Autoimmune thrombocytopenia: Current treatment options in adults with a focus on novel drugs

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet destruction and reduced platelet production resulting in decreased platelet level and an increased risk of bleeding. Based on the immunologic mechanism of ITP, front‐line standard therapy consists of corticosteroids and intravenous immunoglobulins (IVIG). If patients do not respond to the first‐line treatment, or if continuous therapy is required, the disorder is called refractory ITP, and second‐line therapy is indicated. This treatment may consist of rituximab, thrombopoietin receptor agonists, splenectomy, or cytotoxic drugs. Despite significant advances, many patients do not respond to any the treatments listed below, and new treatment options need to be developed for this relapsed and refractory group. Recent clinical studies have indicated promising outcomes for novel drugs, either as single agents or in combination with traditional drugs. This review discusses the latest and the most promising novel drugs for ITP in adults.     

Bacterial infection-associated improvement of platelet counts in two patients with chronic and unresponsive idiopathic thrombocytopenic purpura with normal platelet survival studies

Summary. Approximately 20% of adult patients with idiopathic thrombocytopenic purpura (FTP) do not respond to splenectomy and require alternative therapies to achieve a clinically safe platelet count. A small percentage of these patients have very refractory disease and are either unresponsive or poorly responsive to almost any therapy. In this report we describe two patients with chronic and unresponsive ITP with normal platelet survivals. Neither patient had responded to a large variety of treatments including corticosteroids, splenectomy, IVIgG, anti-D, chemotherapy, and ascorbic acid. However, both had a rapid, but short-lived, rise in their platelet count following a bacterial infection. One patient had a rise in platelet count for 6 months following the acute episode of bacteraemia. The second patient had a shorter response of 1 week. It is possible that these two patients represent a subset of patients with ITP who may benefit from cytokine therapy.     

Antiproteinuric effect of ARB in lupus nephritis patients with persistent proteinuria despite immunosuppressive therapy

Recent immunosuppressive treatments for lupus nephritis have improved renal survival rate, however, there still exists lupus nephritis refractory to these treatments. Angiotensin receptor blockers (ARBs) are known not only to decrease blood pressure but also to have an independent renoprotecting effect by interrupting renin-angiotensin system. The aim of this study was to evaluate whether ARBs have an additive effect on refractory lupus nephritis. Enrolled in this trial were twelve patients with lupus nephritis who were diagnosed by renal biopsy and remained proteinuria despite corticosteroids and/or immunosuppressive treatments. ARB, losartan or candesartan, was administered for six months. Various clinical parameters were compared before and after ARB administration. Proteinuria decreased after ARB treatment in 83% of the patients and the median amount of proteinuria significantly decreased from 2530 mg/g Cr to 459 mg/g Cr (P = 0.03). In addition, serum albumin and cholesterol levels were significantly improved. Systolic blood pressure significantly decreased, but none had symptoms of hypotension. The antiproteinuric effect of ARB did not correlate with the reduction of blood pressure. Interestingly, higher total complement activity levels before ARB treatment were associated with a greater reduction of proteinuria. The addition of ARB would be a safe and effective treatment for lupus nephritis with persistent proteinuria despite corticosteroids and/or immunosuppressive treatments.     

Immune thrombocytopenic purpura in adults

PURPOSE OF REVIEW: A review of recent studies was conducted to determine if guidelines promulgated by the American Society of Hematology and the British Committee for Standards in Haematology need to be updated as these were based mainly on expert opinion rather than outcomes derived from clinical trials. RECENT FINDINGS: Recent studies suggest that most patients with immune thrombocytopenic purpura have a disease that is generally well tolerated, with little morbidity. Splenectomy remains the best 'curative' treatment for adults with chronic disease (at least 6 months of follow up). Other treatments such as anti-D, rituximab or dexamethasone may allow the decision of splenectomy to be postponed, possibly indefinitely, if hemostatic platelet count is attained. Mortality from bleeding may be relevant only in patients refractory to splenectomy. Cytotoxic agents should be reserved for patients with bleeding refractory to other treatments. SUMMARY: Patients with platelet counts less than 30 x 10(9)/l or bleeding have to be treated but management decisions should also be based on lifestyle, age, and other medical conditions that may contribute to the risk of serious bleeding. An aggressive therapeutic approach is justified only in patients with platelet counts below 20 x 10(9)/l and those refractory to splenectomy. Newer therapies may be more targeted in their action.     

Recent trends and future directions for the medical treatment of ulcerative colitis

Recently, several medical treatments for ulcerative colitis (UC) have been developed, including 5-aminosalicylic acids (5-ASAs), corticosteroids, thiopurine, calcineurin inhibitors, and anti-tumor necrosis factor (TNF) α treatments. Treatment options including calcineurin inhibitors and anti-TNF treatment for refractory UC are discussed in this article. Furthermore, upcoming treatments are introduced, such as golimumab, vedolizumab, AJM300, tofacitinib. Budesonide foamwill be used as one treatment option in patients with distal colitis. Herbal medicine, such as Qing-Dai is also effective for active UC and may be useful for patients who are refractory to anti-TNFα treatments. In the near future, physicians will able to use many different treatments for UC patients. However, we should not forget 5-ASA and corticosteroids as the fundamental treatments for UC patients.     

Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP)

Patients with severe immune thrombocytopenic purpura (ITP) may require an acute increase in the platelet count for surgery or ongoing hemorrhage as well as long-term maintenance treatment. Certain of these patients may be refractory to steroids, intravenous anti-D, intravenous immunoglobulin (IVIG), and splenectomy. Therefore, acute platelet increases were studied in 35 patients completely unresponsive to IVIG or high-dose steroid treatment. Because of their lack of response to either or both single agents, these patients were administered a 3- or 4-drug combination including IVIG 1 g/kg, intravenous methylprednisolone 30 mg/kg, Vinca alkaloids (VCR 0.03 mg/kg), and/or intravenous anti-D (50-75 microg/kg). Subsequent maintenance therapy with the oral combination of danazol (10-15 mg/kg) and azathioprine (2 mg/kg) was given to 18 of the 35 patients. Seventy-one percent of the patients responded to the intravenous combination treatment with acute platelet increases of at least 20 x 10(9)/L to a level greater than 30 x 10(9)/L. Two thirds of the patients given maintenance therapy achieved stable platelet counts greater than 50 x 10(9)/L without other treatments. One patient developed an ileus, but otherwise there was little toxicity of combination treatment. Combination chemotherapy is a useful approach for patients with ITP refractory to conventional treatments both for acute induction and for long-term maintenance therapy.     

A pilot study of rhuIL-11 treatment of refractory ITP

The objective of this research was to determine whether rhuIL-11 is an effective treatment in patients with refractory immune thrombocytopenic purpura (ITP). Platelet production is decreased in certain cases of refractory ITP. IL-11 stimulates megakaryocytopoiesis in vitro and was licensed for its clinical effects to ameliorate chemotherapy-induced thrombocytopenia. A pilot study was initiated, intending to enroll 12 patients with ITP. These patients were to receive rhuIL-11 (Neumega) at a dose of 50 microg/kg subcutaneously daily for 21 consecutive days and be observed afterward for 21 additional days. CBC with platelets were obtained twice weekly with visits and physical examinations weekly. The study was terminated after 7 patients were enrolled because of toxicity and lack of efficacy. All 7 patients had had ITP for >9 years and had failed splenectomy, intravenous gammaglobulin, corticosteroids, and a variety of other treatments. The patients at entry all had platelet counts <20,000/microl; 5 of 7 had counts <10,000/microl. The maximal median increase for any day of the study was 6,000/microl. No patient achieved a count of 30,000/microl, and only 3 patients achieved (once each) a platelet count >20,000/microl. Substantial toxicity was seen. The nadir hemoglobin decrease was a mean of 2 g/dl. rhuIL-11 was not effective at increasing the platelet count in any of these patients with refractory ITP. Toxicity was substantial. The lack of platelet response to rhuIL-11 in this study does not exclude the possibility of better effects at other doses and/or in less refractory patients.     

Rapid improvement of thrombotic thrombocytopenic purpura with vincristine and plasmapheresis

Many patients with thrombotic thrombocytopenic purpura (TTP) fail to respond to daily plasmapheresis and the results of alternative treatments have been inconsistent. Vincristine was given weekly with continued plasmapheresis to eight patients who were refractory to plasmapheresis, antiplatelet agents, and/or corticosteroids. A rapid response to the vincristine occurred in all eight patients in 5 days with a marked rise in the platelet count and resolution of symptoms. The results in these patients suggest that early initiation of vincristine therapy in conjunction with plasmapheresis is useful in TTP.     

Diaminodiphenyl sulfone therapy for refractory idiopathic thrombocytopenic purpura--long-term effectiveness and possible mechanisms

Eight patients with idiopathic thrombocytopenic purpura (ITP) refractory to corticosteroids were given oral diaminodiphenyl sulfone (DDS) (75 mg to 150 mg/day). Responses to DDS were observed in 5 patients, and their platelet counts significantly increased to more than 10 x 10(4)/microliter. The duration of treatment required to obtain platelet counts of more than 10 x 10(4)/microliter ranged from 35 to 64 days. In 3 of the 5 responsive patients, platelet counts stabilized at over 10 x 10(4)/microliter during DDS therapy for 3 to 6 years. Although adverse effects including local skin rash and itching were observed in 3 patients, they disappeared after suspension of DDS or in response to medication with antihistamines. Although the exact mechanism by which it increases the platelet counts in ITP patients is still obscure, DDS may inhibit the reticuloendothelial system by excessive red blood cell destruction. We concluded that DDS therapy is well-tolerated and seems to be an effective alternative treatment for patients with ITP that is refractory to other conventional therapies.     

Treatment of idiopathic thrombocytopenic purpura with ascorbate

The treatment of idiopathic thrombocytopenic purpura (ITP) includes corticosteroids, danazol, splenectomy and various immunosuppressives. Treatment can be difficult for those patients refractory to these modalities and/or those patients intolerant of the secondary effects. In this paper we report on the use of ascorbate in the treatment of ITP and its successful use in seven of 11 patients studied. We found that therapy with ascorbate appeared to improve the platelet count and the intravascular survival of platelets. Because of excellent patient compliance and its lack of toxicity, it may be an alternative for the treatment of ITP. The exact role of ascorbate in the treatment of ITP, as well as its mechanism of action, await further study.     

Efficacy of mycophenolate mofetil as single-agent therapy for refractory immune thrombocytopenic purpura

Refractory disease occurs in 25% or more of adults with idiopathic (immune) thrombocytopenic purpura (ITP). Therapy to elevate the platelet count may be required in a proportion of these patients. Immunosuppressive agents such as prednisone, azathioprine, cyclophosphamide, and cyclosporin have been shown to be effective treatments in a proportion of patients with refractory ITP. A newer immunosuppressive medication, mycophenolate mofetil (MMF), has been used successfully with acceptable toxicity in solid organ transplant patients to reduce the risk of organ rejection. The goal of this study was to determine whether MMF is an effective treatment for refractory ITP. Efficacy, defined as a sustained platelet increase to a level greater than 50 x 10(9)/L, was seen in 7 of 18 patients with refractory ITP. Three of these 7 patients have had intermittent thrombocytopenic episodes while continuing the medication. No severe toxicity was seen, although two of the 18 patients discontinued MMF within the first month of treatment because of side effects, i.e., headache. In summary, MMF may be a useful component of a combination protocol but does not appear to be highly effective as sole therapy in patients with refractory ITP. The data suggests that response rates to MMF may be higher in patients who have had a shorter duration of their ITP.     

Effect of corticosteroid therapy on the phagocytosis of antibody-coated platelets by human leukocytes

Patients with idiopathic thrombocytopenic purpura (ITP), a disorder in which antibody coated platelets are cleared from the circulation by phagocytic cells, are often treated with glucocorticoids. The effect of corticosteroids on the recognition and ingestion of sensitized platelets by phagocytes can be quantified in these patients and compared to changes in platelet levels. Six patients with ITP were treated with 96 mg daily of methylprednisolone for 5 days. This treatment raised their platelet count and simultaneously decreased the ability of their granulocytes to phagocytize antibody-coated platelets and C3-coated paraffin oil droplets. Corticosteroid treatment did not affect the binding of antibody to platelets or the quantity of antibody in the patients' serum. The ingestion defect was present in isolated, washed leukocytes and persisted for 3-5 days after the corticosteroids were discontinued. Granulocytes and purified monocytes obtained from patients with other medical disorders receiving corticosteroids also ingested paraffin oil droplets and opsonized platelets at a slower rate. These studies provide direct evidence that corticosteroids induce a generalized phagocytic defect and that this may be the mechanism by which corticosteroids raise the platelet count in patients with ITP.     

Cyclosporin A as an Immunosuppressive Treatment Modality for Patients with Refractory Autoimmune Thrombocytopenic Purpura after Splenectomy Failure

The treatment of autoimmune thrombocytopenic purpura (AITP) remains unsatisfactory in patients refractory to first-line management such as corticosteroid therapy and/or splenectomy. Patients with refractory AITP usually require unacceptably high doses of corticosteroids to maintain a safe platelet count. Immunosuppressive treatment with cyclosporin A (CsA) is a relatively new treatment modality, and no large studies of this drug have been conducted. We used CsA in 6 patients with refractory AITP who had platelet counts of less than 20 x 10(9)/L without any therapy or who had evidence of subcutaneous and mucosal bleeding. All 6 patients had undergone splenectomy. When CsA therapy was begun, 5 of the patients were receiving methylprednisolone (MP) at a daily dose of 32 mg or greater. During the following months, the MP dosage was tapered, or the drug was withdrawn. Three patients achieved a complete remission (CR), whereupon CsA treatment was gradually discontinued. Two of these 3 patients later relapsed, but both responded to an additional course of CsA and achieved a second CR. The remaining 3 patients achieved a partial remission (PR). One patient, a woman with an AITP history of more than 30 years, obtained a stable PR with a platelet count substantially greater than 20 x 10(9)/L, which was successfully maintained by low doses of CsA and MP. The most frequent side effect of CsA therapy in our patients was a painful edema of the lower extremities. Our experience shows that CsA is a safe and effective treatment option for patients with refractory (chronic) AITP. It may be given at a low dose as maintenance therapy, and remissions may be sustained even after the drug has been discontinued.     

Splenectomy does not cure the thrombocytopenia of systemic lupus erythematosus

Fourteen patients with systemic lupus erythematosus had splenectomies done between 1960 and 1982 for treatment of severe thrombocytopenia. Thrombocytopenia persisted or recurred within 1 month postoperatively in five patients and within 6 months in three others. Three patients had late recurrence (18, 30, and 54 months after splenectomy); in two it was probably related to withdrawal of immunosuppressive agents or corticosteroids. Median lowest platelet count before splenectomy and median platelet count at relapse or failure of splenectomy were both 8000/microL. Only two patients maintained normal platelet counts without need for corticosteroids or other treatment. These results differ from those in patients with idiopathic thrombocytopenic purpura. Other treatments should be tried before splenectomy is done for thrombocytopenia in patients with systemic lupus erythematosus.     

A Rational Approach to the Management of Severe Refractory Asthma

Severe refractory asthma is a heterogeneous condition with different patterns of severity and different reasons for loss of asthma control. The three main patterns include asthma with frequent exacerbations, asthma with irreversible airway obstruction, and asthma with reduced sensitivity or resistance to corticosteroids. Each of these patterns has distinct risk factors. The assessment of patients with severe asthma requires a systematic, diagnostic and management protocol. The majority of patients will benefit from thorough analysis and treatment of aggravating factors. In some patients with severe refractory asthma, in particular those with concomitant chronic rhinosinusitis, long-term administration of systemic corticosteroids may be necessary. In these patients all efforts should be directed towards reducing the dose of corticosteroids as much as possible. Although several corticosteroid-sparing agents and immunosuppressants have been proposed in the literature, none of these has gained complete acceptance in clinical practice, either because of limited efficacy or unacceptable adverse effects. Novel potent anti-inflammatory therapies aimed at reducing the need for systemic corticosteroids in patients with severe, refractory asthma are urgently needed.     

Refractory immune thrombocytopenia in systemic lupus erythematosus: response to mycophenolate mofetil

Immune thrombocytopenia (IT) is a common manifestation of systemic lupus erythematosus (SLE). Although severe IT (<20 x 10(9)/L) occurs in about 5-10% of patients, usually in the context of active disease, the absence of randomized controlled trials has not allowed the development of evidence-based guidelines for managing this condition. Conventionally, high-dose glucocorticoids are considered first-line therapy. Adjunctive medical and surgical treatments for patients with an absent or partial response to glucocorticoids have met with varying degrees of success. We describe an SLE patient with IT refractory to high-dose corticosteroids, pulse methylprednisolone and intravenous immunoglobulin therapy, whose platelet counts normalized during therapy with mycophenolate mofetil (MMF). Pending further controlled studies to confirm this observation, we suggest that MMF may be considered as a therapeutic option in the treatment of glucocorticoid-refractory immune thrombocytopenia in SLE.     

Diagnosis and treatment of refractory sprue

Celiac disease is a gluten-sensitive enteropathy characterized by villous atrophy that is reversed by gluten withdrawal. A minority of these patients is resistant to a gluten-free diet or, after a period of remission, they experience relapse despite continued adherence to treatment, which is called unclassified sprue or refractory sprue.The prognosis of refractory sprue may be poor: patients may die of severe malabsorption or from the development of an enteropathy-associated T-cell lymphoma. We report a 72-year-old-woman with a diagnosis of refractory sprue who responded well to treatment with corticosteroids and a gluten-free diet.     

Idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura occurs at all ages, in acute and chronic forms. Children mainly have the acute form, which usually follows a recent viral illness, occurs equally in both sexes, and generally resolves within six months. Chronic idiopathic thrombocytopenic purpura occurs more often in adults, often has an insidious onset, and shows a three:one female preponderance. Both forms are now thought to be due to an antiplatelet antibody, usually of the IgG class (platelet-associated IgG), which coats autologous platelets and leads to their phagocytosis and destruction by the reticuloendothelial system. In most patients, the spleen is the major site of the production of this platelet antibody and the destruction of the platelets. Many methods have been developed to detect this antiplatelet factor in the serum and on the platelets of patients with idiopathic thrombocytopenic purpura. Recent methods are becoming highly sensitive and may soon be simple and fast enough for routine clinical use and should significantly aid the diagnosis and management of these patients. Platelet-associated IgG levels appear significantly higher in patients with idiopathic thrombocytopenic purpura than in normal subjects, and in patients with nonimmune thrombocytopenia. Higher levels are also seen in children than in adults, and in acute cases than in chronic ones. Platelet-associated IgG levels also vary inversely with platelet count and platelet life span, can predict the disease course and response to therapy, and may predict neonatal consequences of maternal idiopathic thrombocytopenic purpura. Evidence of other alterations in immune status, as well as alterations in platelet function and HLA associations, remains controversial. Classic treatment with corticosteroids and splenectomy remains highly successful in most cases. More recent therapies include the use of immunosuppressants and alkaloid-coated platelets, plasma-exchange transfusion, and high-dose immunoglobulin. Overall, fewer than 5 percent of patients have severe hemorrhage or refractory or fatal disease.     

Successful treatment of refractory vasospastic angina with corticosteroids: coronary arterial hyperactivity caused by local inflammation?

BACKGROUND: Although vasospastic angina usually responds well to treatment with calcium antagonists and/or nitrates, there have been anecdotal case reports of refractory vasospastic angina resistant to intensive treatment with high doses of calcium antagonists and nitrates. METHODS AND RESULTS: Four patients with vasospastic angina, which was refractory to intensive treatment with high doses of calcium antagonists and nitrates, were completely controlled after administration of corticosteroids. Although none of the 4 patients showed eosinophilia, all had bronchial asthma or chronic thyroiditis, and in 2 cases, the activity of vasospastic angina corresponded with that of bronchial asthma. CONCLUSIONS: These findings suggest that in these patients, coronary spasm may have been induced by arterial hyperreactivity because of local inflammation in the coronary arterial wall and that the corticosteroids suppressed the arterial hyperreactivity by alleviating the inflammation. Corticosteroids may be considered as a treatment choice for patients with refractory vasospastic angina, particularly when the patient has an allergic tendency, such as bronchial asthma.     

Vincristine-loaded platelet infusion for treatment of refractory autoimmune hemolytic anemia and chronic immune thrombocytopenia: rethinking old cures

We report our experience with vincristine-loaded platelet infusion in patients with refractory immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome. Ten patients with symptomatic thrombocytopenia and/ or hemolytic anemia who failed to respond to two to six different treatment modalities, including corticosteroids and splenectomy, were treated with infusion of vincristine-loaded platelets. Platelets were harvested by plateletpheresis from a healthy ABO compatible blood donor and incubated with 5 mg vincristine. Excess of vincristine was removed, and platelets were resuspended in 50 ml plasma and infused over 30 min. All 10 patients responded, and 6 of them achieved complete remission. The response was prompt, occurring 3-8 days after vincristine-loaded platelet infusion. Two patients with AIHA are still in remission 9 and 8 years posttreatment with no maintenance treatment. Three ITP patients achieved persisted partial response for 6 years, 5 years, and 11 months; in the remaining 5 patients the response lasted for 2-5 months. No side effects were seen. Our results suggest that this inexpensive and well-tolerated treatment modality may be a useful approach in patients with ITP and AIHA refractory to primary therapy.