Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.     

Active tuberculosis in inflammatory bowel disease patients under treatment from an endemic area in Latin America

BACKGROUNDThere has been an increase in cases of inflammatory bowel disease (IBD) in recent years. There is also greater access and availability of immunosuppressive and biological agents, which increase the risk of opportunistic infection despite improving the quality of life and promoting mucosal healing. Tuberculosis (TB) remains a public health problem, and it has a high incidence in several countries. Therefore, knowledge of the risk of developing TB in patients with IBD is important.AIMTo evaluate the risk of active TB in patients with IBD under treatment from an endemic area in Latin America.METHODSA standard questionnaire included demographic variables, clinical aspects of IBD disease, history of active TB during treatment, active TB characteristics and evolution, initial screening and results and time from the start of anti-tumor necrosis factor alpha (TNFα) to TB development.RESULTSAzathioprine, anti-TNFα and the combination of these two drugs were associated with a higher risk of active TB incidence. The TNFα blockers increased the relative risk of developing active TB compared to other treatments. All four multivariable models showed that the use of TNFα blockers alone or in combination with azathioprine was an important risk factor for the incidence of active TB. After adjustment for sex, age, type of IBD and latent TB, anti-TNFα with azathioprine increased the relative risk to 17.8 times more than conventional treatment. Late TB, which was diagnosed 3 mo after the start of anti-TNFα, was the most frequent.CONCLUSIONTreatment with anti-TNFα increased the risk of active TB in IBD patients from an endemic area in Latin America. This risk was increased when anti-TNFα was combined with azathioprine. The time from the beginning of the treatment to the active TB diagnosis suggests a new TB infection.     

Association Between Symptoms of Temporomandibular Disorders and Depression: An Epidemiological Study of the Northern Finland 1966 Birth Cohort

Facial pain and other symptoms of temporomandibular disorders (TMD) are rather common in the adult population. According to clinical studies, psychological factors play an important role in the etiology and maintenance of these symptoms. On the other hand, chronic pain can cause depression. The aim of this study was to evaluate the association between symptoms of TMD and depression in a large population sample of young adults. The study was a part of the 31-year follow-up study of the Northern Finland Birth Cohort consisting of 12,058 live births from the year 1966. Questionnaire information concerning TMD symptoms was collected from a subsample of 5,696 subjects. Depression was measured with a question about reported depression (diagnosed by a doctor) and with the Symptom Checklist depression subscale (SCL-25 DS). Of the TMD symptoms, those related to pain had the most significant relations to indicators of depression. In both genders, the proportion of depression indicated with the SCL-25 DS was significantly higher in subjects with pain-related symptoms of TMD, i.e., facial pain and “pain at jaw rest”, and in men with “pain on jaw movement”, compared with non-pain subjects (p<0.05). Other symptoms of TMD also associated significantly with SCL-25 DS (p>0.05), except “difficulties in mouth opening” among women. Among women, the prevalence of recognized depression was also significantly higher in subjects with pain-related symptoms of TMD, compared with subjects with no pain (p≤0.05). Almost all the associations remained significant after adjusting for marital status, education, and self-rated general health. In conclusion, the results show that depression has an association with TMD symptoms, especially those related to pain. When treating patients with facial pain, dentists should consider the possible presence of psychopathology and, if necessary, consult appropriate mental health professionals.     

Association of Symptoms of TMD and Orofacial Pain with Alexithymia: An Epidemiological Study of the Northern Finland 1966 Birth Cohort

Alexithymia is a term denoting a deficit in the ability to differentiate emotional from physical states and to identify and describe one's feelings, as well as a preference for external oriented thinking. Alexithymia has been linked with various somatic and psychosomatic diseases, especially with chronic pain. The aim of this study was to evaluate the association between alexithymia and symptoms of temporomandibular disorders (TMD) as well as oro-lingual and dental pain, in a large representative population sample of young adults. The study was a part of the 31-year follow-up study of the Northern Finland Birth Cohort originally consisting of 12058 live births in the year 1966. In 1997, 4893 subjects living in northern Finland or in the capital area, who participated in a field study of the project and later returned a postal questionnaire, made up the sample of this study. Information concerning symptoms of TMD and oro-lingual and dental pain was collected from the subjects. To assess alexithymia, the Toronto Alexithymia Scale-20 (TAS-20) was used. In addition, information about depression, marital status and self-rated health was collected. The proportion of alexithymics (TAS score over 60) was higher in subjects with the most orofacial symptoms than in asymptomatic subjects. In men, alexithymia associated significantly with facial pain, difficulties in mouth opening, oro-lingual pain and dental pain, and in women with pain on jaw movement and dental pain. After adjusting for depression, marital status, and self-rated health, a significant association remained between alexithymia and the symptoms mentioned, except for facial pain in men. It can be concluded that alexithymia is connected with orofacial symptoms. Clinicians treating these symptoms should be familiar with the concept of alexithymia.