiratory disorderNOS*ConstitutionChills, rigors, malaise, general symptom, feeling abnormal, lethargyPeripheral vascular diseasesPhlebitis NOS, aortic aneurysm, phlebitis, intermittent claudicationCerebrovascularaccidentCerebrovascular accidentHaematologyWhite blood cell disorder, white blood cell disorder NOS, neutropenia, anaemia, iron deficiency anaemia, anaemia NOSArrhythmiaAtrial fibrillationAutoimmuneSystemic lupus erythematosus, rheumatoid arthritisRenalRenal failure acuteInfectionViral infection, pneumonia, viral infection NOS, pneumonia NOSOral conditionsOral candidiasis, dry mouth, mouth ulceration, oral painHypoglycemiaHypoglycaemia, hypoglycaemia NOSNeoplasm malignantNeoplasm malignantDermatological conditionsLeg ulcer (exc varicose), rash scaly, skin exfoliation, eczema gravitational, stasis dermatitis, decubitus ulcer, pressure sore, folliculitis, skin ulcer, tinea NOS, rash, infected sebaceous cyst, dermatitis diaper, rash NOSHypersensitivityHypersensitivity, hypersensitivity NOSBreast cancerBreast cancer female NOS, breast cancer, breast cancer NOSNeurologyConfusional state, dementia, dementia NOS, confusionDiabetesDiabetes mellitus noninsulin-dependent, diabetes mellitus noninsulin-dependent, diabetes mellitus, diabetes mellitus NOSEdemaPeripheral swelling, oedema peripheralGenitourinaryProstatism, proctalgiaCoronary artery syndrome/myocardial infarctionAcute myocardial infarction, myocardial infarction, angina unstableCongestive heart failureLeft ventricular failure, cardiac failure congestiveGastro intestinalHaemorrhoids, abdominal pain lower, gastro-oesophageal reflux disease, gastro-oesophageal reflux disease, colitis, colitis NOSOphthalmologyDry eye NEC, dry eye, eyelid ptosis, eye pain, dry eye NOS, keratoconjunctivitis siccaMusculo-skeletal conditionsOsteoporosis, hip arthroplasty, ligament sprain, musculoskeletal pain, osteoporosis NOSMood disorderDysthymic disorderNot* otherwise specified.Figure 1
Medical conditions with OR significantly greater than 2 but less than 20.Some of the medical conditions are rare and/or only found in the ITP group. Because of this, odds ratios, even
though quite large (i.e.,>2), they may not be statistically significant. Medical
conditions with odds ratios greater than 2 but with no more than one event in
the control group are thrombocytopenia, petechiae, splenectomy, purpura,
haemorrhagic disorder, sepsis, bronchopneumonia, headaches, gingival, guttate
psoriasis, acute pancreatitis,
pleural effusion, restlessness, and somnolence.


### 3.2. Longitudinal Approach and Cumulative Risk Analysis for Grouped Conditions

Table5 presents, for each of the 26 grouped medical
conditions, over a period of 10 years around the index date, yearly incidence
rate ratios, between cases and controls, and their 95% CI. Results can be summarized
as follows.
(i)
Conditions that have a significantly higher frequency of occurrence in
ITP compared to non-ITP in at least one time period both before and after diagnosis:
haematological diseases, dermatological conditions, bleeding disorders, gastrointestinal  diseases,
autoimmune disorders, and constitution conditions.(ii)
Conditions that have significantly higher frequency of occurrence in ITP compared to non-ITP patients only after index date: oral conditions and infections.(iii)
Conditions that have significantly
higher frequency of occurrence in ITP compared to non-ITP patients
during only the year of ITP diagnosis or a year before: neurological, coronary artery syndrome/myocardial
infarction, genitourinary, musculoskeletal, ophthalmologic, skeletal,
and edema.(iv)
Other conditions with no statistical
association with ITP.Table 5
Rate ratios and 95% CI between ITP and non-ITP patients for 26 grouped medical conditions.
(a)Comorbidity groupRatio ITP/non-ITP[−5 −4[[−4 −3[[3−2[[−2 −1[[−1 diag[Rate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CICASMI1.40.37.40.90.24.32.70.97.83.11.09.34.01.79.5PVD1.70.64.81.10.34.03.00.910.04.61.811.61.50.54.4Heme2.81.35.72.21.05.03.01.46.22.11.14.04.93.27.6RenalNA——0.0——NA——3.60.257.37.20.779.1Pulmonary120.111.50.0——7.20.779.14.81.121.41.20.34.4Oral1.40.72.71.50.73.20.90.42.21.10.62.22.81.45.3Ophthalmologic2.30.95.91.40.53.91.30.53.21.50.73.52.61.25.4Neurological0.0——0.70.16.13.60.525.44.81.121.47.21.828.8Neoplasm3.60.257.41.80.219.8NA——0.0——0.70.16.1Musculo-skeletal1.60.73.71.00.33.11.30.63.21.40.53.52.61.35.3Mood disorder1.80.47.20.0——3.60.257.30.0——Inf——Infections1.30.62.81.30.62.81.40.62.91.40.82.52.91.84.6Hypoglycemia0.0——NA——Inf——0.0——3.60.257.3Hypersensitivity4.81.121.41.40.37.42.70.612.10.0——0.70.23.3GU3.60.717.81.20.34.42.10.67.00.40.12.01.00.33.1GI0.90.42.31.40.72.70.90.42.01.81.03.02.41.53.9Edema1.60.63.81.50.63.60.60.21.71.80.83.81.50.82.7Diabetes1.40.53.90.90.32.51.80.65.31.50.63.31.60.73.4Derm1.10.61.91.51.02.31.20.81.91.61.02.32.51.93.3CV0.0——3.60.525.42.20.59.01.80.39.84.31.314.1Constitution1.40.63.11.30.72.52.31.24.21.71.03.02.81.84.6CHF0.0——2.20.59.01.10.33.92.70.97.81.00.33.1Breast cancer3.60.257.10.90.18.0NA——1.80.39.81.80.39.8Bleeding1.30.82.11.61.02.71.81.22.82.21.53.39.06.811.9Autoimmune3.60.717.95.40.932.6Inf——1.20.111.76.11.525.4Arrhythmia0.70.23.30.0——0.30.02.00.70.23.33.61.49.1(b)Comorbidity groupRatio ITP/non-ITP[diag +1[[+1 +2[[+2 +3[[+3 +4[[+4 +5[Rate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CINtotal ITP/ yearCASMI1.90.75.60.90.24.12.00.58.01.00.19.34.40.921.64.1PVD3.41.29.40.50.12.42.40.96.71.70.38.71.80.39.24.7Heme3.82.26.62.41.34.55.93.011.62.00.85.20.80.22.716.4RenalInf——Inf——0.0——0.0——4.30.368.80.7Pulmonary3.80.915.12.50.87.60.80.16.80.80.17.10.70.16.02.2Oral3.61.96.83.11.56.40.50.12.21.80.65.01.00.33.69.5Ophthalmologic2.81.45.70.90.32.81.10.33.90.90.33.11.30.44.16.5Neurological2.40.96.20.20.01.71.80.55.72.70.89.70.60.15.03.0NeoplasmInf——0.0——8.00.787.80.0——0.0——1.0Musculo-skeletal3.82.17.01.60.64.21.40.44.21.70.74.40.80.23.77.7Mood disorder1.90.220.70.0——0.0——4.10.364.9Inf——0.8Infections1.91.23.11.70.93.02.21.14.22.00.84.50.50.12.013.5Hypoglycemia5.70.933.82.00.221.82.60.415.80.0——NA——0.8Hypersensitivity4.31.611.92.00.57.90.70.13.00.0——0.0——2.4GU3.51.57.92.20.85.90.70.13.01.40.45.12.90.517.34.0GI2.01.13.81.20.62.21.91.03.70.70.31.82.71.26.112.7Edema2.41.43.90.60.21.60.20.10.90.90.32.30.70.22.38.4Diabetes2.10.85.21.00.33.01.20.34.31.20.25.70.70.15.94.8Derm2.51.83.61.00.71.61.61.02.61.30.82.40.90.41.930.1CV1.90.75.00.70.12.92.20.76.60.0——1.20.36.02.8Constitution2.31.63.51.10.71.91.81.03.31.60.83.11.20.53.117.6CHF1.50.73.40.70.12.90.90.24.10.40.13.20.60.14.93.0Breast cancer0.0——0.0——0.0——Inf——0.0——0.8Bleeding2.92.04.13.92.65.71.71.03.00.70.31.72.31.34.240.1Autoimmune15.41.7137.52.00.411.012.21.3117.22.10.223.30.0——2.3Arrhythmia1.60.73.60.0——1.60.38.10.20.01.60.0——2.5None of the conditions was found to have a negative association with
ITP.The analysis of conditions of a priori
interest (the 7 grouped comorbidities) shows that over the 10-year period, none
of the annual incidence rate ratios of the conditions breast cancer, liver disease,
viral hepatitis, and thromboembolic events was statistically different from one,
at the 5% level (Table6). This suggests that there is no evidence of an association
with ITP. However, there was a
suggestion of an association between ITP and myocardial infarction during the last 2 years before ITP diagnosis (RR=3.63 and RR=4.69, resp., see
Table 6)). There was also evidence of an association between ITP and chronic renal failure during years 4 and 5
after the index date (RR=6.21 and RR=6.54, resp.). Although rare (9 total
number of observed events), systemic lupus occurred in ITP patients only (i.e., was not observed in control patients), which suggests an
association between ITP and
systemic lupus (Table 6). Figure 2 shows, for each of the 7 grouped
comorbidities, the evolution of their cumulative risk over time (i.e., the
overall risk over a specific length of time). Table 7 presents
the one- and 5-year risk of all 26 grouped comorbidities together with a log-rank
test of difference of occurrence between ITP and non-ITP. These latest analyses
further suggest ITP association with
medical conditions: neoplasm, constitution, after index date. These associations
were not observed in earlier analyses, probably because of insufficient
numbers.Table 6
Yearly incidence rates
ratios between ITP and non-ITP and their 95% confidence interval of 7 comorbidities of priori interest.
(a)Comorbidity groupRatio ITP/non-ITP[−5 −4[[−4 −3[[3−2[[−2 −1[[−1 diag[Rate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIMI0.90.108.100.60.075.02.60.88.13.61.012.54.71.712.6Breast cancer1.80.219.70.90.18.00.0——1.40.37.32.10.58.9Chronic renal failure1.80.39.81.20.1211.50.90.18.02.70.612.12.60.88.1Viral hepatitis1.20.72.21.50.82.60.90.51.50.70.41.40.70.41.25Liver damage———————————————Systemic lupus1.80.219.8NA——3.60.257.4NA——Inf——Thrombo-embolic1.20.111.50.90.18.11.030.214.97.21.339.41.40.45.1(b)Comorbidity groupRatio ITP/non-ITP[diag +1[[+1 +2[[+2 +3[[+3 +4[[+4 +5[Rate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIMI3.180.9710.41.140.25.52.40.610.11.00.19.34.40.921.6Breast cancer0.90.18.40.0——0.0——inf——2.150.223.7Chronic renal failure3.00.811.30.0——1.90.57.96.21.0437.16.51.139.1Viral hepatitis0.60.31.20.80.41.60.70.31.71.20.62.31.30.53.2Liver damage———————————————Systemic lupusInf——Inf——NA——NA——Inf——Thrombo-embolic1.30.36.31.20.34.30.0——0.80.17.11.70.38.9Table 7
One- and five-year risk of 26-grouped comorbidities and tests over strata after index.
Comorbidities groupedTest over strata ITP/non-ITPITP cohortn=883Non-ITP cohortn=3700log-rank*NNb comor b1-year risk5-year riskNNb comor b1-year risk5-year riskCoronary artery syndrome/myocardial
infarctionNS982150.63%1.95%3601470.25%1.12%Peripheral vascular diseasesNS976220.85%2.86%3598600.19%1.45%Haematological conditionsS912900.00%12.59%34781490.00%4.37%AutoimmuneS1004130.50%1.39%3662140.03%0.28%RenalNS103040.20%0.58%369650.00%0.08%PulmonaryNS1022160.42%1.58%3678450.11%1.06%OralS953512.06%5.76%34681220.61%2.98%OphthalmologicNS974321.40%3.81%3546970.42%2.88%NeurologicalNS1021240.80%2.53%3682720.27%1.82%NeoplasmS102670.51%0.76%3685100.00%0.31%Musculo-skeletalS974512.04%5.17%35401130.59%2.78%Mood disorderNS102140.10%0.29%3661130.05%0.28%InfectionsS946772.52%8.78%35032031.37%5.58%HypoglycemiaNS103080.30%0.69%3696150.05%0.33%HypersensitivityNS1008180.00%2.13%3630490.00%1.77%GenitrourinaryS1000281.03%3.19%3597590.31%1.65%GastroIntestimnalNS907641.96%8.76%33242160.81%5.52%EdemaNS970532.58%5.24%35081981.08%5.50%DiabetesNS972210.74%2.26%3546680.33%2.89%Dermatological conditionsS7881587.19%20.66%31074932.67%13.87%Cerebrovascular conditionsNS1015180.62%2.00%3661560.30%1.53%ConstitutionS9161090.00%14.98%34252990.00%9.50%Congestive heart failureNS1010170.81%1.82%3636700.52%2.05%Breast cancerNS102530.00%0.30%3670150.00%0.44%BleedingS6711679.23%27.82%30594982.55%11.91%ArrhythmiaNS1006140.82%2.32%3629810.52%2.32%NS=* Not significant at 5% level; S = Significant at 5% level.Cumulative risk of 7 grouped conditions over time in ITP and non-ITP populations.
(a)(b)(c)(d)(e)(f)(g)


## 3.1. Description of Cases and Controls

A total of 1033 incident physician-diagnosed ITP cases during the period
1990–2004 were
identified, 578 (56.0%) of whom were females. Table1 presents the distribution
of these patients by age, group, and gender. Approximately, 50% are 50 or over.
Mean age was 46 in females and 44 years in males. Following matching, 883 cases
(85.5%) had at least one matched control, and these 883 cases were used in
further analyses. A total of 3700 controls were selected, and Table 2 presents
the distribution of number of controls per case, 69% of cases had 4 or 5
controls.Table 1
ITP patients by age and gender.
Age (years)GenderTotal N (%*)Femalen (%*)Malen (%*)0–1594 (16.3)131 (28.8)225 (21.7)16–49208 (36.0)95 (20.9)303 (29.3)50 +276 (47.7)229 (50.3)505 (49.9)Total578 (100.0)455 (100.0)1033 (100.0)P*roportions are column proportions.Table 2
Distribution of number of controls per case.
Number of controls per caseFrequency (cases)PercentCumulative percent015014.514.521646.2020.722393.7824.493686.5831.07420619.951.02550649.0100.00ITP patients and their matched controls had a
total 2366 unique medical conditions at the PTL of the MedDRA classification. Figure1 and Table 3  show medical conditions with an odds ratio (OR)
greater than 2 and significant at the 0.1% level. Conditions are sorted in
descending order of OR. Clinical signs or symptoms known to characterize ITP are strongly associated with ITP (i.e., purpura, OR=146; bruise, OR=57; neutropenia,
OR=29; etc.). There is a strong association between ITP and death (OR=60.0; 95% CI [4.47–806.0]). It is also
important to note that more than 90 conditions are associated with ITP in this analysis despite our use of stringent
criteria (i.e., an odds ratio greater than 2 and statistically significant at a
0.1% level). The use of the false discovery rate
procedure to control for the increasing risk of false positives due to multiple
testing indicates that setting the significance level of each individual test at
0.35% would have guaranteed a targeted overall 5% level. So, our choice of 0.1%
as a significance level is on the cautious side with respect to expected false
positives. As noted above, all of these significant conditions were
grouped into 26 broader conditions as shown in Table 4.Table 3
Comorbidities significantly associated with
ITP in the period or 2 years around diagnosis date.
POdds ratioCLPreferred term namePOdds ratioCLPreferred term name<.0001146.0023.48907.97Purpura.00093.301.308.36Breast cancer female NOS<.0001146.0023.48907.97Purpura NOS.00093.301.308.36Condition aggravated<.000160.004.47805.56Death.00083.181.317.75Haemoptysis<.000160.004.47805.56Death NOS.00083.181.317.75Confusion<.000157.3319.85165.60Increased tendency to bruise<.00013.171.586.35Diabetes mellitus noninsulin-dependent.000929.002.11398.24Neutropenia<.00013.171.586.35Diabetes mellitus noninsulin-dependent<.000121.503.34138.56Whole blood transfusion<.00013.141.655.99Prostatism<.000117.3110.8427.65Ecchymosis.00012.941.436.06Left ventricular failure<.000115.639.9724.49Contusion.00082.921.286.69Respiratory disorder.000612.501.8882.96Chills.00082.921.286.69Respiratory disorder NOS.000612.501.8882.96Rigors.00042.811.335.95Analgesic effect<.000111.002.3351.99Chemoprophylaxis NOS<.00012.731.514.93Vaginal haemorrhage<.000111.002.3351.99Prophylactic chemotherapy.00052.711.305.62Dermatitis diaper<.00019.502.4536.79Haematemesis.00072.691.265.71Phlebitis NOS<.00018.434.0717.46White blood cell disorder<.00012.671.444.94Oral candidiasis<.00018.434.0717.46White blood cell disorder NOS.00022.651.355.21Postoperative analgesia<.00017.572.6921.33Pneumonia<.00012.611.544.42Iron deficiency
anaemia<.00017.572.6921.33Pneumonia NOS<.00012.591.584.27Anaemia<.00017.002.0423.98Blister<.00012.591.584.27Anaemia NOS<.00017.001.7727.74Dry mouth<.00012.591.454.65Osteoporosis<.00016.902.8916.50Leg ulcer (exc
varicose)<.00012.591.454.65Osteoporosis NOS<.00016.902.8916.50Leg ulcer (excl
varicose)<.00012.581.424.67Dry eye NEC<.00016.824.0511.49Epistaxis<.00012.581.424.67Dry eye NOS.00096.001.4924.12Dementia<.00012.571.454.56Keratoconjunctivitis
sicca.00096.001.4924.12Dementia NOS.00052.501.264.94Lethargy.00096.001.4924.12Decubitus ulcer<.00012.441.474.07General symptom.00096.001.4924.12Pressure sore<.00012.441.474.07General symptom
NOS.00045.601.6019.56Venesection<.00012.441.533.89Rectal haemorrhage.00045.601.6019.56Venipuncture.00042.371.274.44Mouth ulceration<.00015.552.3912.89Peripheral
swelling.00042.311.264.23Cardiac failure
congestive<.00015.532.8010.90Eczema
gravitational.00082.301.214.38Cerebrovascular
accident<.00015.532.8010.90Stasis dermatitis<.00012.271.603.22Oedema peripheral<.00015.502.2713.33Acute myocardial
infarction.00082.241.214.16Gastro-oesophageal
reflux disease.00055.401.5418.92Intermittent claudication.00082.241.214.16Gastro-oesophageal
reflux disease<.00015.001.9512.80Abdominal pain
lower<.00012.211.583.10Viral infection.00035.001.5815.82Hip arthroplasty<.00012.211.583.10Viral infection
NOS<.00014.712.2110.06Myocardial
infarction<.00012.211.702.87Rash<.00014.242.397.52Feeling abnormal<.00012.211.702.87Rash NOS<.00013.952.117.41Skin ulcer<.00012.151.313.52Menorrhagia<0.00013.711.718.07Dry eye<.00012.131.383.29Diabetes mellitus.00063.671.399.66Folliculitis<.00012.131.383.29Diabetes mellitus
NOS<.00013.641.677.92Acarodermatitis.00042.121.233.65Haematuria<.00013.641.677.92Scabies
infestation<0.00012.121.363.30Haemorrhoids<.00013.601.439.04Angina unstable<.00012.081.333.26Prophylaxis<.00013.352.235.03Malaise<.00012.081.333.26Prophylaxis NOS.00093.301.308.36Oral pain.00022.021.243.29Atrial
fibrillationTable 4
Comorbidities at the PTL of the MedDRA classification and their 26 grouping.
Grouped conditionsMedical conditions at preferred term levelBleedingEcchymosis, haemoptysis, conjunctival haemorrhage, menorrhagia, rectal haemorrhage, gastrointestinal haemorrhageNOS*, haematuria, epistaxis, haematemesisPulmonaryRespiratory disorder, respiratory disorderNOS*ConstitutionChills, rigors, malaise, general symptom, feeling abnormal, lethargyPeripheral vascular diseasesPhlebitis NOS, aortic aneurysm, phlebitis, intermittent claudicationCerebrovascularaccidentCerebrovascular accidentHaematologyWhite blood cell disorder, white blood cell disorder NOS, neutropenia, anaemia, iron deficiency anaemia, anaemia NOSArrhythmiaAtrial fibrillationAutoimmuneSystemic lupus erythematosus, rheumatoid arthritisRenalRenal failure acuteInfectionViral infection, pneumonia, viral infection NOS, pneumonia NOSOral conditionsOral candidiasis, dry mouth, mouth ulceration, oral painHypoglycemiaHypoglycaemia, hypoglycaemia NOSNeoplasm malignantNeoplasm malignantDermatological conditionsLeg ulcer (exc varicose), rash scaly, skin exfoliation, eczema gravitational, stasis dermatitis, decubitus ulcer, pressure sore, folliculitis, skin ulcer, tinea NOS, rash, infected sebaceous cyst, dermatitis diaper, rash NOSHypersensitivityHypersensitivity, hypersensitivity NOSBreast cancerBreast cancer female NOS, breast cancer, breast cancer NOSNeurologyConfusional state, dementia, dementia NOS, confusionDiabetesDiabetes mellitus noninsulin-dependent, diabetes mellitus noninsulin-dependent, diabetes mellitus, diabetes mellitus NOSEdemaPeripheral swelling, oedema peripheralGenitourinaryProstatism, proctalgiaCoronary artery syndrome/myocardial infarctionAcute myocardial infarction, myocardial infarction, angina unstableCongestive heart failureLeft ventricular failure, cardiac failure congestiveGastro intestinalHaemorrhoids, abdominal pain lower, gastro-oesophageal reflux disease, gastro-oesophageal reflux disease, colitis, colitis NOSOphthalmologyDry eye NEC, dry eye, eyelid ptosis, eye pain, dry eye NOS, keratoconjunctivitis siccaMusculo-skeletal conditionsOsteoporosis, hip arthroplasty, ligament sprain, musculoskeletal pain, osteoporosis NOSMood disorderDysthymic disorderNot* otherwise specified.Figure 1
Medical conditions with OR significantly greater than 2 but less than 20.Some of the medical conditions are rare and/or only found in the ITP group. Because of this, odds ratios, even
though quite large (i.e.,>2), they may not be statistically significant. Medical
conditions with odds ratios greater than 2 but with no more than one event in
the control group are thrombocytopenia, petechiae, splenectomy, purpura,
haemorrhagic disorder, sepsis, bronchopneumonia, headaches, gingival, guttate
psoriasis, acute pancreatitis,
pleural effusion, restlessness, and somnolence.


## 3.2. Longitudinal Approach and Cumulative Risk Analysis for Grouped Conditions

Table5 presents, for each of the 26 grouped medical
conditions, over a period of 10 years around the index date, yearly incidence
rate ratios, between cases and controls, and their 95% CI. Results can be summarized
as follows.
(i)
Conditions that have a significantly higher frequency of occurrence in
ITP compared to non-ITP in at least one time period both before and after diagnosis:
haematological diseases, dermatological conditions, bleeding disorders, gastrointestinal  diseases,
autoimmune disorders, and constitution conditions.(ii)
Conditions that have significantly higher frequency of occurrence in ITP compared to non-ITP patients only after index date: oral conditions and infections.(iii)
Conditions that have significantly
higher frequency of occurrence in ITP compared to non-ITP patients
during only the year of ITP diagnosis or a year before: neurological, coronary artery syndrome/myocardial
infarction, genitourinary, musculoskeletal, ophthalmologic, skeletal,
and edema.(iv)
Other conditions with no statistical
association with ITP.Table 5
Rate ratios and 95% CI between ITP and non-ITP patients for 26 grouped medical conditions.
(a)Comorbidity groupRatio ITP/non-ITP[−5 −4[[−4 −3[[3−2[[−2 −1[[−1 diag[Rate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CICASMI1.40.37.40.90.24.32.70.97.83.11.09.34.01.79.5PVD1.70.64.81.10.34.03.00.910.04.61.811.61.50.54.4Heme2.81.35.72.21.05.03.01.46.22.11.14.04.93.27.6RenalNA——0.0——NA——3.60.257.37.20.779.1Pulmonary120.111.50.0——7.20.779.14.81.121.41.20.34.4Oral1.40.72.71.50.73.20.90.42.21.10.62.22.81.45.3Ophthalmologic2.30.95.91.40.53.91.30.53.21.50.73.52.61.25.4Neurological0.0——0.70.16.13.60.525.44.81.121.47.21.828.8Neoplasm3.60.257.41.80.219.8NA——0.0——0.70.16.1Musculo-skeletal1.60.73.71.00.33.11.30.63.21.40.53.52.61.35.3Mood disorder1.80.47.20.0——3.60.257.30.0——Inf——Infections1.30.62.81.30.62.81.40.62.91.40.82.52.91.84.6Hypoglycemia0.0——NA——Inf——0.0——3.60.257.3Hypersensitivity4.81.121.41.40.37.42.70.612.10.0——0.70.23.3GU3.60.717.81.20.34.42.10.67.00.40.12.01.00.33.1GI0.90.42.31.40.72.70.90.42.01.81.03.02.41.53.9Edema1.60.63.81.50.63.60.60.21.71.80.83.81.50.82.7Diabetes1.40.53.90.90.32.51.80.65.31.50.63.31.60.73.4Derm1.10.61.91.51.02.31.20.81.91.61.02.32.51.93.3CV0.0——3.60.525.42.20.59.01.80.39.84.31.314.1Constitution1.40.63.11.30.72.52.31.24.21.71.03.02.81.84.6CHF0.0——2.20.59.01.10.33.92.70.97.81.00.33.1Breast cancer3.60.257.10.90.18.0NA——1.80.39.81.80.39.8Bleeding1.30.82.11.61.02.71.81.22.82.21.53.39.06.811.9Autoimmune3.60.717.95.40.932.6Inf——1.20.111.76.11.525.4Arrhythmia0.70.23.30.0——0.30.02.00.70.23.33.61.49.1(b)Comorbidity groupRatio ITP/non-ITP[diag +1[[+1 +2[[+2 +3[[+3 +4[[+4 +5[Rate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CINtotal ITP/ yearCASMI1.90.75.60.90.24.12.00.58.01.00.19.34.40.921.64.1PVD3.41.29.40.50.12.42.40.96.71.70.38.71.80.39.24.7Heme3.82.26.62.41.34.55.93.011.62.00.85.20.80.22.716.4RenalInf——Inf——0.0——0.0——4.30.368.80.7Pulmonary3.80.915.12.50.87.60.80.16.80.80.17.10.70.16.02.2Oral3.61.96.83.11.56.40.50.12.21.80.65.01.00.33.69.5Ophthalmologic2.81.45.70.90.32.81.10.33.90.90.33.11.30.44.16.5Neurological2.40.96.20.20.01.71.80.55.72.70.89.70.60.15.03.0NeoplasmInf——0.0——8.00.787.80.0——0.0——1.0Musculo-skeletal3.82.17.01.60.64.21.40.44.21.70.74.40.80.23.77.7Mood disorder1.90.220.70.0——0.0——4.10.364.9Inf——0.8Infections1.91.23.11.70.93.02.21.14.22.00.84.50.50.12.013.5Hypoglycemia5.70.933.82.00.221.82.60.415.80.0——NA——0.8Hypersensitivity4.31.611.92.00.57.90.70.13.00.0——0.0——2.4GU3.51.57.92.20.85.90.70.13.01.40.45.12.90.517.34.0GI2.01.13.81.20.62.21.91.03.70.70.31.82.71.26.112.7Edema2.41.43.90.60.21.60.20.10.90.90.32.30.70.22.38.4Diabetes2.10.85.21.00.33.01.20.34.31.20.25.70.70.15.94.8Derm2.51.83.61.00.71.61.61.02.61.30.82.40.90.41.930.1CV1.90.75.00.70.12.92.20.76.60.0——1.20.36.02.8Constitution2.31.63.51.10.71.91.81.03.31.60.83.11.20.53.117.6CHF1.50.73.40.70.12.90.90.24.10.40.13.20.60.14.93.0Breast cancer0.0——0.0——0.0——Inf——0.0——0.8Bleeding2.92.04.13.92.65.71.71.03.00.70.31.72.31.34.240.1Autoimmune15.41.7137.52.00.411.012.21.3117.22.10.223.30.0——2.3Arrhythmia1.60.73.60.0——1.60.38.10.20.01.60.0——2.5None of the conditions was found to have a negative association with
ITP.The analysis of conditions of a priori
interest (the 7 grouped comorbidities) shows that over the 10-year period, none
of the annual incidence rate ratios of the conditions breast cancer, liver disease,
viral hepatitis, and thromboembolic events was statistically different from one,
at the 5% level (Table6). This suggests that there is no evidence of an association
with ITP. However, there was a
suggestion of an association between ITP and myocardial infarction during the last 2 years before ITP diagnosis (RR=3.63 and RR=4.69, resp., see
Table 6)). There was also evidence of an association between ITP and chronic renal failure during years 4 and 5
after the index date (RR=6.21 and RR=6.54, resp.). Although rare (9 total
number of observed events), systemic lupus occurred in ITP patients only (i.e., was not observed in control patients), which suggests an
association between ITP and
systemic lupus (Table 6). Figure 2 shows, for each of the 7 grouped
comorbidities, the evolution of their cumulative risk over time (i.e., the
overall risk over a specific length of time). Table 7 presents
the one- and 5-year risk of all 26 grouped comorbidities together with a log-rank
test of difference of occurrence between ITP and non-ITP. These latest analyses
further suggest ITP association with
medical conditions: neoplasm, constitution, after index date. These associations
were not observed in earlier analyses, probably because of insufficient
numbers.Table 6
Yearly incidence rates
ratios between ITP and non-ITP and their 95% confidence interval of 7 comorbidities of priori interest.
(a)Comorbidity groupRatio ITP/non-ITP[−5 −4[[−4 −3[[3−2[[−2 −1[[−1 diag[Rate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIMI0.90.108.100.60.075.02.60.88.13.61.012.54.71.712.6Breast cancer1.80.219.70.90.18.00.0——1.40.37.32.10.58.9Chronic renal failure1.80.39.81.20.1211.50.90.18.02.70.612.12.60.88.1Viral hepatitis1.20.72.21.50.82.60.90.51.50.70.41.40.70.41.25Liver damage———————————————Systemic lupus1.80.219.8NA——3.60.257.4NA——Inf——Thrombo-embolic1.20.111.50.90.18.11.030.214.97.21.339.41.40.45.1(b)Comorbidity groupRatio ITP/non-ITP[diag +1[[+1 +2[[+2 +3[[+3 +4[[+4 +5[Rate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIRate ratioLower CIUpper CIMI3.180.9710.41.140.25.52.40.610.11.00.19.34.40.921.6Breast cancer0.90.18.40.0——0.0——inf——2.150.223.7Chronic renal failure3.00.811.30.0——1.90.57.96.21.0437.16.51.139.1Viral hepatitis0.60.31.20.80.41.60.70.31.71.20.62.31.30.53.2Liver damage———————————————Systemic lupusInf——Inf——NA——NA——Inf——Thrombo-embolic1.30.36.31.20.34.30.0——0.80.17.11.70.38.9Table 7
One- and five-year risk of 26-grouped comorbidities and tests over strata after index.
Comorbidities groupedTest over strata ITP/non-ITPITP cohortn=883Non-ITP cohortn=3700log-rank*NNb comor b1-year risk5-year riskNNb comor b1-year risk5-year riskCoronary artery syndrome/myocardial
infarctionNS982150.63%1.95%3601470.25%1.12%Peripheral vascular diseasesNS976220.85%2.86%3598600.19%1.45%Haematological conditionsS912900.00%12.59%34781490.00%4.37%AutoimmuneS1004130.50%1.39%3662140.03%0.28%RenalNS103040.20%0.58%369650.00%0.08%PulmonaryNS1022160.42%1.58%3678450.11%1.06%OralS953512.06%5.76%34681220.61%2.98%OphthalmologicNS974321.40%3.81%3546970.42%2.88%NeurologicalNS1021240.80%2.53%3682720.27%1.82%NeoplasmS102670.51%0.76%3685100.00%0.31%Musculo-skeletalS974512.04%5.17%35401130.59%2.78%Mood disorderNS102140.10%0.29%3661130.05%0.28%InfectionsS946772.52%8.78%35032031.37%5.58%HypoglycemiaNS103080.30%0.69%3696150.05%0.33%HypersensitivityNS1008180.00%2.13%3630490.00%1.77%GenitrourinaryS1000281.03%3.19%3597590.31%1.65%GastroIntestimnalNS907641.96%8.76%33242160.81%5.52%EdemaNS970532.58%5.24%35081981.08%5.50%DiabetesNS972210.74%2.26%3546680.33%2.89%Dermatological conditionsS7881587.19%20.66%31074932.67%13.87%Cerebrovascular conditionsNS1015180.62%2.00%3661560.30%1.53%ConstitutionS9161090.00%14.98%34252990.00%9.50%Congestive heart failureNS1010170.81%1.82%3636700.52%2.05%Breast cancerNS102530.00%0.30%3670150.00%0.44%BleedingS6711679.23%27.82%30594982.55%11.91%ArrhythmiaNS1006140.82%2.32%3629810.52%2.32%NS=* Not significant at 5% level; S = Significant at 5% level.Cumulative risk of 7 grouped conditions over time in ITP and non-ITP populations.
(a)(b)(c)(d)(e)(f)(g)


## 4. Conclusion/Discussion

We report here an extensive database exploration of
medical conditions associated with ITP.
First, comparing the frequency of occurrence of each considered disorder in ITP patients and their matched controls, we
systematically selected all medical conditions that are likely to be associated
with ITP. Then, pooling those
selected conditions into more aggregated groups and exploring the trend in their yearly
relative frequency over a ten-year period helped us put observed associations
into perspective.We found that ITP is associated with a considerable number of medical conditions, a good number of
which to our knowledge were not systematically reviewed before. The association
between ITP and some of these
conditions (or group of conditions) is apparent both before and after ITP diagnosis. These conditions are hematological diseases,
dermatological conditions,  bleeding disorders and constitutional conditions,
for example, chills, rigors, malaise, and lethargy. The nature of these
observed associations suggests that either these conditions share similar
causal pathways as ITP or they
predispose to the diagnosis of ITP.There are also conditions associated with ITP only after ITP diagnosis such as oral conditions, infections, gastrointestinal, and autoimmune
disorders. This could be indicative of ITP being on the causal pathway of these conditions, an adverse effect of any of
the medications generally taken by ITP patients or were conditions not screened for prior to diagnosis of ITP. Further
studies are needed here to disentangle the disease (ITP)
effect from potential medication effect and other contributing factors.Conditions associated with ITP only during the years around diagnosis are more likely to be a result of
diagnosis bias as mentioned earlier.Strengths of the current study include design,
simplicity, large sample size, and its systematic nature. Indeed, ITP is a relatively rare disease, and only large
healthcare databases with long follow-up such as the GPRD could provide an appropriate
base population. The design first considers cases and comparable controls and
both a cross-sectional and longitudinal approach. By comparing the frequency in
ITP patients of potential
comorbidities to that in controls matched in practice, gender and length of
follow-up and thus, computing the relative risk within the same study base, numbers
of confounders are controlled for, including seasonality. We also
systematically considered all medical conditions on patients’ medical records
as potential comorbidities. This is an important consideration for a hypothesis
generative study such as this.A potential limitation of this research is perhaps our
subjective grouping of conditions at the preferred term level, in order to obtain aggregated and thus more
prevalent groups. We believe, however, that the differences in potential
grouping would be unlikely to strongly impact the conclusions. Our attempts at
using a more automated and systematic grouping, such as a higher than PTL level
of the MedDRA classification, proved difficult, mainly because of the
overlapping nature of groups at the higher level of the MedDRA classification.Children and adults were mixed. Childhood and
adulthood ITP may differ significantly, and as comorbidities in the two age
groups, it is arguable that a separate analysis of each age group could have
added potentially useful information on the age grouping of identified
comorbidities. However, we believe that given the reduced number of ITP cases, stratifying our sample into adults and children, there would be less power to detect some of the comorbidities and thus may not be able to identify some of the comorbidities identified when the groups were combined.Selection bias is also a concern. Within the current
design, although the use of a registration period of at least 1 year before any
investigation maybe considered standard in database observational research and
increases the confidence that new reports of a disease refer to new incident
conditions, the requirement of having at least 1 year of enrollment after
identification may have biased some estimates. Some patients because of the
severity of their condition may have died or been transferred within a year of their
diagnosis. The likelihood is that these patients had more comorbidities than
those not transferred or who did not die. The impact of this is likely to
result in an underestimate of the associations observed. Other sources of bias
include differential screening between ITP and non-ITP patients. Patients
with a diagnosis of ITP might have
a higher chance of receiving a diagnosis of other disease due to regular
follow-up GP visits. Thus, the likely relation between GP consultation and
frequency of comorbidities imposes cautious interpretation of the extensive
list of conditions found here in association with ITP,
particularly for those associations only evident during the years around
diagnosis date.Our stringent selection criteria also have limitations in this
study. Indeed, we may have missed some of the potential comorbidities because
either their OR was less than 2 or the associatedP-value was greater
than 0.1%. Indeed, the false discovery rate indicates that a significant level
for each individual test of 0.32% would have guaranteed an overall significance
level of 5%. These last two points may explain, for example, why cataracts are
not in our list of conditions found in association with ITP. Indeed, oral corticosteroid
(OS) use is one of the first line treatments of ITP, and it is expected that a substantial
number of our ITP patients would be taking corticosteroids compared with
non-ITP patients [5]. A number of studies have consistently shown an increased
risk of cataracts associated with corticosteroid use, although the risk is
generally not found to be more than two fold [32]. Our stringent criteria excluded comorbidities
with less than a two-fold increase in ITP patients compared to non-ITP, as is
the case of cataracts.Another limitation of the current study is our choice
of the MedDRA classification. Indeed, data in GPRD are reported by physicians in READ or OXMIS codes and
latter mapped to MedDRA. Not all medical conditions would have a correspondent PTL of the MedDRA
classification. This may only limits the number of potential comorbidities we
could explore. Indeed, there
is no reason to believe that conditions with no corresponding PTL on the MedDRA would
be systematically more frequent in cases compared to controls. Thus, its impact is
more likely to be on increasing the list of potential comorbidities, rather
than dismissing some of those selected here.We did not consider medication use, and thus our analyses
are not adjusted for this. Indeed, diseased patients are likely to be taking
medications, some of which are associated with a higher risk of other
conditions, as it is for cataracts and corticosteroids. Hence, some of the
observed associations may be the result of medication use and/or concomitant
use of medications and not the result of the condition itself. Also, age influences the pattern of ITP
expression [33] through its association with medication use, including for
cardiovascular conditions. Hence, some of the identified comorbidities, rather
than being directly linked to ITP, may result from a complex interaction
between other comorbidities and/or medications used against these
comorbidities. Only specific and targeted studies would be able to disentangle
the effects of medication, disease, and other factors.So, to conclude, two or more medical conditions can cooccur
because (1) there is a direct causal relationship between these conditions,
whereby the presence of one makes the other more likely to develop, (2) there
is an indirect causal relationship between the two conditions, whereby one
condition affects a third variable in a way that makes the second condition
more likely to develop, (3) there are common factors that increase the risk of
both disorders, (4) the occurrence of one of the medical conditions is
associated with medication used to treat the other, or (5) other reasons [34]. The
diagnosis of ITP is complex and
based on exclusion of other causes of thrombocytopenia. There is also relatively
little epidemiological evidence on the disease. To the best of our knowledge,
this is the first study using large healthcare databases to systematically
explore comorbidities of ITP. This
study aimed to support what we know and then potentially glean additional
insights from this rich data source, which might then trigger further interest
in setting up additional specific focused studies. This should be done in a variety
of settings. These targeted studies should also help the understanding of the underlying
mechanism. The current exploration suggests that ITP, despite being a rare
disease, is associated with a considerably higher level of mortality risk as
well as an extensive list of comorbid medical conditions. For ITP patients, this increased quantitative
understanding of ITP comorbidities
hopefully may assist in improved disease management of ITP patients.



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*Source: 963506-2009-04-02.xml*