Patricia A. Fraser

Efficacy of Low-Dose Methotrexate in Rheumatoid Arthritis

Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.

Leukemia Following Hodgkin's Disease

To investigate the effect of different treatments for Hodgkins disease on the risk of leukemia, we used an international collaborative group of cancer registries and hospitals to perform a case-control study of 163 cases of leukemia following treatment for Hodgkins disease. For each case patient with leukemia, three matched controls were chosen who had been treated for Hodgkins disease but in whom leukemia did not develop. The use of chemotherapy alone to treat Hodgkins disease was associated with a relative risk of leukemia of 9.0 (95 percent confidence interval, 4.1 to 20) as compared with the use of radiotherapy alone. Patients treated with both had a relative risk of 7.7 (95 percent confidence interval, 3.9 to 15). After treatment with more than six cycles of combinations including procarbazine and mechlorethamine, the risk of leukemia was 14-fold higher than after radiotherapy alone. The use of radiotherapy in combination with chemotherapy did not increase the risk of leukemia above that produced by the use of chemotherapy alone, but there was a dose-related increase in the risk of leukemia in patients who received radiotherapy alone. The peak in the risk of leukemia came about five years after chemotherapy began, and a large excess persisted for at least eight years after it ended. After adjusting for drug regimen, we found that patients who had undergone splenectomy had at least double the risk of leukemia of patients who had not, and an advanced stage of Hodgkins disease carried a somewhat higher risk of leukemia than Stage I disease. We conclude that chemotherapy for Hodgkins disease greatly increases the risk of leukemia and that this increased risk appears to be dose-related and unaffected by concomitant radiotherapy. In addition, the risk is greater for patients with more advanced stages of Hodgkins disease and for those who undergo splenectomy.

Gene–environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis

Background: Previous studies have reported an interaction between ever cigarette smoking and the presence of the human leukocyte antigen (HLA)-DRB1 shared epitope (SE) genotype and rheumatoid arthritis (RA) risk. To address the effect of dosage, a case-control study nested within two prospective cohorts to determine the interaction between heavy smoking and the HLA-SE was conducted. Methods: Blood was obtained from 32 826 women in the Nurses’ Health Study and 29 611 women in the Nurses’ Health Study II. Incident RA diagnoses were validated by chart review. Controls were matched for age, menopausal status and postmenopausal hormone use. High-resolution HLA-DRB1 genotyping was performed for SE alleles. HLA-SE, smoking, HLA-SE* smoking interactions and RA risk, were assessed using conditional logistic regression models, adjusted for age and reproductive factors. Additive and multiplicative interactions were tested. Results: In all, 439 Caucasian matched pairs were included. Mean age at RA diagnosis was 55.2 years; 62% of cases were seropositive. A modest additive interaction was observed between ever smoking and HLA-SE in seropositive RA risk. A strong additive interaction (attributable proportion due to interaction (AP) = 0.50; p<0.001) and significant multiplicative interaction (p = 0.05) were found between heavy smoking (>10 pack-years) and any HLA-SE in seropositive RA risk. The highest risk was in heavy smokers with double copy HLA-SE (odds ratio (OR) 7.47, 95% CI 2.77 to 20.11). Conclusions: A strong gene–environment interaction was observed between HLA-SE and smoking when stratifying by pack-years of smoking rather than by ever smoking. Future studies should assess cumulative exposure to cigarette smoke when testing for gene–smoking interactions.

Association of IL-6 gene alleles with systemic lupus erythematosus (SLE) and with elevated IL-6 expression.

To evaluate the association of alleles of regions having regulatory potential in the IL-6 gene, with SLE, the AT-rich minisatellite in the 3′ flanking region and the 5′ promoter-enhancer of the IL-6 gene were genotyped by PCR- and RFLP-based methods. The AT-rich minisatellite allele distribution pattern was significantly different in SLE (n = 146) as compared to 139 controls (χ27 = 48.97, P = 0.001, Caucasians; and χ27 =19.93, P = 0.006, African-Americans). In either race, short allele sizes (⩽792 bp) were seen exclusively in SLE patients (P = 0.001), whereas the 828-bp allele was over-represented in controls (P = 0.015 and 0.002). In contrast, there was no preferential association of SLE with G/C alleles in the 5′ region of the IL-6 gene. Furthermore, our results suggest that the 3′ minisatellite alleles have biological significance: (1) B lymphoblastoid cells of patients having one or two SLE-associated alleles secreted IL-6 in 3- to 4-fold higher levels than non-allelic cells (P < 0.05); (2) higher percentages (approximately 4-fold) of il-6 positive monocytes were observed in individuals having sle-associated il-6 alleles; (3) in lupus patients having sle-associated minisatellite alleles, il-6 mrna stability was significantly enhanced.

TNF-α promoter single nucleotide polymorphisms are markers of human ancestry

We present a map of single nucleotide polymorphisms (SNPs) in the human tumor necrosis factor (TNF)-α promoter based upon exploratory sequencing of 333 human TNF-α gene promoters from individuals of distinct ancestral backgrounds. We detect 10 TNF-α promoter SNPs that occur with distinct frequencies in populations of different ancestry. Consistent with these findings, we show that two TNF-α SNPs, the −243 SNP and the −856 SNP, are the first SNP markers of a sub-Saharan African-derived extended haplotype and an Amerindian HLA haplotype, respectively. Comparisons of TNF-α promoter SNP allele frequencies can thus help elucidate variation of HLA haplotypes and their distribution among existing ethnic groups and shed light into the history of human populations.

Thrombotic thrombocytopenic purpura and systemic lupus erythematosus.

We report two patients with systemic lupus erythematosus who subsequently developed thrombotic thrombocytopenic purpura. In each case the coexistence of these two conditions was confirmed by pathological findings. Both patients responded to treatment, but one eventually died. A review of the literature suggests a possible relationship between the two disorders.

Development and initial validation of a self-assessed lupus organ damage instrument.

The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) is a validated instrument for assessing organ damage in systemic lupus erythematosus (SLE). Trained physicians must complete it, thus limiting utility where this is impossible.

I-123 Iofetamine SPECT Scan in Systemic Lupus Erythematosus Patients with Cognitive and Other Minor Neuropsychiatric Symptoms: A Pilot Study

Accurate diagnosis of central nervous system (CNS) lupus remains difficult, especially when the manifestations are of subtle cognitive and affective changes. This pilot study reports on the use of I-123 iofetamine single photon emission computerized tomography (SPECT) scans in 18 such patients with documented systemic lupus erythematosus. Eight of the 18 scans were abnormal (44%), four in a diffuse bitemporo-parietal pattern previously noted only in Alzheimers disease, and four with large focal deficits. Neither the existence of the abnormal scan nor the particular pattern of abnormality correlated with the results of other diagnostic tests. These preliminary results raise the possibility that SPECT scans may offer an additional valuable diagnostic instrument in CNS lupus, although further studies are necessary to delineate their precise role.

MICA, HLA-B haplotypic variation in five population groups of sub-Saharan African ancestry.

The human major histocompatibility complex (MHC) class I chain-related gene A (MICA), located 46 kb centromeric to HLA-B, encodes a stress-inducible protein, which is a ligand for the NKG2D receptor. In addition to its primary role in immune surveillance, data suggest that MICA is involved in the immune response to transplants and in susceptibility to some diseases. In this study, 152 subjects from the Yoruba (n=74), Efik (n=32), and Igbo (n=46) tribes of southern Nigeria, 39 nationwide African-American stem cell donors, and 60 African-American individuals residing in the metropolitan Boston area were studied for MICA, HLA-B allelic variation, haplotypic diversity, and linkage disequilibrium (LD). MICA and HLA-B exhibited a high degree of genetic diversity among the populations studied. In particular, MICA allele and HLA-B–MICA haplotype frequencies and LD in the Efik and Igbo tribes were significantly different from the other study groups. HLA-B and MICA loci demonstrated significant global LD in all five populations (P-values <0.00001). LD also varied in a haplotype-specific manner. A novel MICA allele was detected in the Boston population. These findings are important from an anthropologic perspective, and will inform future HLA-linked disease association studies in related ethnic groups of African-derived ancestry.

Designing an Intervention for Women with Systemic Lupus Erythematosus from Medically Underserved Areas to Improve Care: A Qualitative Study

Objective Systemic lupus erythematosus (lupus) disproportionately affects women, racial/ethnic minorities and low-income populations. We held focus groups for women from medically underserved communities to discuss interventions to improve care. Methods From our Lupus Registry, we invited 282 women, ≥18 years, residing in urban, medically underserved areas. Hospital-based clinics and support groups also recruited participants. Women were randomly assigned to three focus groups. Seventy-five-minute sessions were recorded, transcribed and coded thematically using interpretative phenomenologic analysis and single counting methods. We categorized interventions by benefits, limitations, target populations and implementation questions. Results Twenty-nine women with lupus participated in three focus groups, (n = 9, 9, 11). 80% were African American and 83% were from medically underserved zip codes. Themes included the desire for lupus education, isolation at the time of diagnosis, emotional and physical barriers to care, and the need for assistance navigating the healthcare system. Twenty of 29 participants (69%) favored a peer support intervention; 17 (59%) also supported a lupus health passport. Newly diagnosed women were optimal intervention targets. Improvements in quality of life and mental health were proposed outcome measures. Conclusion Women with lupus from medically underserved areas have unique needs best addressed with an intervention designed through collaboration between community members and researchers.