|Year : 2014 | Volume
| Issue : 3 | Page : 86-90
Dapsone as a cheap and safe second-line drug for chronic immune thrombocytopenia in developing countries: A prospective cohort study
Yasir Bashir Khan1, Asif Ahmed2, Syed Sajad Geelani1, Shabeer Ahmad Mir3, Javid Rasool Bhat1, Nusrat Bashir4, Javeed Iqbal Bhat2
1 Department of Clinical Hematology, SKIMS, Soura, Jammu and Kashmir, India
2 Department of Pediatrics, SKIMS, Soura, Jammu and Kashmir, India
3 Department of General Surgery, SKIMS, Soura, Jammu and Kashmir, India
4 Lab Hematology, SKIMS, Soura, Jammu and Kashmir, India
|Date of Web Publication||30-Sep-2014|
Department of Pediatrics, SKIMS, Soura, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Objective: The aim was to evaluate the efficacy and safety profile of dapsone as a cheap second-line treatment for chronic immune thrombocytopenia (ITP) in developing countries. Materials and Methods: A prospective study on 100 chronic ITP patients. These patients were put on dapsone after ruling out glucose 6 phosphate dehydrogenase deficiency and secondary causes of ITP. Results: The basic work up for secondary causes of ITP was negative. All these patients had been treated with steroids in the past. Anti-D had been given acutely in 20 patients, and intravenous immunoglobulin G had been given in 10 patients. Vincristine had been given to 20 of these patients. Dapsone was started in these patients, and 44% patients showed a response to treatment. The mean time to onset of response was 21 days. Out of these 44 patients, 21 (47.7%) went into remission and had platelet count >100,000/μl at 2 years post tapering of the treatment. Remaining 23 patients were kept on low dose dapsone and maintained their platelet counts. Adverse drug reactions included mild skin eruptions in 5% of patients, pruritus in 10% of patients, dose-related hemolysis in 1% of patients, methemoglobinemia in 1% of patients and Stevens Johnson syndrome in 1% of patients. 56 patients were nonresponders to the available, affordable conventional medical treatment and were referred to the surgical department for splenectomy, with a cure rate of 86% postsurgery. Conclusions: Dapsone is a safe, cheap and effective treatment option for patients with chronic ITP, who cannot afford the usual costlier second-line drugs.
Keywords: Dapsone, immune thrombocytopenia, treatment
|How to cite this article:|
Khan YB, Ahmed A, Geelani SS, Mir SA, Bhat JR, Bashir N, Bhat JI. Dapsone as a cheap and safe second-line drug for chronic immune thrombocytopenia in developing countries: A prospective cohort study. J Appl Hematol 2014;5:86-90
|How to cite this URL:|
Khan YB, Ahmed A, Geelani SS, Mir SA, Bhat JR, Bashir N, Bhat JI. Dapsone as a cheap and safe second-line drug for chronic immune thrombocytopenia in developing countries: A prospective cohort study. J Appl Hematol [serial online] 2014 [cited 2019 Mar 18];5:86-90. Available from: http://www.jahjournal.org/text.asp?2014/5/3/86/141991
| Introduction|| |
Immune thrombocytopenia (ITP) (also called idiopathic thrombocytopenic purpura) is an immune-mediated acquired disease of adults and children characterized by transient or persistent decrease of the platelet count and depending upon the degree of thrombocytopenia, increased risk of bleeding. 
The condition is usually asymptomatic, but the patient may have mucocutaneous bleeding like epistaxis, menorrhagia or oral bleed. A life-threatening bleed may occur very rarely, like an intracranial bleed in 0.1-0.5% of cases.  Wet purpura (blood blisters in the mouth) and retinal hemorrhages may herald crisis in ITP with a life-threatening bleeding. 
The condition occurs due to immune-mediated platelet destruction and possibly less release of platelets from the megakaryocytes.  This condition is usually an acute self-limiting illness in children, usually occurring 1-4 weeks after a viral infection. 70-80% of children with ITP have a spontaneous remission within 6 months.  In adults, it usually has a more chronic course with a durable remission in only 20-40% of cases.  ITP is reported in approximately 5/100,000 children and 2/100,000 adults per year.  ITP is termed as secondary if it is associated with the underlying cause. The usual associated diseases include autoimmune disorders especially systemic lupus erythematosus (SLE), infections like hepatitis C and human immunodeficiency virus (HIV).  The role of Helicobacter pylori infection in ITP and role of its eradication in the treatment of ITP in adults is still under review. ,
Sartorius  in 1984 was the first to report the benefit of prednisolone in ITP. Another study by Buchanan and Holtkamp  in the same year reaffirmed that prednisolone boosts platelet counts by day 7 of treatment. Corticosteroids act by impairing the clearance of opsonized platelets in bone marrow and peripheral organs and reducing autoantibody levels in the body.  Many prospective, randomized studies confirm that corticosteroids increase platelet levels more rapidly than no treatment. 
Imbach et al.  were the first to propose the role of intravenous immunoglobulin G (IVIG) in the reversal of thrombocytopenia. IVIG acts by impairing the clearance of opsonized platelets, probably mediated through the FcgRIIb receptor.  Some studies also suggest that IVIG might cause increased clearance of antiplatelet antibodies via saturation of the neonatal Fc salvage receptor for IgG. 
Salama et al.  in 1983 reported an increase in platelet counts in ITP patients who were also positive for rhesus D antigen, after the infusion of IV anti-D. Current wisdom favors the notion that IV anti-D coats the red blood cells (RBCs) that are positive for D antigen, and these opsonized RBCs in turn compete with opsonized platelets in the spleen for sequestration. 
In the case of patients not responding to the first-line treatment, the options are second-line drugs comprising mainly of immunosuppressants such as Azathioprine, cyclophosphamide, and cyclosporine. Dapsone, mycophenolate mofetil, danazol, and vinca alkaloids are a few other second-line drugs.
Rituximab is a human-murine monoclonal antibody against the CD20 antigen on B lymphocytes that are used to treat lymphoma. It is also used in the treatment of refractory ITP. Severe side-effects after rituximab therapy are rare, but include neutropenia and the reactivation of chronic infections such as tuberculosis.
Dapsone has been shown to cause a rise of platelet count in 40-50% of patients.  The recommended dose is 25 mg to 100 mg/day, and generally about a month passes before the response is apparent. The effects of the drug reportedly remain for a few months before relapse, which demands the continuation of therapy. Some clinicians recommend dapsone in addition to prednisone for patients who require low-dose steroids to maintain a high platelet count.
In our third world countries, cost of treatment is a major deciding factor for modality of treatment. It precludes IVIG and anti-D as a first-line treatment option and rituximab and other immunosuppressants as second-line treatment options in poor patients of third world. Dapsone is a cheap and safe drug, which is used as a second-line therapeutic agent and can be very promising option in poor nations of the third world.
| Materials and methods|| |
This study was carried out prospectively in a 650 bedded tertiary care institute. 100 patients were included in this study. These were patients with chronic ITP, who had not responded to the first-line treatment with steroids. Twenty of these patients had received anti-D acutely, and IVIG had been given in 10 patients. Vincristine had been given to 20 of these patients none of the patients had undergone splenectomy. A platelet count of <100 × 10 9 /l was used as a threshold for diagnosis of ITP after all other possible causes were excluded.  Chronic ITP was defined as a disease lasting for >12 months. 
A work up to rule out a secondary cause of ITP such as HIV, hepatitis C, SLE, thyroid disorders, H. pylori infection and bone marrow examination when needed, was done in all these patients. These patients were then started on treatment with dapsone 1-2 mg/kg/day per orally (ma × 100 mg) after ruling out glucose 6 phosphate dehydrogenase (G6PD) deficiency in them. These patients were followed-up regularly for monitoring of their platelet counts and complications occurring in them. Dose of dapsone was increased or decreased as per the response.
| Results|| |
A total of 100 patients were included in this study. The age of patients varied from 3 to 60 years, with a mean age of 36 ± 6.2 years. Male:female ratio was 1:3. There were 30 children and 70 adults in the study. Mean baseline platelet count in these patients was 8000 ± 347/μl. The basic work up for hepatitis C, HIV, SLE, thyroid dysfunction and H. pylori infection was negative in these patients. Bone marrow examination was done in 8 patients. All these 8 patients had splenomegaly and among these, two had anemia as well. Bone marrow examination was not suggestive of any other disorder in them.
All these patients had been treated with steroids in the past. Anti-D had been given acutely in 20 patients, and IVIG had been given in 10 patients. All of these patients had developed chronic ITP. Vincristine had been given to 20 of these patients, but they had either developed neuropathy or aches and pains, and it was discontinued. About 80% of the patients were steroid dependent responders, and 20% were refractory to steroids.
Dapsone was started in these patients, and 44% patients showed a response to treatment. The mean time to onset of response was 21 days (range 8-97). The mean interval between onset of ITP and start of dapsone treatment was 2 years. The mean duration of treatment with dapsone in responders was 3 years. The response was categorized as complete response, response and no response [Table 1]. Of these 44 patients, 21 (47.7%) went into remission and had platelet count >100,000/μl at 2 years post tapering of the treatment. Remaining patients were kept on low dose dapsone, and they maintained their platelet counts. These patients are still on our follow-up. Maximum follow-up time is 5 years. Out of 30 children, 12 (40%) had a complete response, and 3 (10%) showed response to dapsone, while as 15 children (50%) showed no response to treatment.
Drug reactions from dapsone occurred in the first 8 weeks of treatment. Mild skin eruptions were seen in 5% of patients. Pruritus occurred in 10% of patients. It was treated by antihistaminics without stopping dapsone. Clinically relevant hemolysis was seen in 1 patient (1%). It was dose related. This patient had not responded to low dose of dapsone, and when dose was increased, he developed jaundice and had increased reticulocyte count. Methemoglobinemia was suspected in 1 patient (1%) at 2 months of treatment. This child had a mildly elevated methemoglobin level and responded to Vitamin C. One patient (1%) developed Stevens Johnson syndrome from dapsone. This patient was managed with intravenous steroids, antihistaminics, topical steroids and histocalamine. This patient also had mild transaminitis. No significant chronic side-effects were seen.
Fifty-six patients were nonresponders to the available, affordable conventional medical treatment and were referred to the surgical department for splenectomy, with a cure rate of 86% postsurgery.
| Discussion|| |
Chronic ITP is a serious issue both for the patient and the doctor. The patient wants to get his ailment treated and at the same time, cost of the treatment is an important consideration in the developing countries where all people do not have health insurance and governments are poor. The doctor wants to provide a treatment regimen with minimum adverse effects for the patients and tries to save him from risks of surgery. Dapsone can be the answer for both these problems in the developing third world countries.
Dapsone (diphenylsulfone) is a sulfone bacteriostatic antibiotic. It is mainly used in the treatment of leprosy. It has also been used in treating lupus, dermatitis herpetiformis and rheumatoid arthritis. The safety profile of dapsone is very good with few side-effects like hemolysis in G6PD deficient individuals, allergic dermatitis, methemoglobinemia and rarely sulfone syndrome (including high fever, anemia, exfoliative dermatitis, and a mononucleosis-type blood picture).
We saw a very good response rate of 44% with dapsone in chronic ITP patients in our study. These results are comparable to other studies.
Vancine-Califani et al.  in their study on dapsone as second-line drug in ITP saw that among 52 steroid-dependent or refractory patients, dapsone resulted in sustained increases in platelet counts in 44.2% of patients, after a median follow-up of 21.10 months after treatment initiation.
In another study by Zaja et al.,  55% of patients showed response to dapsone as a second-line drug and 20% had a complete response with platelet counts >100,000/μl.
Godeau et al.  in their study used dapsone in 66 adults with chronic auto ITP purpura and platelet count <50 × 10 9 /l. A response was observed in 33 patients (50%). The median duration of treatment required to obtain a response was 21 days (range 8-90). The median maximal platelet count on treatment was 130 × 10 9 /l (range 71-355). Dapsone was continued in 20/33 responders for a median of 12.5 months (range 1-48) and the response persisted in 19. Treatment was intentionally withdrawn in the other 13 responders, and thrombocytopenia immediately recurred in 12. Reversible side-effects required cessation of treatment in 7 patients. Dutta et al.  in their study used dapsone in 8 patients of chronic ITP. They were treated with 100 mg of dapsone daily until response (in the form of the rise of platelet count in the blood) was seen. Later, these patients were put off dapsone for a minimum of 4 weeks, and then rechallenged with the drug. Four (50%) patients responded to treatment. The mean predapsone and postdapsone platelet counts of blood were 29.6 × 10 9 /l and 142.5 × 10 9 /l respectively during the first phase of the trial. The rechallenge was done in 5 patients following withdrawal of the drug and the mean values of platelet count before and after rechallenge were 32.2 × 10 9 /l and 83 × 10 9 /l, respectively. There was a remarkable response in 2 patients.
Fifty percent of children treated with dapsone overall responded to the treatment in our study. Forty percent of these had a complete response, and another 10% showed a response to dapsone. These results are very encouraging. Damodar et al.  had conducted a study on 90 patients (55 adults and 35 children) with chronic ITP and a platelet count of <50 × 10 9 /L. These patients were treated with dapsone at a dose of 1-2 mg/kg/d. A response was observed in 57 (63.3%) patients. Overall response rates of 65.7% and 61.8% were observed in children and adults respectively were seen in their study.
Dapsone is very cheap and easily available drug, with a cost of Indian Rupees 0.50 (0.0082 US$) per 100 mg tablet. It puts an end to the question of affordability of costlier second-line drugs like rituximab with a cost of Indian Rupees 25000 (410 US$) per dose, which is the most successful second-line drug presently. The safety profile of dapsone is also very good. Complications from dapsone are a few and usually amenable to treatment. Thus, the patient is saved from deadlier complications of the usual second line immunosupressants and rituximab. The adverse effects from dapsone use in our patients were mostly mild, requiring minimal treatment. Dapsone had to be stopped in 1 patient developing Stevens Johnson syndrome. Other studies too have found a mild adverse effect profile of dapsone. Damodar et al.  treated chronic ITP patients with dapsone at a dose of 1-2 mg/kg/d. A response was observed in 57 (63.3%) patients. They observed side-effects requiring discontinuation of therapy in only 3 (2%) patients.
The follow-up of patients on dapsone is also quite easy and no special monitoring is needed.
| Conclusions|| |
Dapsone is an effective, cheap, and safe alternative for chronic ITP patients who cannot afford the usual costlier second-line drugs.
| References|| |
|1.||Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011;117:4190-207. |
|2.||Imbach P, Kühne T, Müller D, Berchtold W, Zimmerman S, Elalfy M, et al. Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS). Pediatr Blood Cancer 2006;46:351-6. |
|3.||Udvardy M. Immune thrombocytopenic purpura (ITP). Orv Hetil 2001;142:2723-30. |
|4.||Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, et al. Disorders of platelets and vessel wall. Harrison′s Principles of Internal Medicine. 18 th ed., Ch. 115. The McGraw-Hill Companies, Inc: New york; 2012. |
|5.||Scott JP, Montgomery RR. Idiopathic (autoimmune) thrombocytopenic purpura. Nelson Textbook of Pediatrics. 19 th ed., Ch. 478. 1. Elsevier Saunders: Philadelphia USA; 2012. |
|6.||Stevens W, Koene H, Zwaginga JJ, Vreugdenhil G. Chronic idiopathic thrombocytopenic purpura: Present strategy, guidelines and new insights. Neth J Med 2006;64:356-63. |
|7.||Fogarty PF, Segal JB. The epidemiology of immune thrombocytopenic purpura. Curr Opin Hematol 2007;14:515-9. |
|8.||Blanchette V, Bolton-Maggs P. Childhood immune thrombocytopenic purpura: Diagnosis and management. Pediatr Clin North Am 2008;55:393-420, ix. |
|9.||Arnold DM, Bernotas A, Nazi I, Stasi R, Kuwana M, Liu Y, et al. Platelet count response to H. pylori treatment in patients with immune thrombocytopenic purpura with and without H. pylori infection: A systematic review. Haematologica 2009;94:850-6. |
|10.||Stasi R, Sarpatwari A, Segal JB, Osborn J, Evangelista ML, Cooper N, et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: A systematic review. Blood 2009;113:1231-40. |
|11.||Sartorius JA. Steroid treatment of idiopathic thrombocytopenic purpura in children. Preliminary results of a randomized cooperative study. Am J Pediatr Hematol Oncol 1984;6:165-9. |
|12.||Buchanan GR, Holtkamp CA. Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic purpura. A randomized clinical trial. Am J Pediatr Hematol Oncol 1984;6:355-61. |
|13.||Sandler SG, Tutuncuoglu SO. Immune thrombocytopenic purpura-current management practices. Expert Opin Pharmacother 2004;5:2515-27. |
|14.||George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura: A practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:3-40. |
|15.||Imbach P, Barandun S, d′Apuzzo V, Baumgartner C, Hirt A, Morell A, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981;1:1228-31. |
|16.||Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001;291:484-6. |
|17.||Hansen RJ, Balthasar JP. Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia. Blood 2002;100:2087-93. |
|18.||Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 1983;2:193-5. |
|19.||Stasi R, Provan D. Management of immune thrombocytopenic purpura in adults. Mayo Clin Proc 2004;79:504-22. |
|20.||Vancine-Califani SM, De Paula EV, Ozelo MC, Orsi FL, Fabri DR, Annichino-Bizzacchi JM. Efficacy and safety of dapsone as a second-line treatment in non-splenectomized adults with immune thrombocytopenic purpura. Platelets 2008;19:489-95. |
|21.||Zaja F, Marin L, Chiozzotto M, Puglisi S, Volpetti S, Fanin R. Dapsone salvage therapy for adult patients with immune thrombocytopenia relapsed or refractory to steroid and rituximab. Am J Hematol 2012;87:321-3. |
|22.||Godeau B, Durand JM, Roudot-Thoraval F, Tennezé A, Oksenhendler E, Kaplanski G, et al. Dapsone for chronic autoimmune thrombocytopenic purpura: A report of 66 cases. Br J Haematol 1997;97:336-9. |
|23.||Dutta TK, Goel A, Ghotekar LH, Hamide A, Badhe BA, Basu D. Dapsone in treatment of chronic idiopathic thrombocytopenic purpura in adults. J Assoc Physicians India 2001;49:421-5. |
|24.||Damodar S, Viswabandya A, George B, Mathews V, Chandy M, Srivastava A. Dapsone for chronic idiopathic thrombocytopenic purpura in children and adultsa - report on 90 patients. Eur J Haematol 2005;75:328-31. |