Biomedical subjects
M Tikly
Publications and source records attributed to M Tikly.
A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis.
OBJECTIVE: To compare the clinical efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis (RA). METHODS: In this multicentre, double-blind trial, 999 subjects with active RA were randomized to leflunomide (n = 501; loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) or methotrexate (n = 498; 10-15 mg/week) for 52 weeks. After 1 yr the subjects could choose to stay for a second year of double-blind treatment. The primary end-points were tender and swollen joint counts and overall physician and patient assessments. Analyses were of the intent-to-treat group. RESULTS: After 1 yr, the mean changes in the leflunomide and methotrexate groups, respectively, were -8.3 and -9.7 for tender joint count; -6.8 and -9.0 for swollen joint count; -0.9 and -1.2 for physician global assessment; -0.9 and -1.2 for patient global assessment; -14.4 and -28.2 for erythrocyte sedimentation rate. Improvements seen with methotrexate were significantly greater than those with leflunomide. No further improvement occurred after the second year of treatment and the distinction between the two treatments in terms of tender joint count and patient global assessment was lost. During the first year of treatment, a small and equivalent degree of radiographically assessed disease progression was seen with both drugs. After 2 yr, disease progression was significantly less with methotrexate. The most common treatment-related adverse events in both groups were diarrhoea, nausea, alopecia, rash, headache, and elevated plasma liver enzyme levels. Over 2 yr, 21 subjects receiving methotrexate were withdrawn due to elevated plasma liver enzymes vs eight subjects taking leflunomide. Two drug-related deaths from pulmonary causes were recorded with methotrexate vs no drug-related deaths among the subjects receiving leflunomide. CONCLUSIONS: Both leflunomide and methotrexate are efficacious for prolonged treatment of RA. At the doses used, some clinical benefit of methotrexate over leflunomide was observed in the first year of treatment. This benefit must be weighed against the potential toxicity of this drug when used without folate supplementation.
Distribution of corticotropin-releasing hormone promoter polymorphism in different ethnic groups: evidence for natural selection in human populations.
The regulatory region of the corticotropin-releasing hormone (CRH) is highly conserved across species and plays a crucial role in the response of the organism to stress. Release of CRH initiates a cascade of events leading to the release of cortisol and the regulation of inflammatory and immune events. In this report we describe polymorphisms in the 5' regulatory region of the CRH gene in humans. We studied the distribution of CRH alleles in three different African populations, in white UK Caucasoids, and in a Chinese population. In the African and UK populations we found three new polymorphisms which cosegregated, resulting in two alleles, A1 and A2. Gene frequencies for A1 and A2 were extremely divergent between the African and the UK populations. The African A1 frequency ranged from 0.27-0.3, while the UK Caucasoid frequency was 0.9. Compound alleles could be assigned by taking into account the previously described biallelic polymorphism at position 225 in the CRH promoter. The A2B1 compound allele is the commonest in contemporary African human populations (allele frequency range 0. 44-0.61) and was the only allele observed in a population of chimpanzees from Sierra Leone. Wright's F(ST )for the A2B1 allele over the four sampled populations was 0.612, a value exceeded in human populations only by loci which have apparently been subject to natural selection. Taken together, these findings support A2B1 as the ancestral allele and suggest that the CRH genomic region may have been subject to strong disruptive selection throughout human evolution.
Clinical and laboratory manifestations of systemic sclerosis (scleroderma) in Black South Africans.
A retrospective study of systemic sclerosis (SSc) in Blacks attending a tertiary hospital on the Witwatersrand, South Africa, was undertaken. The female:male ratio of the 63 patients was 4.6:1 and the mean age of onset of SSc was 36.1 yr. Four of the 11 males were ex-goldminers and nine females resided close to goldmines. Forty-one patients had diffuse cutaneous SSc (dcSSc), 18 had limited cutaneous SSc (lcSSc) and four were unclassified. Overall, 56% had pulmonary fibrosis, 37% had myositis and 98% were antinuclear antibody (ANA) positive, with a notable absence of anti-centromere antibodies. Subset comparisons showed myositis and a reduced forced vital capacity to be significantly more common with dcSSc than lcSSc. The only significant sex differences were that arthralgia/arthritis was more common in women, while calcinosis occurred more frequently in men. Seven of the eight known deaths occurred in patients with dcSSc. These findings, particularly the age of disease onset, predominance of the dcSSc subset, inflammatory features of myositis and a raised erythrocyte sedimentation rate, and absence of anti-centromere antibodies, are similar to those reported previously in African-Americans.
Mannose-binding protein gene polymorphism in South African systemic lupus erythematosus.
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Risk factors for gout: a hospital-based study in urban black South Africans.
The clinical features of 90 Black South African patients with gout seen at a large urban hospital were reviewed. The mean age of the patients was 54.3 and 55.3 years for men and women, respectively. The male:female ratio was 3.3:1. All except one of the women were postmenopausal. Seventy-nine percent of patients were from the lower income groups of "blue collar" workers, old-age pensioners or the unemployed. Polyarticular gout was observed in 44.4% of the patients. Tophi were noted in 51.1% of patients but none had a history of renal calculi. Risk factors were assessed by comparing the gouty patients to an equal number of age- and sex-matched hospital controls. Case-control analysis showed a "white collar" occupation (odds ratio = 7.4), obesity (odds ratio = 5.3), alcohol intake (odds ratio = 3.5) and hypertension (odds ratio = 3.3) to be significant risk factors for gout in the overall group of both men and women. In the subgroup of men only, obesity (odds ratio = 7.8), a "white collar" occupation (odds ratio = 6.4), hypertension (odds ratio = 4.9) and alcohol intake (odds ratio = 3.5) were similarly associated with gout. In women, a history of alcohol intake was the only significant risk factor associated with gout (odds ratio = 5.0). These findings suggest that in a population where gout was previously rare, changing dietary habits and lifestyle, together with improving socioeconomic conditions are contributing significantly to the increasing prevalence of the disease.
Gonococcal endocarditis in a patient with systemic lupus erythematosus.
There is mounting evidence that patients with systemic lupus erythematosus (SLE) are prone to disseminated neisserial infections. We describe the first proven case of gonococcal endocarditis affecting the pulmonary valve in a patient known to have SLE. The clinical clues and pitfalls in diagnosis are discussed, and the role of echocardiography is highlighted. Possible reasons for the association of gonococcal endocarditis with SLE include pre-existing Libman. Sacks endocarditis, complement deficiency and abnormalities of the reticuloendothelial system.
Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature.
We analyzed the clinical, radiologic, and immunologic characteristics of 50 patients with chorea and the antiphospholipid syndrome (APS) (6 from our clinics and 44 from a MEDLINE computer-assisted review of the literature from 1985 through 1995). Forty-eight (96%) patients were female and 2 (4%) were male. Twenty-nine (58%) patients had defined systemic lupus erythematosus (SLE), 6 (12%) had "lupus-like" syndrome, and 15 (30%) patients had "primary" APS. Mean age of patients in this series was 23 +/- 12 years (range, 6-77 yr); mean age at presentation of chorea was 21 +/- 12 years (range, 6-77 yr). In 11 (22%) patients, the onset of chorea was in childhood (6-14 yr), and in 2 (4%) patients it presented at 60 years or more. Six (12%) patients developed chorea soon after they started taking estrogen-containing oral contraceptives, 3 (6%) developed chorea gravidarum, and 1 (2%) patient developed chorea shortly after delivery. Most patients (66%) presented only 1 episode of chorea. Chorea was bilateral in 55% of patients. Computed tomography and magnetic resonance imaging scans reported cerebral infarcts in 35% of patients. The following antibodies were detected: lupus anticoagulant (92%), anticardiolipin antibodies (91%), antinuclear antibodies (82%), anti-DNA (59%), anti-Ro (10%), anti-RNP (8%), anti-La (2%), and anti-Sm (2%). The chorea in these patients responded to a variety of medications, for example, steroids, haloperidol, antiaggregants, anticoagulants, or a combination of therapy, usually prescribed in the presence of other manifestations of APS or SLE. However, many patients responded well to haloperidol and to the discontinuation of oral contraceptives if this was the precipitating factor.
Autoantibodies in black South Africans with systemic lupus erythematosus: spectrum and clinical associations.
The clinical features and autoantibody profile of 111 black South Africans (103 females and 8 males) with systemic lupus erythematosus were retrospectively analysed. The mean age of the patients was 35.1 years and mean duration of disease 3.5 years. The commonest clinical and laboratory features noted were arthritis (62.2%), hypocomplementaemia (61.2%), haematological abnormalities (60.5%) and malar rash (55%). The serological abnormalities included antinuclear antibodies (98.2%), anti-dsDNA (66.2%), anti-Sm (44.2%), anti-RNP (65.5%), anti-Ro (60.5%), anti-La (28.4%) and rheumatoid factor (10.1%). Positive clinicoserological associations observed included: combination of anti-dsDNA antibodies and low C4 levels with renal disease; anti-dsDNA antibodies with cutaneous vasculitis; anti-Sm antibodies with psychosis; anti-RNP antibodies with Raynaud's phenomenon; anti-Ro antibodies with renal disease, psychosis and malar rash. Anti-La antibodies showed a weak negative association with serositis and Raynaud's phenomenon. Most of these clinical correlates are consistent with past studies. The high frequency of anti-Sm and anti-RNP antibodies is similar to the observations in African-Americans and Afro-Caribbeans.
Autoantibodies in black South Africans with systemic lupus erythematosus: spectrum and clinical associations.
The clinical features and autoantibody profile of 111 black South Africans (103 females and 8 males) with systemic lupus erythematosus was retrospectively analysed. The mean age of the patients was 35.1 years and mean duration of disease 3.5 years. The commonest clinical and laboratory features noted were arthritis (62.2%), hypocomplementaemia (61.2%), haematological abnormalities (60.5%) and malar rash (55%). The serological abnormalities included antinuclear antibodies (98.2%), anti-dsDNA (66.2%), anti-Sm (44.2%), anti-RNP (65.5%), anti-Ro (60.5%), anti-La (28.4%) and rheumatoid factor (10.1%). Positive clinicoserological associations observed included: combination of anti-dsDNA antibodies and low C4 levels with renal disease; anti-dsDNA antibodies with cutaneous vasculitis; anti-Sm antibodies with psychosis; anti-RNP antibodies with Raynaud's phenomenon; anti-Ro antibodies with renal disease, psychosis and malar rash. Anti-La antibodies showed a weak negative association with serositis and Raynaud's phenomenon. Most of these clinical correlates are consistent with past studies. The high frequency of anti-Sm and anti-RNP antibodies is similar to the observations in African-Americans and Afro-Caribbeans.
Cystic lung disease in systemic sclerosis: a case report with high resolution computed tomography findings.
A 31-year old black female presented with limited scleroderma. Although she had no chest symptoms, chest radiographs showed a basal reticular pattern with large cysts in both lung fields. High resolution computed tomography revealed almost complete effacement of normal lung architecture by multiple large cysts, honeycombing and interstitial fibrosis. Cystic lung disease is an uncommon manifestation of interstitial lung disease in systemic sclerosis, and its natural history needs to be better defined.
Interethnic differences in the association of tumor necrosis factor promoter polymorphisms with systemic lupus erythematosus.
OBJECTIVE: To assess the role of polymorphisms in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene in susceptibility to systemic lupus erythematosus (SLE). METHODS: Two ethnically different populations of patients with SLE (49 white from the UK and 49 black from South Africa) were genotyped for TNF-238 and TNF-308 polymorphisms using amplification refractory mutation system-polymerase chain reaction (PCR). HLA-DR genotypes were assigned to the patients and controls either serologically or by PCR and sequence specific oligonucleotides. The frequencies of the respective variants were compared between patients and ethnically matched controls. RESULTS: No significant differences were found in the frequency of the TNF-238 variants in either ethnic group. At TNF-308, the TNF2 variant was significantly increased (p = 0.04) in white patients with SLE compared to controls. However, TNF2 was strongly associated with HLA-DR3 (p = 0.00002), which also showed a strong trend of increase in the white patients (p = 0.06). In contrast, in the black patients with SLE in whom DR2 but not DR3 was increased, the frequency of TNF2 was actually reduced rather than increased. CONCLUSIONS: The increase of TNF2 in Caucasians with SLE is most likely due to linkage disequilibrium between TNF2 and DR3. Furthermore, the observation that TNF2 seems to be reduced in blacks with SLE strongly suggests this polymorphism is not an independent risk factor for SLE. Overall, our data indicate that the TNF-238 and TNF-308 promoter polymorphisms do not confer susceptibility to SLE.
HLA class II antigens associated with systemic lupus erythematosus in black South Africans.
OBJECTIVE: To assess the associations of HLA class II antigens with systemic lupus erythematosus (SLE) in black South Africans. METHODS: HLA-DRB1 genotype frequencies assigned by polymerase chain reaction (PCR) amplification and sequence specific oligonucleotide probes were compared between 49 black SLE patients from Baragwanath Hospital and 87 ethnically matched controls. HLA-DQA1 and -DQB1 genotypes were also assigned in 45 of the SLE patients and 74 controls by PCR using sequence specific primers. RESULTS: HLA-DRB1*02 was increased in the patients compared with controls (odds ratio = 3.67; 95% confidence interval = 1.49 to 9.02; p < 0.005). HLA-DQB1*0201 was not associated with development of the disease itself, but was associated with the presence of Ro antibodies (p = 0.01). HLA-DRB1*03 was less strongly linked to DQB1*02 in this population than in white populations and was not associated with SLE. CONCLUSIONS: In black South Africans there is evidence for a locus on DR2 haplotypes contributing to SLE. Another gene, possibly HLA-DQB1*02, not linked to DR2 is involved in the subset of patients exhibiting Ro antibodies.
Interleukin 1 beta, hand and foot bone mineral content and the development of joint erosions in rheumatoid arthritis.
OBJECTIVE: To assess the relationship between plasma levels of the cytokine interleukin-1 beta (IL-1 beta) and the progression of rheumatoid arthritis (RA). METHODS: Two subgroups of patients, one with persistently raised ESR (>/= 50 mm/hour, n = 16, group A) and one with persistently low ESR (</= 28 mm/hour), n = 18, group I) were chosen to represent stable extremes of inflammatory activity from a prospective study of 106 patients with active RA studied over one year in a single centre. The change from baseline in hand, foot and calcaneal bone mineral content measured by single photon absorptiometry and radiographic score of joint damage was measured over 12 months, together with plasma IL-1 beta and erythrocyte sedimentation rate. RESULTS: Significant progression of joint damage occurred in both subgroups over one year (p < 0.0001, paired t test) though progression was significantly less in the subgroup with low ESR (p < 0.05, ANOVA). Hand and foot bone mineral content decreased by almost 10% in the subgroup with raised ESR (p < 0.005, paired t test). Stepwise linear regression analysis revealed significant independent relationships between radiographic progression over one year and plasma IL-1 beta and ESR (multiple R 0.674, F = 11.64, p < 0.0002). No such relationships were observed for changes in bone mineral content parameters. CONCLUSIONS: Plasma IL-1 beta levels correlate weakly with progression of joint damage though not with loss of peripheral bone density in RA. A significant reduction in peripheral bone mineral content occurs over one year in patients with active RA with persistently raised ESR.
HLA-DR antigens and rheumatoid arthritis in black South Africans: a study of ethnic groups.
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Infective endocarditis, rheumatoid factor, and anticardiolipin antibodies.
Serum samples from 22 patients with infective endocarditis were analysed for the presence of antibodies to cardiolipin, false positive Venereal Disease Research Laboratory (VDRL) test, and rheumatoid factor in order to determine the prevalence of anticardiolipin antibodies, their level, and to ascertain whether there was any correlation with the presence of rheumatoid factor. Although the latex test was positive in 10/22 (45%) patients, anticardiolipin antibodies, usually of a low level, were raised in only four (18%), and the VDRL test was positive in two patients in whom other antibodies were negative. These results show a clear discordance between these three tests, indicating that B cell production of these antibodies is separate and distinct. As with other infections which result in anticardiolipin antibody production, no thrombotic events were encountered.
Photosensitivity and anti-Ro (SS-A) antibodies in black patients with systemic lupus erythematosus (SLE).
Ninety-two patients with SLE, 36 black and 56 white, were studied prospectively for photosensitivity and anti-Ro (SS-A) and anti-La (SS-B) antibodies. Photosensitivity was found in 19% of black patients, compared to 71% of white patients (p = 0.001). Anti-Ro antibodies were found in 69% of black and 54% of white patients (p = 0.013). Photosensitivity was present in 87% of Ro-positive white patients and in 54% of Ro-negative white patients (p = 0.007). However, in black patients with SLE there was a strong negative association: 4% of Ro-positive patients were photosensitive while 55% of Ro-negatives were photosensitive (p = 0.001). This suggests that black SLE patients may possess a factor which 'blocks' photosensitivity, perhaps by preventing local tissue damage caused by the interaction of Ro antibodies and ultraviolet light.
Computed tomographic findings in amebic brain abscess.
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