Risk of Systemic Lupus Erythematosus in Patients with Idiopathic* Thrombocytopenic Purpura: A Population-Based Cohort Story
ITP is a diagnosis of exclusion. ITP that occurs in the absence of any other condition (idiopathic) is called primary ITP. However, ITP is considered secondary when it occurs in the context of another disorder, such as system lupus erythematosus (SLE). ITP can develop at the time SLE is diagnosed or may precede symptoms of SLE for months to years. There are well-accepted clinical and laboratory criteria used to make a diagnosis of SLE usually requiring the presence of at least four SLE traits, and can include secondary ITP as one.
In this study from Taiwan, the investigators used a nation-wide population-based data set from the National Health Insurance Research Database (NHIRD) to determine the prevalence of SLE in patients with a diagnosis of ITP compared with the general population. They used a Propensity Score Matching (PSM) system to reduce the impact of other variables such as gender, age, and other differences. This means their control population (non-ITP patients representing the general population) were matched for these as well and other characteristics of the ITP population to improve the likelihood that the SLE features are attributable to ITP itself. A total of 668 ITP patients and 1,336 healthy patient controls were included who were newly diagnosed with ITP between 2000 and 2013 and were followed for a average of 80 months. They used statistical approaches (regression models) to assess the relationship between the occurrence of ITP and SLE. Regression models similarly try to take other variables that might influence SLE and ITP and “hold them constant” so that if a relationship is found, it will not be due to one or more of these “extraneous” variables.
The study revealed that the incidence of SLE was significantly greater among the group of patients with ITP than in the non-ITP group. The overall incidence of SLE was 4.7% in the ITP population compared with 0.19% among the controls (56.5 vs 2.6 per 100,000 persons, respectively). This increased prevalence of SLE among individuals with ITP compared to controls was observed using all statistical approaches. The risk was higher in females and those with another autoimmune disorder, Sjogren’s syndrome.
*The term idiopathic is no longer used. The term “Immune thrombocytopenia” is the current name for ITP.
Comments from PDSA’s medical advisors:
This article affirms our current understanding of the statistical relationship between ITP and SLE based on many studies conducted during the past several decades. About 5% of patients who are initially diagnosed with primary ITP will eventually develop SLE. Although this figure is clearly higher than the incidence of SLE in the general population as reported in this paper, this means that approximately 95% of patients with ITP will not receive a diagnosis of SLE over the next 5+ years. The risk is likely to be higher in women with ITP in whom SLE itself is more common. About 33-50% of patients with ITP will have positive tests for anti-nuclear antibodies (ANA) or anti-phospholipid antibodies (APA), which are also more prevalent in SLE. However, most patients with ITP even with these antibodies do not develop SLE. Although reassuring that the absolute risk of developing SLE is relatively low, it is important for patients with ITP to alert their doctors if they develop symptoms such as fever, rash, joint or chest pain, new profound fatigue, or any other complaint outside the typical bleeding/bruising caused by a low platelet count. This is because: a) SLE can affect important organs such as the kidney, heart and brain; b) active SLE needs to be treated irrespective of the platelet count; c) there is more than one cause of thrombocytopenia in patients with SLE; and d) because the approach to managing patients with secondary ITP who have SLE differs somewhat from typical management for patients with primary ITP.
Fatigue, Executive Function and Psychological Effects in Children with Immune Thrombocytopenia: A Cross-Sectional Study
This study examines the health-related quality of life (HRQoL) in children living with persistent or chronic primary ITP as it relates to their fatigue level, mental health and behavior, and cognitive functioning. Two pediatric hematology outpatient clinics within the United Kingdom (UK) recruited participants (parents and their children with ITP) over a six-month period between April 2014 – February 2015. Thirty-seven families were included. Participants were asked to fill out two different surveys specific to the age of their child. Children over five years were able to contribute their input into the surveys.
Among the 37 children enrolled in the study, there was a slight male predominance, average age at consent was 9.8 years, most children had a diagnosis of chronic ITP (86%) and had lived with their disorder for an average of 28 months. Average platelet count was 63, 000/µL and 41% had reported a change in the severity of their bleeding symptoms since their last clinic visit. Most children in the study reported only mild bleeding events (Grade 1-2 bleeding). One child reported Grade 3 bleeding. While 51% reported being previously treated for their ITP, only 16% were actively receiving treatment. Eight children (22%) had a second medical condition in addition to their ITP. Some of these additional health concerns also impacted the immune system, such as IgA and IgM deficiency, and Evan syndrome.
Results revealed that children with ITP were reported to have levels of fatigue (70.6%) and problems with executive function problems (19.4%) that were well above assessments of the general population. Overall emotional and behavioral problems in children with ITP were reported to be “high” or “very high” in severity (25.7%) exceeding the expectation based on assessments of the general population. The rate of emotional and behavioral problems self-reported by children however were in line with expected levels in the general population. Higher levels of fatigue, emotional/behavioral problems, and executive functioning challenges did not correlate with bleeding severity or platelet count. Emotional and cognitive functioning was unrelated to levels of fatigue. There were disparities among the child, their parents, and their clinician regarding the severity of the child’s ITP. Clinicians provided the most conservative rating.
Comments from PDSA’s medical advisors:
This article describing effects of ITP on children beyond platelet counts and bleeding is very valuable for widening the scope of our appreciation of the impact of ITP. Findings of fatigue in more than half of the children as well as the high incidence of emotional disturbances are very important. The authors highlight their use of validated scales to validate their findings.
However, the findings have limitations and might be considered more “hypothesis-generating” or “pilot” and not confirmed facts. These include the relatively small number of patients at varied ages (37), the fact that the average platelet count was more than 60,000/µL and, quite remarkably, the fact that only 6 of the children were still on treatment. While (as stated by the authors) this could result in an under-estimate of the impact of ITP, it makes it less representative of children with ITP requiring management. However, I believe that the biggest limitation is that all of the “controls” used to compare to the children with ITP were not generated concurrently by the investigators but rather from past studies almost all of which were from 2000-2004. Many things have changed over time, including greater concerns about the world around us, even pre-COVID. These include international conflicts, climate change, and widening disparities between socioeconomic classes which probably contributes to unrest in race relation. While one could say either “so what there have always been issues” or “what does this have to do with ITP”, in the context of evaluating children it likely has a major impact and could possibly exaggerate the findings. Alternatively, it could suggest that even if a childs ITP improves (counts > 50,000/uL), there could be a delayed effect.
Therefore, while this article is thoughtful and eye opening, it needs to be confirmed in a number of ways to ensure that it is appropriate to pursue problems it has uncovered. The study confirms the substantial impact of “ITP” on childrens’ overall quality of life and implies that these effects need to be diagnosed and addressed. Furthermore, the lack of relationship of the platelet counts and bleeding with the findings reported here is yet another demonstration that treating the platelet count alone, and thus preventing bleeding, is too limited to be the sole approach to the management of children with ITP.