Lionel Deforges

High-Dose Immunoglobulin Therapy for Severe IgA Nephropathy and Henoch-Schonlein Purpura

IgA nephropathy (IgAN) is characterized by IgA and C3 deposits in the mesangium [1] and is the most common form of primary glomerulonephritis [2]. Chronic renal failure occurs in approximately 25% of patients 10 years after diagnosis and in as many as 40% to 50% after 20 years [2-4]. Idiopathic Henoch-Schonlein purpura (HSP) is a more severe and systemic form of IgAN [4]. The causes of IgAN are still poorly understood. Glomerular damage might be related to deposits of IgA-containing immune complexes [4, 5], resulting from an uncontrolled mucosal immune response to chronic exposure to environmental antigens or from an anomaly of the medullary IgA system, which is thought to be a second line of defense against foreign antigens [6]. Studies have identified factors associated with poor outcome, such as heavy proteinuria, hypertension, altered renal function, and high histologic grade [2, 4, 7, 8]. Although renal insufficiency develops slowly in most patients, a subset of patients experiences a more severe disease course that requires dialysis within 1 to 5 years [2-4, 7, 9]. Unfortunately, despite the fact that glomerular injury is immunologically mediated, IgAN and HSP do not respond to steroids and immunosuppressive drugs [3]. We previously reported a partial IgG subclass deficiency (mainly involving IgG1) in proteinuric IgAN and HSP [10]. We postulated that such an IgG imbalance might favor viral and bacterial infections [11, 12], a known trigger of flare-ups in these diseases, or activate noxious isotypic compensatory mechanisms [13]. Because high-dose intravenous immunoglobulins are effective in some human immune-mediated diseases [14], we began a prospective trial of high-dose intravenous immunoglobulins in patients with severe IgAN and HSP who had indicators of poor prognosis. Methods Patients Ten men and one woman were enrolled in the study. The criteria for eligibility were idiopathic IgAN or HSP at histologic stage II/III, III, III/IV, or IV; proteinuria level greater than 2 g/d; and glomerular filtration rate greater than 35 mL/min per 1.73 m2. The local ethics committee approved the trial and all patients gave informed consent. Nine had IgAN and two had HSP. Five patients with IgAN were referred by their general practitioner for heavy proteinuria, whereas the remaining four were referred for severe IgA nephropathy by the nephrology units of two general hospitals. One patient with HSP was found to have nephritis while being treated in the dermatology unit of our institution, and the second was referred to our nephrology unit by his general practitioner for HSP with renal involvement. The median age was 24 years (range, 18 to 36 years). The median time between diagnosis and therapy was 5 months (range, 1 to 18 months) (Table 1). All patients had been treated for focal infections and had tonsillectomy for chronic tonsillitis or for reasons of immunity [15]. Two patients were treated unsuccessfully with high-dose steroids at least 3 months earlier. No patient received nonsteroidal anti-inflammatory drugs in the year before the trial. Nine of the 11 patients were treated for hypertension before entry into the trial, and their blood pressure levels rapidly returned to normal during therapy with -blockers alone (atenolol or betaxolol) or combined with prazosin; these drugs were pursued during the trial. None of the patients had severe hypertension: Results of the fondus oculi, hemogram, and heart ultrasound examinations were normal. Treatment of hypertension did not reverse the decline in renal function, despite prolonged follow-up before immunoglobulin therapy. Nine of the 11 patients had altered renal function (median glomerular filtration rate of the group, 57.5 mL/min per 1.73 m2; range, 39 to 134 mL/min per 1.73 m2). The median monthly rate of renal function decline before therapy was 3.78 mL/min (range, 13.80 to 0 mL/min) (Table 1), with a median total decline in renal function before therapy of 27.5 mL/min (range, 55 to 0 mL/min). All patients had heavy proteinuria (median protein level, 5.20 g/d; range, 2.37 to 10.70 g/d) (Table 1), a high histologic grade (1 with stage II/III; 4 with stage III; 3 with stage III/IV; 3 with stage IV), a high histologic index of activity (median, 5; range, 2 to 10), and a moderate histologic index of sclerosis (median, 4; range, 0 to 9) (Table 1). All had dense IgA and C3 mesangial deposits; four patients also had IgA deposits along the glomerular capillary wall. Immunoglobulin G deposits were absent, whereas mild IgM deposits were found in 5 of the 11 patients. The two patients with HSP also had articular effusion, extensive cutaneous purpura, abdominal pain, and diarrhea. Table 1. Changes in Renal Function and Urinary Variables with Immunoglobulin Therapy* Intervention The patients received 1 g/kg of body weight per day (in a 12-hour infusion) of pepsin-pH 4 intravenous immunoglobulins (Biotransfusion, Roissy, France) on 2 successive days each month for 3 successive months, followed by intramuscular immunoglobulins (Polygamma, 16.5%; Association Nationale pour la Distribution des Fractions Plasmatiques Humaines, Paris, France) at a dose of 0.35 mL/kg of body weight twice each month for another 6 months. To avoid serum sickness related to formation of immune complexes between free circulating environmental antigens and infused IgG, a complication previously reported with IgG deficiency [16], the first intravenous immunoglobulin infusion was preceded by single 3-L plasmapheresis with albumin replacement. We examined patients monthly during their hospital stay for the first 3 months, as outpatients from the third to the eighth month, and in the hospital at the end of the study (ninth month). After the 9-month trial, patients received the same maintenance therapy (0.35 mL/kg of intramuscular immunoglobulins twice each month) and were examined every 3 months as outpatients. Angiotensin-converting-enzyme inhibitors, calcium channel blockers, corticosteroids, and nonsteroidal anti-inflammatory drugs were not allowed during the trial. The patients ate a normal protein diet (1.5 to 2 g/kg per day of protein). Follow-up We assessed clinical, renal, viral, and immunologic tolerance at each visit during the 9-month study period and then every 3 months thereafter. Measurements Renal Histologic Findings Global Histologic Grading: We used the grading system of Lee and associates [7], which requires that at least nine glomeruli be scored. Biopsy specimens were blindly scored in five grades of increasing severity [7], accounting for both cellular proliferation and sclerosis. Stage I corresponded to normal glomeruli or occasional segmental mesangial thickening with or without cellularity. In stage II, fewer than one half of the glomeruli showed localized mesangial proliferation and sclerosis. Stage III was characterized by diffuse mesangial proliferation and thickening with focal and segmental variation, and focal interstitial edema and infiltrates may be present as small crescents and adhesions. In stage IV, marked diffuse mesangial proliferation and sclerosis were evident, with crescents in as many as 45% of the glomeruli. Partial or total glomerulosclerosis was frequently seen as tubular atrophy and interstitial infiltrates. Lesions classified as stage V were the same as in stage IV but more severe. Some biopsy specimens were given intermediate scores. Histologic Activity Index: We noted proliferation of mesangial and epithelial cells blindly using a final scale of 14 points; we required that at least nine glomeruli be examined. In evaluating mesangial cell proliferation, we accounted for the intensity (absent = 0; mild = 1; moderate = 2; severe = 3) and extent of the lesions (no glomeruli affected = 0; <25% of glomeruli = 1; >25% but <50% = 2; >50% but <75% = 3; >75% = 4). We noted epithelial cell proliferation in the same way. Histologic Sclerosis Index: We evaluated two parameters blindly (mesangial plus glomerular sclerosis, and interstitial sclerosis) and required that at least nine glomeruli be scored. Mesangial sclerosis accounted for both the intensity (absent = 0; moderate = 1; severe = 2) and extent of the lesions (no glomeruli affected = 0; <25% of the glomeruli = 1; >25% but <50% = 2; >50% but <75 % = 3; >75% = 4). With regard to interstitial sclerosis, we evaluated interstitial fibrosis on a 2-point scale (absent = 0; moderate = 1; severe = 2) and tubular atrophy in the same way (absent = 0; moderate = 1; severe = 2). Immunofluorescence Studies: We used a direct immunofluorescence technique with fluorescein-labeled goat antisera derived from the same batches (Institut Pasteur, Marnes la coquette, France, and Behring Institut, Marburg, Germany) directed against IgA, IgG, IgM, C1q, C3, and C4. The fluorescence intensity was scored blindly from 0 to 3. Biochemical Measurements of Renal Disease Activity We assayed protein levels at 24 hours using a dye-based method derived from Bradfords technique. We determined the proteinuria selectivity index by studying the IgG:albumin clearance ratio, which we measured using a nephelometer and specific polyclonal antisera (Behring Institut). We measured urinary erythrocyte and leukocyte counts during a 3-hour morning rest period and assayed urinary fibrin-fibrinogen degradation products according to the method of Merskey and Kleiner [17]. Using a specific enzymatic method, we measured plasma creatinine. We assessed global renal function through measurements of creatinine clearance (according to Cockroft and Gault [18]) and an inulin analog clearance (polyfructosan). Because evaluation of renal function decline with both the 1/creatinine ratio and the slope of the glomerular clearance curve was recently criticized (because the decline in renal function is not always linear [19, 20]), we evaluated the rate of renal function decline as follows: loss in glomerular filtration rate during the period studied (mL/min per 1.73 m2) divided by

Evaluation of a New Test, GenoType HelicoDR, for Molecular Detection of Antibiotic Resistance in Helicobacter pylori

ABSTRACT The eradication rate of Helicobacter pylori by standard therapy is decreasing due to antibiotic resistance, mainly to clarithromycin. Our aim was to provide a new molecular test to guide the treatment of new and relapsed cases. We first studied 126 H. pylori strains for phenotypic (MIC) and genotypic resistance to clarithromycin (rrl mutation) and levofloxacin (gyrA mutation) and then developed a DNA strip genotyping test on the basis of the correlation results and literature data. Clinical strains (n = 92) and gastric biopsy specimens containing H. pylori (n = 105) were tested blindly with the new molecular test GenoType HelicoDR. The presence of mutations or the absence of hybridization with wild-type sequences was predictive, in rrl for clarithromycin resistance in 91 cases (mostly the A2147G mutation) and in gyrA for levofloxacin resistance in 58 cases (mutations at codon 87 or 91). Genotyping revealed a mix of genotypes in 33% of the cases, reflecting a coinfection or selection for resistant mutants. The sensitivity and specificity of detecting resistance were 94% and 99% for clarithromycin and 87% and 98.5% for levofloxacin, respectively. The concordance scores were 0.96 for clarithromycin and 0.94 for levofloxacin. With global resistance rates of 46% for clarithromycin and 25% for levofloxacin, which were observed for consecutive positive biopsy specimens from 2007 and 2008, the positive and negative predictive values for detecting resistance were 99% and 94% for clarithromycin and 96% and 96% for fluoroquinolone. GenoType HelicoDR is efficient at detecting mutations predictive of antibiotic resistance in H. pylori when applied to strains or directly to gastric biopsy specimens.

Hepatitis C virus infection and autoimmune thrombocytopenic purpura

BACKGROUND/AIMSnChronic hepatitis C virus infections are often associated with extra-hepatic immunological manifestations, including various autoimmune disorders. The aims of this study were: (i) to determine the prevalence of hepatitis C virus markers in patients with autoimmune thrombocytopenic purpura, and (ii) to determine whether a relationship could exist between autoimmune thrombocytopenic purpura and hepatitis C virus infections.nnnMETHODSnOne hundred and thirty-nine patients with autoimmune thrombocytopenic purpura (45 men, 94 women, mean age 42 years, range 16-90) were studied.nnnRESULTSnAnti-HCV antibodies were sought in their first and last available cryopreserved sera. In case of seropositivity, all their available cryopreserved sera were tested for anti-HCV antibodies and for HCV-RNA. Anti-HCV antibodies were detected in 14 of the 139 patients (10%). Four patients had transient anti-HCV seropositivity due to passive transfer of anti-HCV antibodies secondary to the infusion of intravenous immunoglobulin concentrates. Three patients seroconverted during follow up, due to intravenous drug use in one case, transfusion of non-HCV-screened blood units in one case, and infusion of intravenous immunoglobulins in one case. Seven patients had chronic hepatitis C discovered at the same time as autoimmune thrombocytopenic purpura. In two of them, hepatitis C virus transmission was the consequence of autoimmune thrombocytopenic purpura treatment but, in five cases, hepatitis C virus infection predated autoimmune thrombocytopenic purpura, so that the role of hepatitis C virus in autoimmune thrombocytopenic purpura could be suggested.nnnCONCLUSIONSnWhereas hepatitis C virus does not appear to be the main etiological agent of autoimmune thrombocytopenic purpura can be envisaged. On the other hand, treatment of autoimmune thrombocytopenic purpura or autoimmune thrombocytopenic purpura-related symptoms by blood product infusion can be complicated by hepatitis C virus transmission.

Fast and Accurate Quantitative Detection of Helicobacter pylori and Identification of Clarithromycin Resistance Mutations in H. pylori Isolates from Gastric Biopsy Specimens by Real-Time PCR

ABSTRACT Rapid identification of patients infected with clarithromycin-resistant Helicobacter pylori without the need for culture can help to avoid useless prescriptions of clarithromycin. We developed and tested a routine real-time quantitative PCR assay dedicated to that purpose. One hundred ninety-six consecutive gastric biopsy specimens were examined by culture, histology performed by a trained physician, and rapid PCR with the LightCycler apparatus. Infection was defined as (i) positivity of culture, (ii) positivity of histology, or (iii) positivity of PCR if confirmed by positivity of a concomitant indirect test (serology or urea breath test). Susceptibility to clarithromycin was tested by E-test and PCR. The prevalence of infection was 33.7% (66 of 196 samples). The sensitivities of culture, histology, and PCR were 90.9% (60 of 66 samples), 87.9% (58 of 66 samples), and 97.0% (64 of 66 samples), respectively. The specificity of PCR was 94.6% (123 of 130 samples). The linearity of the PCR results was achieved over a 6-log range of input DNA, and we were able to accurately quantify as few as 300 bacteria and to qualitatively detect as few as 30 bacteria per DNA sample. For clarithromycin susceptibility testing, there was 98.2% (55 of 56 samples) concordance between E-test and PCR. Forty-eight strains were clarithromycin susceptible, and 9 strains were clarithromycin resistant. The single discrepancy concerned a culture which was a mixture of mutant and wild type, with a susceptible-to-resistant ratio of 11.5: the resistant population was detected by E-test but not by PCR. Our PCR assay is accurate for fast detection of H. pylori as well as of clarithromycin resistance and is also able to objectively determine bacterial density.

Immunomodulation with Low-Dose Immunoglobulins for Moderate IgA Nephropathy and Henoch-Schönlein Purpura

Recently, our group has shown that a 3-month course of intravenous immunoglobulin (2 g/kg/monthly) followed by 6 months of intramuscular immunoglobulins (IMIG, 16.5%, 0.35 ml/kg every 15 days) was able to slow or to stop the decline in the glomerular filtration rate, to reduce proteinuria, hematuria, leukocyturia and the histological index of activity on renal biopsy in patients with severe forms of IgA nephropathy (IGAN) and Henoch-Schönlein purpura (HSP). The aim of this open prospective trial was to evaluate the efficacy and safety of low-dose immunoglobulin therapy in moderate IGAN and HSP with permanent proteinuria. Fourteen patients with moderate IGAN [idiopathic IGAN: n = 11; chronic idiopathic HSP: n = 3] and permanent albuminuria were treated with polyvalent IMIG (16.5%) for 9 months (0.35 ml/kg once a week for 1 month, followed by 0.35 ml/kg every 15 days for a further 8 months). Eligibility criteria in the study were Lee histological stage I, II or III, albuminuria between 300 and 2,000 mg/day and a glomerular filtration rate > 70 ml/min/1.73 m2. IMIG were well tolerated and only 1 patient withdrew from the trial. No viral, renal or immunological side effects were observed. IMIG induced a significant decrease in albuminuria as well as in the histological activity index in the 11 cases in which a follow-up biopsy was performed. There was also a decrease in serum IgA, serum beta 2-microglobulin and IgA immune complex levels, and an increase in serum IgG1 levels. Twelve of the 13 evaluable patients improved during treatment.

Clinical Management of Rapidly Growing Mycobacterial Cutaneous Infections in Patients after Mesotherapy

BACKGROUNDnIncreasing numbers of patients are expressing an interest in mesotherapy as a method of reducing body fat. Cutaneous infections due to rapidly growing mycobacteria are a common complication of such procedures.nnnMETHODSnWe followed up patients who had developed cutaneous infections after undergoing mesotherapy during the period October 2006-January 2007.nnnRESULTSnSixteen patients were infected after mesotherapy injections performed by the same physician. All patients presented with painful, erythematous, draining subcutaneous nodules at the injection sites. All patients were treated with surgical drainage. Microbiological examination was performed on specimens that were obtained before and during the surgical procedure. Direct examination of skin smears demonstrated acid-fast bacilli in 25% of the specimens that were obtained before the procedure and 37% of the specimens obtained during the procedure; culture results were positive in 75% of the patients. Mycobacterium chelonae was identified in 11 patients, and Mycobacterium frederiksbergense was identified in 2 patients. Fourteen patients were treated with antibiotics, 6 received triple therapy as first-line treatment (tigecycline, tobramycin, and clarithromycin), and 8 received dual therapy (clarithromycin and ciprofloxacin). The mean duration of treatment was 14 weeks (range, 1-24 weeks). All of the patients except 1 were fully recovered 2 years after the onset of infection, with the mean time to healing estimated at 6.2 months (range, 1-15 months).nnnCONCLUSIONSnThis series of rapidly growing mycobacterial cutaneous infections highlights the difficulties in treating such infections and suggests that in vitro susceptibility to antibiotics does not accurately predict their clinical efficacy.

Helicobacter pylori and gastric lymphoma: high seroprevalence of CagA in diffuse large B-cell lymphoma but not in low-grade lymphoma of mucosa-associated lymphoid tissue type.

OBJECTIVE:Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type is closely related to Helicobacter pylori (H. pylori) infection. In vitro studies have demonstrated H. pylori-induced B cell proliferation to be strain dependent. High prevalences of CagA protein and FldA protein have been reported in strains obtained from patients with gastric lymphoma of MALT type. The aims of the present study were to evaluate the prevalence of H. pylori infection and to search for antigenic particularities in 53 patients with primary gastric lymphoma in comparison with a group of infected patients with benign disease.METHODS:Of the 53 patients, 37 presented with low-grade lymphoma of MALT type (LGLM) and 16 with diffuse large B-cell lymphoma (DLBCL). They were compared to a group of 162 H. pylori-infected subjects comprising the control group: 111 had gastric or duodenal ulcer (GDU) and 51 nonulcer dyspepsia (NUD). Diagnosis of gastric lymphoma was established on histological examination of endoscopic specimens. Anti-H. pylori antibodies were assayed by third-generation ELISA. Western blot assay was used to detect antibodies against nine antigens (including CagA protein), which were recognized on the basis of their molecular weight.RESULTS:Of the 53 patients with gastric lymphoma, 45 were H. pylori-positive (85%); of these, 25 (56.5%) had anti-CagA antibodies. The prevalence of H. pylori seropositivity was 78% (29/37) in LGLM and 100% (16/16) in DLBCL. The prevalence of CagA seropositivity in H. pylori-positive patients was 44.8% (13/29) and 75% (12/16), respectively (p < 0.05). In comparison, the seroprevalence of CagA was 77.4% (86/111) in GDU patients and 43.1% (22/53) in NUD patients. The prevalence of antibodies to other antigenic proteins detected with Helicoblot 2.0 (19.5kd, 30kd, 35kd, VacA, HSPb, Urease A, and Urease B) did not differ among the groups except for 35kd protein, which was significantly higher (p < 0.01) in GDU than in NUD and in LGLM (76.6% vs 49% and 46.7%).CONCLUSION:These findings suggest that in patients who develop gastric lymphomas in response to H. pylori, virulent strains expressing CagA protein are preferentially associated with DLBCL.

Gastroduodenal ulcer and erosions are related to portal hypertensive gastropathy and recent alcohol intake in cirrhotic patients.

Gastroduodenal ulcers and gastroduodenal erosions are particularly frequent in cirrhotic patients, but their precise cause is unclear. The aim of this study was to identify pathogenic factors associated with ulcers and erosions in patients with cirrhosis. We studied 64 consecutive patients with cirrhosis referred for gastroscopy. The severity of portal hypertensive gastropathy was graded with an endoscopic score. H. pylori status was determined by histological examination of gastric biopsy samples or by the [13C] urea breath test. The daily alcohol intake within the preceding week was recorded. The Child-Pugh score was determined. Fifteen patients had gastroduodenal ulcer and 20 had gastroduodenal erosions. Cirrhosis was related to alcohol in 44 patients and hepatitis B or C virus in 14 patients. The portal hypertensive gastropathy was graded as severe in 12 patients and mild in 25 patients. H. pylori infection, found in 37 patients, was not related to the gastroduodenal lesions. Univariate and multivariate analysis showed the links between gastroduodenal erosions and hypertensive gastropathy and recent heavy drinking. Gastroduodenal ulcer was independently associated only with the severity of the gastropathy. In conclusion, in these patients with cirrhosis, the presence of gastroduodenal ulcer was significantly related to hypertensive gastropathy but not to H. pylori infection. Recent alcohol intake favored the occurrence of gastroduodenal erosions.

Seroprevalence of eight Helicobacter pylori antigens among 182 patients with peptic ulcer, MALT gastric lymphoma or non-ulcer dyspepsia. Higher rate of seroreactivity against CagA and 35-kDa antigens in patients with peptic ulcer originating from Europe and Africa.

BACKGROUNDnIt has been suggested that Helicobacter pylori may induce more or less severe gastroduodenal disease according to the strain virulence.nnnDESIGNnWe used Western blot to determine antigenic profiles associated with duodenal or gastric ulcer disease, MALT lymphoma and non-ulcer dyspepsia, and to identify geographical differences.nnnMETHODSnOne hundred and eighty-two consecutive patients with H. pylori infection were studied. H. pylori infection was diagnosed by a rapid urease test or histological examination of gastric biopsy samples. Bacterial density and gastritis were assessed histologically by using the Sydney scoring system. Western blot was used to identify antibodies against eight antigens (CagA, VacA, urease A, heat shock protein B, and 19.5, 26.5, 30 and 35 kDa). Patients were questioned on their smoking habits and place of birth and childhood.nnnRESULTSnThere were 73 patients with duodenal ulcer, 30 with gastric ulcer, eight with erosive duodenitis, 17 with gastric MALT lymphoma and 54 with non-ulcer dyspepsia. Most (>85%) were seropositive for the heat shock protein B and 26.5-kDa antigens. The prevalence of the other antigens ranged from 45% (VacA) to 68% (urease B). The seroprevalence of CagA antigen was significantly higher (P < 0.01) in cases of gastroduodenal ulcer (84%) than non-ulcer dyspepsia (37%). Similarly, 35-kDa antigen reactivity was more frequent (P < 0.05) in duodenal ulcer patients (75%) than in those with non-ulcer dyspepsia (50%). The antigenic profiles associated with MALT gastric lymphoma and non-ulcer dyspepsia were similar. Multivariate analysis showed that only gastroduodenal ulcer was significantly associated with CagA. Gastroduodenal ulcer and a childhood spent in Africa were both associated with 35-kDa and combined CagA-35-kDa reactivity.nnnCONCLUSIONSnThis study confirms the strong seroprevalence of H. pylori CagA antigen and shows a high prevalence of the 35-kDa antigen in patients with gastroduodenal ulcer, especially those raised in Africa. There was no difference in the serological pattern between patients with non-ulcer dyspepsia and those with MALT lymphoma. Tests for antibodies to the CagA-35-kDa antigen combination might be used to select H. pylori-infected dyspeptic patients warranting treatment.

Hepatitis B Vaccination in Diabetic Patients: Randomized trial comparing recombinant vaccines containing and not containing pre-S2 antigen

OBJECTIVE To investigate the immunogenicity of two recombinant hepatitis B vaccines containing S antigen alone (Engerix B) or both S and pre-S2 antigens (GenHevac B) in diabetic patients. RESEARCH DESIGN AND METHODS Of the adult diabetic patients, 71 (26 IDDM, 45 NIDDM) were randomized to receive Engerix B or GenHevac B at 0, 1, 2, and 12 months in a single-blind clinical trial; if the antibody to hepatitis B surface antigen (anti-HBs) titers were < 10 <10 IU/1 at month 4, a fourth injection of vaccine was given. A positive response was defined by anti-HBs titer ≥ 10 IU/l at month 13. RESULTS The anti-HBs response rate and the titers of anti-HBs did not differ significantly between the two types of vaccine. Overall, > 90% of the patients responded at month 13. In patients vaccinated with GenHevac B, anti-pre-S2 antibodies appeared earlier than anti-HBs. The anti-HBs response tended to decrease with age (P = 0.07) and tended to be higher in IDDM patients than in NIDDM patients (P = 0.06). Metabolic control, as assessed by HbA1c level, did not influence the response rate. The presence of the HLA DQ2 allele was associated with a low response. CONCLUSIONS A large majority of diabetic patients can be efficiently vaccinated against the hepatitis B virus using a booster dose at month 4. The choice of the vaccine (with or without pre-S2 antigen) appears to have little influence, if any, on the response rate.