How does dapsone work in immune thrombocytopenia? Implications for dosing

To the editor:

Dapsone is a standard second-line treatment of primary immune thrombocytopenia (ITP), with response rates of 27% to 63%. Most adult studies used 100 mg daily, but the rationale for dose selection is unclear, and no ITP study has sought an association between dose and response.

Dapsone’s mechanism of action in ITP is not fully understood. Its metabolism into dapsone hydroxylamine (DDS-NOH) results in hemolysis, and the prevalent theory is that dapsone-induced hemolysis leads to erythrophagocytosis by the reticuloendothelial (RE) system, preventing sequestration and destruction of platelets. The hemolysis is dose dependent, and in 15 healthy volunteers taking 25 to 300 mg, there was a reasonably linear relationship between hemolysis severity and the dapsone dose in milligrams per kilogram of body weight.¹  Intravenous anti-D is thought to act through a similar mechanism in ITP, and its dose influences the platelet count response. If dapsone’s activity is principally though RE blockade, a dose-sensitive platelet count response would be anticipated.

An alternative hypothesis stems from dapsone’s better-studied anti-inflammatory activity in skin disorders. Its mechanism of action is still debated but may involve inhibition of neutrophil adhesion and migration to the site of tissue damage, inhibition of their prostaglandin production, or myeloperoxidase-mediated cytotoxicity. In vitro dapsone results in a dose-dependent inhibition of neutrophil adhesion to basement membrane-bound antibody from patients with bullous skin disorders.²  Adhesion is mediated by the mobilization and activation of the β₂-integrin molecule Mac-1 (CD11b/CD18). Several groups have shown that dapsone reduces adhesion of activated neutrophils through downregulation of Mac-1 expression. For example, dapsone at a concentration of 0.1 to 80 µg/mL reduced their adhesion to epidermal cells in a frozen section adhesion assay prepared from healthy skin preincubated with interferon.³  Dapone also inhibits the CXC-chemokine interleukin (IL)-8 and has shown dose-dependent inhibition of bullous pemphigoid immunoglobulin G-induced IL-8 release from cultured keratocytes at a posttranscriptional level.³  IL-8 is a potent chemotactic factor for leukocytes and is involved in their transmigration into the tissues. It regulates neutrophil expression of the β₂-integrins Mac-1 and CD11c/CD18 (p150,95), increases Mac-1 binding activity, and promotes neutrophil adhesion to endothelial cells through interaction with Mac-1.⁴ 

In ITP, antibody-coated platelets are cleared by circulating monocytes and macrophages of the RE system in an Fc-dependent manner. Complement fixation-enhanced RE clearance of opsonized platelets may also be an important mechanism.⁵  Mac-1 is expressed on monocytes and macrophages. It appears to work cooperatively with complement receptor 1 (CD35) to achieve stable adhesion of complement-opsonized particles.⁶  It is also involved in antibody-dependent cellular cytotoxicity and Fc receptor (FcR)-mediated cytotoxicity toward tumor cells, parasites, virus-infected cells, and erythrocytes.⁷  Intravenous immunoglobulin is thought to act through modulation of FcγR expression. Dapsone may therefore interfere with FcR-mediated platelet clearance by reducing expression of Mac-1. Furthermore, platelets have recently been shown to be an important source of serum IL-8, with a significant association between platelet count and serum IL-8 in ITP patients.⁸  Whether dapsone’s inhibitory effect on IL-8 and Mac-1 is enhanced by low serum IL-8 in severely thrombocytopenic patients and whether dapsone influences macrophage FcR function is unknown, and the hypothesis awaits investigation. Interestingly, however, unpublished data suggest dapsone can inhibit expression of the β₂-integrin p150,95 in a macrophage cell line.³ 

Despite a linear relationship between dapsone dose (milligrams per kilogram) and serum concentration, evidence for a clear dose-response association is lacking in inflammatory skin disorders, and the dose range to achieve symptom control is wide; for example, 25 to 400 mg daily (mean, 141 mg) in 20 patients with dermatitis herpetiformis.⁹  There is a 10-fold intersubject variability in DDS-NOH clearance, which is closely associated with variability in the oral clearance of dapsone (r = 0.96),¹⁰  and topical studies suggest DDS-NOH may itself have anti-inflammatory properties.³  Whether variation in DDS-NOH concentration accounts for dapsone’s wide dose range is unknown.

In ITP studies, dapsone 100 mg daily is well tolerated, with 0% to 11% of patients discontinuing therapy because of side effects. However, hemolysis and methemoglobinemia are dose dependent and may limit further dose titration. Some important contraindications, adverse effects, and an approach to monitoring are presented in Table 1. N-hydroxylation occurs through the P-450 system, and coadministration of the P-450 inhibitor cimetidine 400 mg 3 times daily can reduce methemoglobin levels by 25% to 30%. Although potentially also reducing dapsone’s anti-inflammatory effect, some authors have advocated its use at higher doses or for pronounced hematologic toxicity.³ 

The implication of both postulated mechanisms (hemolysis or immunomodulation) is that dapsone’s efficacy in ITP is likely to be dose sensitive. The overall response rate to dapsone might be improved by careful dose titration in patients unresponsive to 100 mg daily, and a phase 2 dose-finding study is needed.