The incidence of many rare diseases is rising rapidly, especially in the Western world, and advancements in therapeutics have not quite caught up. In the United States, for example, billions of dollars are being spent annually for treating autoimmune disorders and conducting trials to find future solutions.
Immune thrombocytopenia (ITP) is one such disease; it is a diagnosis of exclusion and is most notably characterized by a reduction in peripheral blood platelet count. This is driven by a failure of both production and supply: the body’s ability to produce platelets is compromised, and platelets are destroyed prematurely. ITP is deemed primary if there is no detectable underlying cause.
Read more about ITP etiology
As an autoimmune disorder, ITP suffers from the same major pitfall as the rest: the lack of treatment alternatives that can achieve lasting remission. In fact, the frequency of relapses is a primary source of healthcare resource utilization among patients with autoimmune diseases; these can be unpredictable, long, and painful. Hence, there has always been a deep emphasis on preserving quality of life in autoimmune disease care. To achieve this, clinicians have experimented with different models of treatment.
“The treatment models in current medical practice [for treating ITP] include: the infectious disease model, oncologic disease model, metabolic disease model, and transplant rejection model,” Provan and Semple wrote in EBioMedicine.
The current treatment model most in vogue is the “transplant rejection model,” which seeks to suppress the immune system in order to alleviate symptoms. However, immunosuppression is always risky; some studies find that this treatment model ends up reducing overall quality of life.
Therapeutics in ITP
In eClinicalMedicine, Wang and colleagues conducted a systematic review and network meta-analysis on the efficacy and safety of treatments commonly prescribed in adults newly diagnosed with ITP. First-line therapeutics include corticosteroids and intravenous immunoglobulin — both prominent immunosuppressants. More recent additions to the arsenal of ITP therapeutics include rituximab and thrombopoietin receptor agonists. In addition, a number of drugs have been repurposed to treat ITP, such as tacrolimus, all-trans retinoic acid, and oseltamivir.
The challenge of conducting studies involving these drugs is that it is difficult to perform one-to-one comparisons on any two therapeutics, both for practical and ethical reasons. Wang et al hence conducted a meta-analysis to indirectly compare available data from randomized clinical trials involving the drugs above.
The research team conducted their literature search using academic search engines and included 18 randomized controlled trials in their study. The primary outcomes of concern were early response to treatment, as well as 6-month sustained response. The researchers also looked into the frequency of adverse events, especially those that were severe in nature.
To compare different treatment choices, the researchers generated network plots using Stata (version 15.0). They then performed a network meta-analysis using a Bayesian framework. For head-to-head trials, the researchers were further able to perform pairwise conventional meta-analysis using the frequentist method.
Among the 18 studies chosen, a number of them provided for head-to-head comparisons, including dexamethasone and prednisolone. Wang and colleagues discovered that early response was achieved in 67.2% of patients on dexamethasone and 62.0% of patients on prednisolone; sustained response rate for dexamethasone was 51.1% and 43.5% for dexamethasone.
Researchers then looked into combined regimens and found that they performed better than monotherapies. For example, all 3 of the following combinations — all-trans retinoic acid + dexamethasone, tacrolimus + dexamethasone, and oseltamivir + dexamethasone — achieved a statistically significant better early response compared to dexamethasone/prednisolone monotherapy. This was also the case for 6-month sustained response.
Read more about ITP treatment
As for adverse events, Wang and colleagues reported that 14.5% of patients who received a combination of rituximab and dexamethasone had adverse events that were grade 3 and above — the highest among other treatment regimens under investigation. As for other treatment choices, the proportion of adverse events grade 3 and above hovered between 2% to 5%; almost all were clinically manageable.
“Our study demonstrated that compared with dexamethasone or prednisolone monotherapy, all the combination regimens containing corticosteroids achieved more satisfactory results in both early and sustained response,” the authors of the study concluded.
What does this tell us about the state of ITP therapeutics today? First, immunosuppression is still a key treatment strategy, despite its flaws. Second, the combination of traditional immunosuppressants with drugs that have a completely different mechanism of action (such as thrombopoietin receptor agonists) have impressive synergistic effects.
Here we must acknowledge that the findings of the studies by Provan and Semple, as well as Wang and colleagues, do not harmonize as readily as expected. While Provan and Semple seek a “shift in emphasis away from immune suppression” as a therapeutic strategy, Wang and colleagues wrote that their findings “are favorable to dexamethasone both in short-term and long-term response.”
In the treatment of rare diseases, stark choices often need to be made. The most likely pathway for ITP care in the near future is the use of immunosuppression as part of a wider therapeutic strategy until more modern drugs remove the risk of immune disturbances altogether.
Provan D, Semple JW. Recent advances in the mechanisms and treatment of immune thrombocytopenia. EBioMedicine. Published online January 20, 2022. doi:10.1016/j.ebiom.2022.103820
Wang Y, Sheng L, Han F, et al. Efficacy and safety of treatments in newly diagnosed adult primary immune thrombocytopenia: a systematic review and network meta-analysis. EClinicalMedicine. Published online December 14, 2022. doi:10.1016/j.eclinm.2022.101777