Duration Of Immunosuppressive Treatment Research Articles

The role of tissue IgG4 levels in steroid therapy in patients with idiopathic granulomatous mastitis

Idiopathic granulomatous mastitis (IGM) is a benign, chronic inflammatory lesion of the breast. Immunoglobulin G4 (IgG4) associated disease is rare in the breast. In our study, we aimed to evaluate the efficacy of steroid treatment on IgG4 levels in tissue in patients diagnosed with IGM. Between 2008 and 2017, 55 patients diagnosed with IGM in our clinic were included in the study. Demographic, clinical, microbiologic and histopathologic characteristics, treatment modality and recovery time were evaluated retrospectively. Patients were divided into 3 groups according to tissue IgG4 levels: negative (Group I), infrequently and slightly positive (Group II), and highly positive (Group III). Group I patients had a complete response rate of 77.8%. In the rest of the patients (22.2%), insufficient response was detected from the beginning of the treatment. In Group II, the response rate was 91.3% and the permanent success rate after treatment was 87.0%. Although group III patients had a complete response at the beginning (95.65%), they relapsed in a short period of time (26.1%) after discontinuation of steroid treatment. At least one steroid-related side effect was observed in 47 (85.8%) patients in all groups. There is no consensus on the dose and duration of immunosuppressive treatment in IGM. In this study, responses to steroid treatment according to IgG4 concentration in pathologic breast tissue and recurrences after the end of treatment were determined. We think that high IgG4 concentration in the tissue is associated with recurrence and other immunosuppressive drugs should be added as maintenance after steroid treatment.

Gene Therapy for Hemophilia B: Achievements, Open Issues, and Perspectives.

Hemophilia B is the first bleeding disorder for which gene therapy clinical programs began. Presently, adenovirus-associated vectors represent the best means to deliver the transgene, and their administration by intravenous route has been used in recent clinical trials. The natural occurring factor IX (FIX) Padua variant, which allows for a 5- to 8-fold higher activity of FIX, while maintaining a normal protein concentration, was subsequently used to enhance the level of transgene expression. All the recent trials using this variant showed good results, and accumulating data suggest that long-term expression durability could be maintained at a significant hemostatic level. However, the risk of loss of transgene expression associated to immune response with liver enzymes elevation remains a concern, especially as to the efficacy and duration of immunosuppressive treatment. Notwithstanding this limitation, the results of clinical trials suggest that gene therapy in hemophilia B has the potential to provide long-term benefits with sustained factor activity levels predicted to last several years in many patients.

Drug-free remission is an achievable target with immunosuppressive treatment in idiopathic granulomatous mastitis.

Idiopathic granulomatous mastitis (IGM) is a rare inflammatory breast disease, in which there is no clear established treatment algorithm. Several physicians keep away from using immunosuppressive(IS) treatments in routine clinical practice. This study aimed to evaluate the rates of drug-free remission of the patients with IGM in a period of 3-year follow-up. This retrospective study conducted with 55 biopsy-proven IGM patients, who were followed up between February, 2011, and November, 2021, in rheumatology outpatient clinic of Gulhane Training and Research Hospital. The demographic and clinical characteristics of the patients were obtained from patients' files. The 3-year follow-up data were assessed for long-term outcome analyses. There were 55 female patients with a mean age of 36.8 ± 6.3years. Fifty-four (98.1%) patients were in drug-free remission at the end of 3years. The median duration of drug-free remission in patients receiving methotrexate (MTX), only corticosteroid (CS), and azathioprine was 19.7, 32.9, and 14.7months, respectively. The drug-free remission duration for the patient who received cyclosporine A as IS was 28.3months. The median duration of IS treatment was 15.8months, and the median duration of treatment with CS and other IS combination was 6.7months. Recurrence was observed in 4 (80%) patients without IS therapy after surgery, of whom MTX was used in 3 (75%) patients and achieved remission. IS agents provide high rate of prolonged drug-free remission and should be considered a part of routine medical care of the patients with IGM.

Chronic viral hepatitis B and rheumatic diseases: Modern view on problem

Infection caused by hepatitis B virus (HBV) is one of the most common hemocontact infections. The special life cycle of the hepatitis B virus, the course of infection, often hidden, and the high risk of developing life-threatening conditions, such as fulminant hepatitis and hepatocellular carcinoma, make it necessary to exercise special caution when choosing therapeutic tactics for rheumatological patients, since the vast majority of drugs used in rheumatological practice have immunosuppressive properties. This review updates information on the risks of reactivation of HBV infection in the treatment of currently used antirheumatic drugs, considers difficult to curate variants of chronic hepatitis B with delta agent and extrahepatic manifestations, in particular, thrombocytopenia. The most systematic and consistent approach to ranking the risk of reactivation of HBV infection (low [less than 1 %], moderate [1–10 %] and high [higher than 10 %]), in accordance with the serological status of the patient, as well as the type and duration of immunosuppressive treatment used, is proposed by the American Gastroenterological Association. The authors have attempted to unify the current literature data according to this classification.

Comparative study of laser flare photometry versus slit-lamp cell measurement in pediatric chronic non-infectious anterior uveitis.

To evaluate the role of laser flare photometry (LFP) for monitoring the course of intraocular inflammation in children with chronic anterior uveitis. Seventy-six eyes of 43 children with non-infectious chronic anterior uveitis were reviewed retrospectively. The median follow-up was 48.6 ± 23.1 months. Patients on immunosuppressive treatment at last follow-up, showed significantly higher flare values than patients who discontinued treatment (20.47 ± 15.49 vs. 6.33 ± 4.87 p < 0.001). The higher LFP values were correlated with the duration of immunosuppressive treatment, total duration of topical corticosteroid use and the risk for development of ocular complications at all follow-ups (all p < 0.001). No significant correlation was found between the AC cell grades and the duration of immunosuppressive treatment, topical corticosteroid use and the prevalence of complications. LFP measurements have a predictive value of monitoring the course of uveitis and the occurrence of ocular complications, and it should be considered as a primary modality to monitor intraocular inflammation in children with chronic anterior uveitis.

O30 Case report of Cogan syndrome in a child with audiovestibular dysfunction and ocular inflammation

Case report - IntroductionCogan syndrome is a very rare disorder of probable autoimmune vasculitic origin, first described in 1934. The age of onset seems to range from 3 to 50 years with an average age of disease onset at 29 years. It is characterised by audiovestibular dysfunction and ocular inflammation. The cause remains unknown and the epidemiology of the disease is purely based on case reporting. As of 2015, there were fewer than 250 case reports. Interestingly, it seems extremely rare in Arabic and Middle Eastern countries in which a new case has been recently diagnosed and is being reported in this abstract.Case report - Case descriptionA 14-year-old girl of Arabic origin first presented to the ENT specialist with a 3-week history of balance problems, left tinnitus and sensorineural hearing loss in both ears worse on the left. She first received treatment for vestibular neuritis with no improvement. Two months later, she complained of bilateral red eyes and excessive lacrimation when diffuse interstitial keratitis was diagnosed by the ophthalmologist. An array of blood tests including a full autoimmune disease was arranged and a rheumatology opinion was sought.The patient had a normal inflammatory response and her screen for antinuclear antibodies, extractable nuclear antigen, rheumatoid factor and antineutrophil cytoplasmic antibodies were all negative. A full virology screen was also negative. Having failed to respond to all supportive treatment modalities, a trial of a tapering 2-week course of prednisolone starting at 25mg daily was instigated. The patient’s symptoms improved by more than 50% on glucocorticoids subsequent to which the diagnosis of Cogan syndrome was anticipated. As the patient’s symptoms relapsed when glucocorticoids were stopped, she was recommenced on prednisolone 25mg in line with azathioprine 100mg daily. The patient’s hearing, which was almost lost in the left ear, improved significantly by more than 70% initially, and then to normal hearing as stated by the patient supported by special ENT testing. Her balance problems and vertigo also improved remarkably. Her tinnitus, which was the last symptom to resolve, almost went away over the subsequent 2 months. The patient had already come off glucocorticoids 6 months down the line, and stayed on azathioprine 75-100mg daily for almost a year after which gradual weaning was trialled and then eventually succeeded. She has now been off azathioprine for 6 months without experiencing any disease relapse.Case report - DiscussionCogan syndrome can be difficult to diagnose particularly in children. The diagnosis is essentially clinical depending on the presence of audio-vestibular symptoms and interstitial keratitis along with a prompt response to immunosuppressive medication.In this patient, the consistent clinical picture supported by the positive response to glucocorticoids especially in the absence of an alternative diagnosis would have made the diagnosis of Cogan syndrome likely.Given the rarity of this disorder, there are no classification criteria as yet hence the ongoing need for case reporting. Moreover, there is no clear guidance on the duration of immunosuppressive treatment of this condition.Case report - Key learning pointsIt is pivotal in managing conditions with a suspected autoimmune origin to have a multidisciplinary approach involving other relevant specialties in a holistic approach.The prompt response to glucocorticoid therapy still remains the key in securing the diagnosis of a number of conditions in clinical practice especially in the absence of diagnostic criteria and/ or supportive investigations such as serological and tissue-based testing.Case reporting has a crucial role in enhancing awareness of rare medical conditions.

Increased Cancer Risk in Autoimmune Hepatitis: A Danish Nationwide Cohort Study.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease and as such may increase the risk of cancer. We examined cancer risks in a nationwide cohort of patients with AIH. This study was based on nationwide Danish healthcare registries. We identified all persons diagnosed with AIH between 1994 and 2018. We included 1805 patients with AIH and 16,617 age- and sex-matched population controls. We estimated cumulative risks of cancers and risk ratios (RRs) between patients and controls. Within the cohort of patients with AIH, we examined the impact of immunosuppressive treatment (IST) and cirrhosis on cancer risks. The 10-year risk of any cancer was 13.6% (95% confidence interval [CI] 11.7-15.6) in patients with AIH with an RR of 1.5 (95% CI 1.3-1.7) compared with controls. Patients with AIH had a 10-year risk of 0.5% (95% CI 0.2-1.1) for hepatocellular carcinoma. The 10-year risk was 1.6% (95% CI 1.0-2.5) for colorectal cancer (RR: 2.1 [95% CI 1.3-3.5]) and 4.0% (95% CI 3.0-5.3) for nonmelanoma skin cancer (RR: 1.8 [95% CI 1.3-2.5]). Among patients with AIH, the risk of cancer was higher for those with cirrhosis (hazard ratio: 1.3 [95% CI 1.0-1.7]), and it also increased 1.05-fold (95% CI 1.0-1.1) for every year the patient was on IST. AIH was associated with a 1.5-fold increased 10-year risk of cancer compared with age- and sex-matched controls. Among patients with AIH, the risk of cancer was higher for those with cirrhosis, and it also increased slightly with longer duration of IST.

The effects of a multidisciplinary high-throughput skin clinic on healthcare costs of organ transplant recipients.

A long-term complication among organ transplant recipients (OTRs) is skin malignancies which are associated with level and duration of immunosuppressive treatment, sun exposure and age. Dermatological surveillance is recommended for OTRs at high risk of skin malignancies, but evidence is lacking on the benefits of such services. To examine the economic impact on patients and on the hospital service of a multidisciplinary high-throughput skin cancer clinic in Brisbane, Australia, dedicated to dermatological and surgical care of high-risk OTRs. In a pre/postdesign, hospital admission and cost data were obtained for 101 consecutively enrolled study participants from 12months prior to the introduction of the clinic (to February 2016), the 3-month 'run-in' period (March to May 2016) and 12months subsequent (to June 2017). Differences between pre- and post-clinic hospital costs were tested using non-parametric bootstrapping and interrupted time series analysis. A survey of patient out-of-pocket costs and perceived financial burden was also undertaken during the clinic. Overall hospital costs were higher after the clinic but 3-monthly hospital costs for skin procedures trended downwards. Despite 3-monthly mean, hospital visits increasing from 85 to 314, mean 3-monthly costs reduced by AU$1491 (P<0.001) indicating greater cost efficiency. Total patient out-of-pocket costs were AU$18377 over 3months. Clinical costing data revealed higher, more rapid throughput and significantly lower per patient costs pre- and postestablishment of a multidisciplinary skin cancer clinic for OTRs.

Possible benefit of splenectomy in liver transplantation for autoimmune hepatitis

Liver transplantation for autoimmune hepatitis (AIH) is usually successful with excellent long-term outcomes, but primary disease may recur. The recurrence of AIH is a significant cause of graft loss. This study was to analyze the effect of splenectomy in preventing AIH relapse. The clinical courses of 12 patients who had transplantation for AIH were analyzed retrospectively. All patients were subjected to transplantation for end-stage liver disease caused by chronic AIH. Based on the duration of immunosuppressive treatment before liver transplantation, simultaneous splenectomy was performed in ten patients. Two patients underwent liver transplantation without splenectomy, one of them developed recurrent AIH and died from graft failure caused by AIH relapse. However, no episode of AIH recurrence was observed in patients who had undergone simultaneous splenectomy. Splenectomy might be an option to prevent AIH relapse in some patients with high risk factors.

Skin Changes Following Organ Transplantation

The immunosuppressants used in transplantation medicine significantly elevate the incidence of neoplasia, particularly in the skin. The cumulative incidence of non-melanocytic skin cancer (NMSC) in renal transplant recipients was 20.5% in a study carried out in German centers. Data on more than 35 000 renal transplant recipients in the USA document a cumulative NMSC incidence of over 7% after 3 years of immunosuppression. The authors selectively review publications obtained by a PubMed search to discuss the incidence of, and major risk factors for, skin tumors and infectious diseases of the skin in immunosuppressed patients. The main risk factors for skin tumors are age at the time of transplantation, light skin color, previous and present exposure to sunlight, and the type and duration of immunosuppressive treatment. Squamous-cell carcinoma (SCC) is the most common kind of skin tumor in immunosuppressed patients. Human herpesvirus 8 and Merkel-cell polyoma virus also cause neoplasia more often in immunosuppressed patients than in the general population. Surgical excision is the treatment of choice. Actinic keratosis markedly elevates the risk that SCC will arise in the same skin area (odds ratio 18.36, 95% confidence interval 3.03-111). Patients with multiple actinic keratoses can be treated with photodynamic therapy or with acitretin. To lower the skin cancer risk, organ transplant recipients should apply medical screening agents with a sun protection factor of at least 50 to exposed skin areas every day. 55% to 97% of organ transplant recipients have skin infections; these are treated according to their respective types. Squamous-cell carcinoma of the skin adds to the morbidity and mortality of transplant recipients and is therefore among the major oncological challenges in this patient group. Structured concepts for interdisciplinary care enable risk-adapted treatment.

Chronic cutaneous varicella zoster virus infection complicating dermatomyositis

Chronic cutaneous varicella zoster virus (VZV) infection has not been previously reported or characterized as a complication of dermatomyositis. Two patients with non-malignancy-associated dermatomyositis, treated with long-term prednisone and methotrexate, developed persistent, painless ulcers ultimately established to be secondary to chronic VZV. The absence of pain or a history suggestive of acute VZV, and the lack of characteristic histopathology, resulted in a lengthy delay in diagnosis. Polymerase chain reaction and tissue immunohistochemistry were positive for VZV, and treatment with valacyclovir resulted in complete clearance. Diagnostic testing for VZV should thus be considered in the evaluation of ulcerative lesions in patients with dermatomyositis. The increased incidence of acute VZV in combination with the nature and duration of immunosuppressive treatment in this patient population may be contributory.

Clinical significance of subcategory and severity of chronic graft-versus-host disease evaluated by National Institutes of Health consensus criteria

To evaluate the clinical significance of subcategory and severity of chronic graft-versus-host disease (GVHD) as defined by the National Institutes of Health (NIH) consensus criteria, we retrospectively studied 211 patients with hematologic neoplasms who survived beyond 100days after allogeneic hematopoietic cell transplantation. Endpoints included chronic GVHD-specific survival (cGSS), duration of immunosuppressive treatment, and non-relapse mortality (NRM). A total of 96 patients fulfilled the NIH diagnostic criteria for cGVHD. In univariable analysis, patients with NIH overlap syndrome tended to exhibit lower cGSS compared to those with NIH classic cGVHD [hazard ratio (HR)=2.76, P=0.060], while patients with severe cGVHD at onset had a significantly lower cGSS compared to those with mild-to-moderate cGVHD (HR=3.10, P=0.034). The duration of immunosuppressive treatment was not significantly affected by either subcategory or severity of NIH cGVHD. In multivariable analysis treating cGVHD as a time-dependent covariate, development of overlap syndrome (HR=3.90, P=0.014) or severe cGVHD at peak worsening (HR=6.21, P<0.001) was significantly associated with higher risk of NRM compared to the absence of cGVHD. Our results suggest that both the subcategory and severity of NIH cGVHD are partly correlated with cGSS and may play a useful role in distinguishing patients at high risk for NRM, warranting validation of this approach through future prospective studies.

Prognostic Implications of the NIH Consensus Criteria in Children with Chronic Graft-versus-Host Disease

PurposeIn this study, we analyzed a cohort of children with chronic graft-versus-host disease (GvHD) according to the NIH consensus classification (NCC) in order to observe whether global assessment at diagnosis correlates with GvHD-specific endpoints. We then studied the clinical course of these patients, specifically with regards to episodes of GvHD exacerbation requiring treatment escalation.Materials and MethodsRecipients of either allogeneic bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) from January 2006 to August 2008 at the Department of Pediatrics, The Catholic University of Korea were evaluated for chronic GvHD, which was diagnosed according to the NCC. The course of chronic GvHD in these patients was then followed.ResultsOf 59 evaluable patients, 23 developed chronic GvHD for a cumulative incidence of 39.3%. Upon multivariate analysis, previous acute GvHD (≥grade II) had a significant impact on chronic GvHD incidence. With a median duration of systemic treatment for chronic GvHD of 501 days, no significant relationship was found between initial global severity of chronic GvHD and either duration of immunosuppressive treatment or final clinical response to treatment. Fifteen patients (65%) experienced at least one episode of chronic GvHD exacerbation during the period of follow-up, with a median of four exacerbations in the subgroup of patients who experienced such events. Lung GvHD resulted in the highest number of exacerbations per diagnosed patient, followed by oral GvHD.ConclusionAnalysis of this small cohort indicates that global assessment as proposed by the NCC may have limited correlations with GvHD-specific endpoints, possibly due to the favorable response of children to treatment.

Cyclosporin‐Induced Gingival Overgrowth: A Clinical–Epidemiological Evaluation of 121 Italian Renal Transplant Recipients

Although other immunosuppressive agents have been recently introduced (e.g., tacrolimus), it has been calculated that in the next decade about 1 million people will still be taking cyclosporin (CsA). The association between gingival overgrowth (GO) and the use of CsA is still not clear. In the present study we evaluated the prevalence and the degree of GO in a group of Italian renal transplant patients and the possible relationship between gingival lesions and demographic, oral, systemic, and pharmacological variables. One hundred twenty-one renal transplant recipients receiving immunosuppressive therapy with CsA were evaluated in this study. Patients were classified in two groups. In the first (screening group), we included all those patients referred by the Parma University Renal Transplant Center for a general oral checkup, with no specific indications for GO. The second group (non-screening group) included all those patients who specifically had been referred to the Oral Pathology and Oral Medicine Unit because of GO. We considered the following variables: gender, daily CsA dose, duration of immunosuppressive treatment, CsA plasma concentration, concomitant use of another immunosuppressive agent (azathioprine), use of other GO inducers (calcium channel blockers, anti-epileptic drugs), oral hygiene scores, and other drugs taken at the time of oral examination. Fisher's exact test and chi square test demonstrated that in the screening group, duration of immunosuppressive treatment and oral hygiene scores were associated both with the prevalence and the high GO scores (P (1) (DIT) <0.0001; P (2) (DIT)=0.0023; P (1) (hyg)=0.0084; P (2) (hyg)=0.0068). In the screening group, concomitant use of CsA and azathioprine is related to a low development degree of GO (P=0.0088). In the non-screening group, we found a significant association between poor oral hygiene and high degree of GO (P=0.0349). In addition to a probable genetic predisposition, duration of immunosuppressive treatment and oral hygiene status are the most important variables related to development and degree of GO during the use of CsA in this study.

Prevalence, detection rate and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection

Objective. To determine the prevalence of cytomegalovirus infection in patients with steroid-refractory ulcerative colitis who required colonic resection, and to assess its possible association with the use of immunosuppressive and steroid treatment and outcome after colectomy. Patients and methods. The study included surgical specimens and related pre-operative endoscopic biopsy specimens of 77 consecutive ulcerative colitis patients (34 females) who underwent colectomy because of intractable steroid-refractory ulcerative colitis (55 patients), toxic megacolon (6 patients), dysplasia or cancer (7 patients) or loss of function of the colon (9 patients). Clinical features and current and past treatments were analysed. Haematoxylin and eosin and specific immunohistochemical staining for cytomegalovirus were used to detect inclusion bodies in all specimens. Results. Cytomegalovirus infection was found in 15 of 55 steroid-refractory ulcerative colitis patients (27.3%) and in 2 of 22 non-refractory patients (9.1%) ( p = 0.123). Only six patients had positive staining for cytomegalovirus in pre-operative endoscopic biopsy specimens. Detection of cytomegalovirus inclusion in biopsy specimens was not related to the number of biopsies or to time that had elapsed since colonoscopy and index surgery. Cytomegalovirus-positive patients were more likely to be on systemic corticosteroids ( p = 0.03). In contrast, current use and duration of immunosuppressive treatment, number of steroid cycles since diagnosis and in the last year, as well as chronic use of steroid in the last year were not significantly related to cytomegalovirus infection. Cytomegalovirus-positive patients did not receive antiviral therapy following proctocolectomy but did not show endoscopic or histological cytomegalovirus reactivation in the ileo-anal pouch and in the remaining bowel. Conclusions. Cytomegalovirus infection is frequently found in surgical specimens of patients with steroid-refractory ulcerative colitis and is more likely in patients on corticosteroid treatment. Cytomegalovirus infection is frequently unrecognised in pre-operative biopsy specimens, thus raising concerns about the accuracy of the available diagnostic tools. Unrecognised and untreated cytomegalovirus infection does not affect the outcome of ulcerative colitis patients following proctocolectomy.

Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease.

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have proven efficacy in the treatment of Crohn disease (CD). The immunosuppressive properties of AZA/6-MP are mediated by the intracellular metabolism of 6-MP into its active metabolites, 6-thioguanine nucleotides (6TGN) and 6methylmercaptopurine (6-MMP). Preliminary studies have suggested that the red blood cell concentration of 6TGN (RBC 6TGN) is a potential guide to therapy. The aims of the study were to evaluate the RBC 6TGN concentrations in adult patients with CD under long-term AZA/6-MP therapy and to correlate it with response to treatment and haematological parameters. Twenty-eight CD patients treated for at least 3 months with AZA/6-MP were prospectively studied. Patients were separated into three main groups: group 1 (n = 19), corresponding to quiescent CD receiving AZA (dose: 2.05 +/- 0.4 mg/kg/day for a mean of 28.6 +/- 25 months) or 6-MP (dose: 1.4 +/- 01 mg/kg/day for a mean of 7.5 +/- 3.5 months) alone; group 2 (n = 6), corresponding to quiescent CD treated by AZA (dose: 2.14 +/- 0.5 mg/kg/day for a mean of 29.5 +/- 22 months) with oral steroids; and group 3 (n = 3), corresponding to active CD on AZA (dose: 1.94 +/- 0.6 mg/kg/day for a mean of 31.3 +/- 35 months) as the only treatment. An assessment was also made by merging groups 1 and 2 forming a larger group of patients (n = 25) defined by clinical remission and groups 2 and 3 forming a larger group of patients (n = 9), non-complete responders with AZA/6-MP alone. Crohn disease index activity (CDAI), blood samples for full blood count and differential white cell count and measurement of RBC 6TGN and 6-MMP concentrations were evaluated at inclusion and at 6 months (n = 17). RBC 6TGN were measured using high performance liquid chromatography (HPLC) on heparinized blood. The baseline characteristics of the three groups of patients were similar. There was no significant difference among the three groups of patients regarding the dose and the duration of immunosuppressive treatment. There was no significant difference between groups according to various parameters tested. Particularly, the median RBC 6TGN concentration at inclusion was similar in the three groups of patients (166 (105-688), 183 (90-261) and 160 (52-194) pmol/8 x 10(8) RBC, respectively). The majority of patients had no detectable level of 6-MMP metabolite, except for 3 patients. There was also no difference between merging groups. Furthermore, there was no significant correlation between RBC 6TGN concentrations and the various biological parameters tested except for the mean erythrocyte volume. At 6 months, all patients of group 1 remained in remission and median RBC 6TGN concentration remained stable. No side effects were observed. There is, contrary to preliminary studies, a broad overlap in RBC 6TGN levels as well as for haematological parameters in patients in remission or not and responders or not to AZA/6-MP therapy. This suggests, beside a variability in the metabolism of these drugs, the existence of complex mechanisms of action. Nevertheless, beside the use of RBC 6TGN determination to confirm compliance to therapy, this dosage could be useful in non-responding patients, allowing, in absence of leukopenia, to increase the dose of AZA/6-MP safely.