Primary immune thrombocytopenia, or idiopathic thrombocytopenic purpura (ITP), is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated platelet destruction and impaired platelet production. Autoantibodies against platelet surface glycoproteins, such as GPIIb/IIIa and GPIb/IX complexes, play major roles in both platelet destruction and impaired platelet production, although autoantibody-independent mechanisms, such as T cell-mediated cytotoxicity, may also be involved in its pathogenesis. Recent advances in the localization of autoantigenic epitopes and the characterization of T cell functional abnormalities in ITP patients have improved our understanding of the pathophysiology of this disease. Although corticosteroids and splenectomy remain central to the treatment of ITP, a new class of drugs, i.e., thrombopoietin receptor agonists (TPO-RAs) and rituximab, have substantially broadened the therapeutic options for refractory ITP patients. Moreover, the success of TPO-RAs in ITP patients shows that reduced platelet production caused by impaired megakaryocytopoiesis plays a greater role in ITP than previously recognized.

PURPOSE:

To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost.

METHODS:

This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated.

RESULTS:

A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30 months) in 69.2 % of patients showing a short-term response. Median cost per patient was <euro> 5,187.5 (IQR <euro> 5,187.5-7,781.3).

CONCLUSIONS:

In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

We report a 60-year-old woman with idiopathic thrombocytopenic purpura who experienced acute infarction of the middle cerebral artery. She was treated with an antiplatelet agent and prednisolone to limit platelet activation and destruction. In parallel with clinical amelioration, levels of plasma platelet microparticles (PMPs), a procoagulant factor in platelet activation, decreased after treatment but increased after reduction of the prednisolone dose, resulting in progression of vascular stenosis. Immunosuppressive therapy with cyclosporine normalized plasma PMP levels, and no additional vascular events occurred during the 3-month follow-up period. Immunosuppressive therapy to decrease plasma PMP levels is warranted after acute ischemic stroke in the context of idiopathic thrombocytopenic purpura.

Intracranial hemorrhage is a rare devastating complication of idiopathic thrombocytopenic purpura (ITP), mostly presenting as intraparenchymal or subarachnoid haemorrhage. Isolated chronic subdural haematoma (SDH) is still very rare and the optimal management is unsettled. Spontaneous resolution of chronic SDH in patients with idiopathic thrombocytopenic purpura is possible. We report a case of spontaneous chronic SDH in a patient with ITP with hemiparesis where the haematoma significantly decreased in size with complete resolution of hemiparesis as a result of platelet transfusions and continuing therapy with steroids. Surgical treatment of subdural haematoma with consequent bleeding complications can be avoided in this scenario.

BACKGROUND AND OBJECTIVES:

Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare, clinically diagnosed disorder characterized by widespread intravascular platelet thrombosis. The pathophysiology involves acquired deficiency of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats), the enzyme responsible for cleavage of high molecular weight vonWillebrand factor multimers. Disease mortality is high, although prompt treatment with plasma exchange is generally effective. A readily available and highly reliable method of identifying ADAMTS13-deficient patients for appropriate plasma exchange is therefore of interest.

MATERIALS AND METHODS:

Our initial study involved the assessment of multiple clinical and laboratory variables in patients with clinically suspected TTP for whom ADAMTS13 assay was performed. Five variables were found to be of significant predictive power. This enabled the development of a point-based scoring system to efficiently determine the likelihood of TTP and response to plasma exchange in a given patient. This current study involved a separate validation cohort of patients with clinically suspected TTP who underwent ADAMTS13 testing within two large healthcare systems in Utah between 2009 and 2011. The previously derived score was applied to this cohort and its performance was analysed. Additionally, the original and validation cohorts were combined to revisit the predictive power of individual variables and the five-variable prediction score.

RESULTS:

A total of 84 (11 paediatric cases excluded) patients comprised the validation population. The percentage of TTP diagnoses in this group (10%) was identical to that in the initial cohort. Using an ADAMTS13 activity of <10% of normal, our original score correctly predicted or excluded severe ADAMTS13 deficiency in all patients in the second cohort when data for all variables was available. Individual variables retained predictive power and the performance of a three-variable parsimonious model, as well as the ultimate diagnoses for patients in the second cohort are described.

CONCLUSION:

This work confirms the predictive power of a simple point-based score to exclude TTP as evidenced by severe ADAMTS13 deficiency in appropriately selected patients. It may enable clinicians to rapidly begin plasma exchange or to pursue an alternative cause of thrombotic microangiopathy.

We describe a 22-year-old male with idiopathic autoimmune thrombocytopenia whose diagnosis was made at age of eight. He underwent splenectomy at age ten and ITP recurred at age 21 with episodes of infection and severe neutropenia (absolute count around 170/μl). He showed no response to immunoglobulin, corticosteroids, danazol, cyclosporine and azathioprine. Anti-CD20 antibody was administered at a dose of 375 mg/m(2) once a week for 2 weeks. After the second infusion of rituximab, the platelet count increased from 4,000 to 516,000/mm(3) and neutrophils count raised from 180 to 545/mm(3). The response improvement persisted during follow up for 9 months (neutrophil count 4,390/mm(3)). This observation indicates that B-cells may play a central role in the pathogenesis of ITN. Anti-CD20 antibody therapy may be an efficient treatment for the patients with chronic or recurrent ITN.

Primary immune thrombocytopenia is an acquired bleeding disorder with no clinically apparent cause of thrombocytopenia. Clinical indicators of ITP include easy bruising of the skin, prolonged bleeding on injury, mucocutaneous lesions such as petechiae and ecchymosis, epistaxis, gastrointestinal bleeding, hematuria and bleeding from the gums. It is important for a dentist to be aware of the clinical manifestations of ITP as it may not only lead to successful management of the patient, but in some cases it may even lead to formation of a provisional diagnosis of the condition in previously undetected cases. However, very few cases of ITP have been reported in dental practice making it difficult for a dentist to identify the disorder when a patient suffering from ITP reports for dental treatment. A case report of a female patient with ITP is thus described with emphasis on the importance of periodontal health in such patients to prevent consequent unwanted sequelae. It is followed by discussion of oral manifestations of the disorder and dental management of such patients.