Erythema nodosum leprosum (ENL) is a painful inflammatory complication of leprosy occurring in 50% of lepromatous leprosy patients and 5-10% of borderline lepromatous patients. It is a significant cause of economic hardship, morbidity and mortality in leprosy patients. Our understanding of the causes of ENL is limited. We performed a systematic review of the published literature and critically evaluated the evidence for the role of neutrophils, immune complexes (ICs), T-cells, cytokines, and other immunological factors that could contribute to the development of ENL. Searches of the literature were performed in PubMed. Studies, independent of published date, using samples from patients with ENL were included. The search revealed more than 20,000 articles of which 146 eligible studies were included in this systematic review. The studies demonstrate that ENL may be associated with a neutrophilic infiltrate, but it is not clear whether it is an IC-mediated process or that the presence of ICs is an epiphenomenon. Increased levels of tumor necrosis factor-α and other pro-inflammatory cytokines support the role of this cytokine in the inflammatory phase of ENL but not necessarily the initiation. T-cell subsets appear to be important in ENL since multiple studies report an increased CD4+/CD8+ ratio in both skin and peripheral blood of patients with ENL. Microarray data have identified new molecules and whole pathophysiological pathways associated with ENL and provides new insights into the pathogenesis of ENL. Studies of ENL are often difficult to compare due to a lack of case definitions, treatment status, and timing of sampling as well as the use of different laboratory techniques. A standardized approach to some of these issues would be useful. ENL appears to be a complex interaction of various aspects of the immune system. Rigorous clinical descriptions of well-defined cohorts of patients and a systems biology approach using available technologies such as genomics, epigenomics, transcriptomics, and proteomics could yield greater understanding of the condition.

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A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum.

There is no data available on the ABO/Rh(D) frequencies in the Mauritanian population. We retrospectively analysed records of a 5-year database that contained ABO/Rh phenotype and ethnic origin of 10 116 volunteers giving blood at the national blood transfusion centre to derive the frequencies of ABO/Rh(D) groups in the Mauritanian population. The two race categories in the country and their sub-ethnic groups: the Moors (whites and black) and the black Africans (Pulhars, Soninkes and Wolof) were included in this study. Globally, group O had the highest frequency (49.10%) followed by A (28.28%), B (18.56%) and AB (4.05%). This order more common in North African populations was found in four of the five ethnic groups composing our population. Allele frequencies were, respectively, 70.20%, 17.74% and 12.04% giving the same order of O > A > B. We observed no significant variation in these frequencies between the different ethnic groups. Rhesus study showed that with a percentage of 94.23% Rh(D) positive is by far the most prevalent, while Rh(D) negative is present only in 5.77% of the total population. This frequency distribution supports the mixed-race composition of the Mauritanian population.

Frequencies and ethnic distribution of ABO and Rh(D) blood groups in Mauritania: results of first nationwide study.

Resume But de l’etude Peu de travaux documentes ont ete consacres a l’etude des groupes sanguins en Guinee. La presente etude a pour but de determiner les frequences phenotypiques et geniques des antigenes des systemes ABO et rhesus D dans la population guineenne. Methodes Les groupages sanguins ABO et rhesus D ont concerne 59 452 sujets comprenant les donneurs de sang et les malades preleves dans les quatre regions naturelles et dans la zone speciale de Conakry. Les phenotypes ABO et rhesus D ont ete determines par la double methode de Beth-Vincent et de Simonin sur plaque ou en tube, avec des serums tests monoclonaux et des hematies tests preparees localement. Les frequences geniques ont ete calculees selon les formules de Bernstein. Resultats Les frequences phenotypiques des antigenes de groupes sanguins A, B, AB et O sont respectivement egales a : 0,2254 ; 0,2386 ; 0,0472 et 0,4888. Celle de l’antigene rhesus D est de 0,9594 pour le rhesus positif et de 0,0406 pour le rhesus negatif. Les frequences des genes A, B et O dans la population sont de 0,1470 ; 0,1548 ; 0,6983. Ces frequences ne varient pas significativement entre les regions et les groupes ethniques. Elles sont proches de celles observees en Afrique subsaharienne. Conclusion Les resultats obtenus confirment le caractere negroide de la population guineenne.

Fréquence des groupes sanguins ABO et rhésus D dans la population guinéenne

A considerable number of studies have postulated significant associations between susceptibility to the different clinical manifestations of leprosy and the MHC. In this investigation, the association between the MHC class III complement proteins C2, BF, C4A and C4B and leprosy in a patient population of Southern Brazil was studied. A total of 109 non-related leprosy patients was investigated; 73 presented with lepromatous leprosy (LL), 46 of them had the immunopathological reaction of erythema nodosum (ENL), the remaining 36 were tuberculoid, borderline and indeterminate leprosy (TIBL) patients. The control group included 172 healthy individuals matched with the patients according to their ethnic and geographical origin. C2, BF, C4A and C4B allotypes were determined by standard technologies including Western blots for C2 and C4 variant alleles with monoclonal and polyclonal antibodies. Non-expressed ('silent') C4 alleles in hemizygously deficient individuals were estimated semiquantitatively on the basis of the C4A and C4B isotype ratio and by the MASC ('minimal chi-square') method. The results showed a significantly elevated presence of the non-expressed C4B allele (C4B*Q0) in the LL and ENL patient groups in comparison with the controls. The most significant difference was observed in the ENL group when compared with the controls. In addition, all patients who were homozygously C4B-deficient had ENL, and most of them had the BF*F1 allele. The comparison between LL patients with and without ENL also showed a statistically significant difference in the presence of C4B*Q0, indicating that C4B deficiency itself is associated with ENL. The relative risk of LL patients with the C4B*Q0 allele suffering from ENL was 5.3 compared with LL patients without C4B*Q0. Since immune complexes (IC) are considered to be the pathogenic cause of ENL, our findings indicate that C4B deficiency may play an important role in the abnormal immune response against Mycobacterium leprae and in the lack of IC clearance, leading to ENL reactions. Individuals with this allele seem to be at a higher risk of developing pathological immune reactivity in lepromatous leprosy.

Association of C4B deficiency (C4B*Q0) with erythema nodosum in leprosy.

The association of chloroquine and proguanil is widely used for antimalarial prophylaxis in Plasmodium falciparum – endemic countries with limited to moderate chloroquine resistance [1]. We report the 1st case of acute generalized exanthematous pustulosis (AGEP) due to this drug combination. A 34-year-old woman with a previous history of maculopapular skin rash induced by mefloquine in 1995 was referred to our department in February 1996 because of the rapid onset of a generalized eruption of 2 days’ duration. The eruption began on the face and trunk and subsequently spread to the limbs. It consisted of a diffuse erythema with multiple superficial nonfollicular pustules. A few target lesions were present on the limbs. The rash was highly pruritic. There was no mucosal involvement. She was slightly pyrexial (38°C). She had been taking chloroquine (100 mg/day) and proguanil (200 mg/day) for 10 days as an antimalarial prophylaxis during a travel across Togo (West Africa). She had not been given other medication in the past 3 months and had no history of psoriasis. Laboratory investigations disclosed hyperleukocytosis (22.7× 10/l) with polynucleosis (20×10/l) and eosinophilia (1×10/l). Histopathologic examination of a skin biopsy specimen showed multilocular spongiform subcorneal pustules containing polymorphonuclears and eosinophils. Chloroquine and proguanil were stopped. The eruption resolved after 8 days with no further recurrence. Epicutaneous tests performed 6 months later with chloroquine, proguanil and mefloquine were negative. AGEP is a recently described entity [2] mostly related to drugs, principally antibiotics (beta-lactams and macrolides). Four cases of AGEP due to hydroxychloroquine have been previously reported, the last in 1995 [3] but no case of AGEP induced by chloroquine or proguanil has ever been published. Chloroquine, an amino-4 quinoleine has a few cutaneous side effects apart from pruritus (which may occur in up to 75% of patients) and exacerbation of psoriasis [4, 5]. Proguanil and cycloguanil, two biguanide derivatives, may induce mouth ulcers [6] without any particular skin side effects. They are seldom used alone and mostly given in combination with chloroquine. Finally, mefloquine, an amino-alcohol, can produce life-threatening adverse cutaneous reactions [7] but has no known cross-hypersensitivity with chloroquine. In our case, it was not possible to distinguish between chloroquine and proguanil as the culprit of the AGEP and future antimalarial prophylaxis was further complicated by skin reaction to mefloquine. Reports of severe cutaneous toxicity in patients taking antimalarials and possible cross-reactions are highly warranted.

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Acute generalized exanthematous pustulosis due to the combination of chloroquine and proguanil.

Resume La determination des groupes ABO et sous-groupes de A, ainsi que des frequences geniques, chez 4.083 sujets Senegalais, montre une grande frequence du gene O (0,7042), des frequences des genes A et B comparables Les frequences des genes A1 et A2 sont respectivement de 0,1248 et 0,0223.

Phénotypes érythrocytaires et fréquences des gènes du système ABO dans la population sénégalaise

The authors wanted to determine the motivations and attitudes of the Senegalese with regard to the important problem of blood donation. An investigation, by means of a questionaire, has been carried out on a selected cross-section of 1,710 people.

[Blood transfusion in Senegal: psychophysiologic study of blood donation].

50 lepromatous patients among whom 34 shared repeating ENL reactions and a reference group of 150 blood donors were typed for HLA antigens. In the comparison of the lepromatous group to the reference group, the HLA-B 8 was the only antigen which turned out to be significantly increased within the lepromatous patients. Some changes reported by other authors have also been pointed out (decrease in HLA-A2 and HLA-A3, increase in HLA-AW 23 within the lepromatous patients) but those are not significant in this study. In the lepromatous group itself, not any significant change has been pointed out between the patients sharing ENL and those who did not show any. Nevertheless a non-significant increase in HLA-BW 35 in the patients with ENL is to be pointed out.

[HLA and leprosy in Dakar: distribution of histocompatibility antigens in leprous patients and their relationship to ENL reactions].

[Blood transfusion in Senegal: psychosociological study of blood donation].

The Kell gene frequencies, determined in Senegal are as follows:
 
$$K = 0.00502, k = 0.99498.$$

 Our data enter the limits already known for black African populations.

Blavy G

Papers

Phénotypes érythrocytaires et fréquences des gènes du système ABO dans la population sénégalaise

[Blood transfusion in Senegal: psychophysiologic study of blood donation].

[HLA and leprosy in Dakar: distribution of histocompatibility antigens in leprous patients and their relationship to ENL reactions].

[Blood transfusion in Senegal: psychosociological study of blood donation].

The Kell System in Senegal: Phenotype and Gene Frequencies