Mortality and prognostic factors in Spanish patients with systemic sclerosis

OBJECTIVE: To determine survival and mortality in a cohort of Spanish patients with scleroderma (systemic sclerosis, SSc) and to analyse whether survival is influenced by demographic, clinical or immunological variables or the extent of skin involvement. METHODS: The study included 79 patients diagnosed with SSc and taking part in a study to determine the extent of sclerosis, visceral involvement and immunological alterations. We studied the number of observed and expected deaths (the expected number being based on age- and sex-specific rates in the background population) and derived standardized mortality ratios with their 95% confidence intervals (CI). Cumulative survival after onset of the first symptom was estimated according to the Kaplan-Meier method. The Cox method was used to identify the prognostic factors. RESULTS: The mortality rate was 0.0249 deaths per person-year. Survival at 15 yr was 0.62 (95% CI 0.410-0.778). The standardized mortality ratio was 429.4% (95% CI 222-750). On crude analysis, lung involvement [forced vital capacity (FVC) <70%, pulmonary hypertension], SSc renal crisis, an active capillaroscopic pattern, pericardial effusion and age over 60 yr at diagnosis were associated with shorter survival. On multivariate analysis, only age at diagnosis over 60 yr, FVC <70% and SSc renal crisis were independent prognostic factors. CONCLUSIONS: The mortality rate associated with SSc showed a four-fold increase compared with the background population. Lung involvement and sclerodermal renal crisis were found to be independently associated with reduced survival.     

Autoantibodies to RNA-polymerases in Italian patients with systemic sclerosis

OBJECTIVE: To assess the frequency and clinical correlates of the systemic sclerosis-related autoantibodies to RNA polymerases in Italian patients. METHODS: Sera from 115 patients with systemic sclerosis (SSc) and 10 patients with systemic sclerosis-overlap syndromes recruited from a single center in northern Italy were investigated for antibodies to RNA polymerase I, II, and III by means of immunoprecipitation using 35S-labeled HeLa cell antigen extract. Twenty-five normal volunteers and 91 patients with different connective tissue diseases were studied as a control group. RESULTS: Antibodies to RNA-polymerases were found in 14/115 SSc patients (12.1%). None of the normal controls and none of the patients with other connective tissue diseases, including overlap syndromes, were positive. Antibodies reacting with RNA-polymerase I and III (+/- RNA-polymerase II) were found in 9/115 patients (7.8%) and were mutually exclusive with respect to other scleroderma-related autoantibodies. Isolated anti-RNA polymerase II reactivity was found in 5 patients and was associated with anti-topoisomerase I antibodies in 4 cases. Anti-RNA-polymerase I and III antibodies were associated with diffuse cutaneous involvement and male gender. Only two patients from our series had scleroderma renal crisis, and one of them had anti-RNA polymerase antibodies. CONCLUSIONS: Anti-RNA-polymerase antibodies appear to be less frequent in Italian patients than in Caucasian patients from the United Kingdom or USA. This might be associated with the lower frequency of scleroderma renal crisis.     

HLA-DR antigens and anticardiolipin antibodies in northern Italian systemic lupus erythematosus patients

Eighty systemic lupus erythematosus (SLE) patients attending 3 clinical centers were evaluated immunologically and immunogenetically. No HLA class II antigens were found to be significantly associated with SLE in these patients. A highly significant (P = 6.17 x 10(-7) association was observed between anticardiolipin antibodies and DR7. A lesser association (P less than 0.025) was also observed between DR2 and/or DR3 and anti-Ro (SS-A) antibodies. No relationship was found between any DR antigen and anti-Sm/RNP, anti-double-stranded DNA, or anti-La (SS-B) antibodies.     

Survival prognostic factors and markers of morbidity in Spanish patients with systemic sclerosis

OBJECTIVE—To identify survival prognostic factors and markers of morbidity among patients with systemic sclerosis (SSc).
PATIENTS AND METHODS—The study included 72 patients diagnosed with SSc. According to the extent of skin involvement, three groups of patients were established: group 1, without sclerosis and with sclerosis of fingers and neck; group 2, with sclerosis of face and distal to elbows and knees; group 3, with generalised sclerosis including the trunk. All patients were included in a study protocol to determine visceral involvement. Cumulative survival after first symptom has been estimated according to the Kaplan-Meier method. The association between a hypothetical prognostic factor and cumulative survival after first symptom was assessed by log rank test. The association between a hypothetical risk factor and the prevalence of severe morbity was assessed by the odds ratio. Multiple logistic regression models were used to identify the main predictors of severe morbidity.
RESULTS—Survival was estimated to be 85% 10 years after first SSc symptom. Survival was higher among SSc patients with skin involvement distal to elbows and knees than among the rest of patients; a forced vital capacity (FVC) on spirometry lower than 70% of expected value was associated with a shorter survival, even after adjustment for diffuse SSc. Skin involvement proximal to elbows or knees was associated with a higher prevalence of severe morbidity (OR = 46.57; p<0.001). According to a multiple logistic regression, severe morbidity was higher among patients with skin involvement proximal to knees or elbows (OR = 40.92; p<0.001) or among patients with pulmonary hypertension detected by Doppler echocardiography (OR = 23.66 p<0.001).
CONCLUSIONS—In patients with SSc the extent of skin sclerosis was found to be a determining factor on the prognosis. According to skin sclerosis extent two main subsets of SSc patients with different survival incidence and degree of morbidity could be clearly established: limited SSc, formed by patients with no skin sclerosis or with sclerosis distal to elbows and knees and diffuse SSc, formed by patients with skin sclerosis distal and proximal to elbows and knees. Moreover, lung involvement (FVC<70% on survival study and pulmonary hypertension on morbidity study) was an important and independent prognostic factor.

     

Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis

Our objective was to study the presence of microchimerism in a series of 47 female Spanish patients with scleroderma (SSc) and to compare with a control group. Polymerase chain reaction was used to identify Y-chromosome sequences in DNA extracted from peripheral blood cells. Y-chromosome sequences were found in DNA from peripheral blood cells in four out of 47 (8.5%) patients with scleroderma (two limited and two diffuse) and in two out of 40 (5%) healthy women (no statistical differences were found). When we compared SSc patients and healthy controls who had had at least one male child, four out of 29 (13.7%) and two out of 26 (7.6%) had microchimerism respectively (no statistically significant differences were found). Patients with both scleroderma and persistent microchimerism had had a male offspring. Foetal microchimerism does not seem to play a major role in most cases of female Spanish patients with SSc.     

Geographic distribution of cervical cancer-associated human leucocyte antigens and cervical cancer incidence in Finland

Cervical cancer (CxCa) is a long-term sequelae caused by persistent human papillomavirus (HPV) infection. Genetic susceptibility to the persistent infection and CxCa is associated with certain human leucocyte antigen (HLA) types. The same susceptibility genes may also determine whether a woman will be protected against the persistent infection and against CxCa by HPV vaccination or not. A systematic review of literature identified following HLAs to be associated with CxCa: A11 (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.1-2.0); B7 (1.5, 1.1-2.0); B15 (0.6, 0.4-0.8); DR2 (1.2, 1.1-1.4) and DR6 (0.6, 0.5-0.8). In the Caucasian population, HLA-B7 and DR6, and DR2 and B15 antigens showed at least borderline associations. In view of a bone marrow donor registry at the Finnish Red Cross and the Finnish Cancer Registry, we created geographic distribution maps of index HLA frequencies and CxCa incidence in the fertile-aged Finnish population. Increased incidence of CxCa was found in a region of western coastal Finland, where frequency of two CxCa susceptibility genes (HLA-DR2 and B7) was increased, and frequency of one CxCa resistance gene (HLA-B15) was decreased. Whether or not HLA type determines also regional susceptibility to persistent HPV infection, and the success of HPV vaccination in preventing both the persistent infection and CxCa warrants further investigation.     

Pulmonary hypertension in Spanish patients with systemic sclerosis. Data from the RESCLE registry

Clinical Rheumatology - Our objective was to evaluate the pulmonary hypertension (PH) data for Spanish patients with systemic sclerosis (SSc), define the PH types and determine the associated...     

Analysis of lymphocyte subpopulations in systemic sclerosis.

Systemic sclerosis (SSc) is a chronic inflammatory connective-tissue disease of unknown etiology, characterized by fibrosis and microvascular injury in affected organs. It has become clear that the activated cellular-immune system plays a central role in the pathogenesis of SSc. This study analyzes the numbers of lymphocyte subpopulations and their relations with clinical and laboratory manifestations. We studied a group of 42 patients with SSc and a group of 28 matched normal controls by flow cytometry using the lymphocyte cell-surface markers CD2, CD3, CD4, CD8, CD19, CD25, CD45RA, CD56, CD71, HLA-DR, TCR alpha/beta, and TCR gamma/delta. Patients with SSc had similar percentages of CD2+, CD3+, CD3+ CD4+, CD3+, CD8+, CD25+, CD4+ CD45RA+, CD8+ CD45RA+, CD71+ cells, and CD4+/CD8+ cell ratio when compared to normal controls. In contrast, the percentages of TCR gamma/delta cells were significantly lower in SSc patients with diffuse and late-stage disease with pulmonary involvement, muscle involvement, and the presence of anti-Scl-70 antibodies. Patients with diffuse SSc in early- and late-stage disease had significantly increased percentages of HLA-DR in CD4+ and CD8+ cells. Patients with late-stage disease had increased percentages of CD4+ CD45RA+ T-cells. Patients with limited and early-stage disease had smaller percentages of B-cells (CD19+). Patients with diffuse and late-stage disease had smaller percentages of NK-cells (CD56+). These results suggest that T-, B-, and NK-cell alterations may be involved in the onset of the disease, and/or in the perpetuation of disease, and may eventually be useful as a prognostic indicator in selected patient subgroups.     

Disease expression and class II HLA antigens in systemic lupus erythematosus.

The aim of this investigation was to examine the relationship between Class II HLA antigens and disease expression in systemic lupus erythematosus (SLE). HLA-DR and DQ antigen frequency was studied serologically in 217 SLE patients followed prospectively and compared to 320 healthy controls. The relationship between HLA antigens and the presence of disease manifestations, as well as death was investigated in 117 SLE patients enrolled within the first year of their disease. A univariate analysis confirmed the association between HLA-DR3 and SLE. HLA antigen DR1, DR6, DR7, DQw1 and DQw3 were decreased in patient group compared to the controls. A logistic regression model showed a significantly negative association with HLA-DR1, DR6 and DR7, and a positive association with HLA-DR3. The reduced frequency of HLA-DQw1 and DQw3 was maintained using a logistic procedure. Cox Proportional Hazards models revealed no association between HLA-Class II antigens and death. Logistic regression models revealed no associations between central nervous system (CNS) disease nor musculoskeletal manifestations with any of the DR antigens. There was a trend towards a lower frequency of HLA-DR6 in patients with renal involvement and lower prevalence of HLA-DR1 and HLA-DR7 in patients with vasculitis.     

Human leucocyte antigens in Crohn's disease and ulcerative colitis

The frequency of occurrence of 15 of the commoner human leucocyte antigens was determined in 18 patients with Crohn's disease and in 16 patients with ulcerative colitis, using an in-vitro lymphocyte cytotoxicity test (Harris, Wentzel, Cocking, Dodsworth, and Ukaejiofo, 1970). The overall results showed that, with the exception of human leucocyte antigen 3 in patients with Crohn's disease, in neither disease was there any major difference in any of the other antigen frequencies compared with a panel of 50 healthy controls. Nor was there an excess frequency of any particular antigen occurring in both Crohn's disease and colitis.     

Association of HLA class II genes with systemic sclerosis in Koreans

OBJECTIVE: To investigate HLA class II associations with systemic sclerosis (SSc) in Koreans according to anti-topoisomerase I (anti-topo I), anti-centromere antibody (ACA), and anti-U1 ribonucleoprotein (RNP) status. METHODS: HLA class II alleles (DRB1, DRB5, DQB1) were determined by DNA typing in 200 healthy control subjects and 74 patients with SSc: 35 anti-topo I positive, 3 ACA positive, and 19 anti-U1 RNP positive; among them were 34 diffuse and 40 limited subtypes, and 16 overlap syndrome. RESULTS: Anti-topo I positive SSc was strongly associated with DRB1*1502 compared with both controls (23% vs 5%; Pcorr = 0.003) and anti-topo I negative patients (23% vs 3%; p = 0.009); our study confirms observations in Japanese. HLA-DR 67FLEDR71, especially 38V-67FLEDR71 sequence (carried on DRB5*0102 in linkage disequilibrium with DRB1*1502, DRB1*0802, DRBI*1101), showed the strongest association with anti-topo I response (46% vs 16% in controls; Pcorr = 0.001), and 38L-67FLEDR71 group alleles were not associated with anti-topo I response. Anti-topo I response was not significantly associated with HLA-DQB1 alleles in Koreans. There were only 3 ACA positive patients, and all patients had DRB1*1501 and DQB1*0602 as heterozygotes. Anti-U1 RNP occurred at a high frequency (63%) among patients with overlap syndrome, and was not associated with HLA-DR or DQ genes. Among anti-topo I negative patients, diffuse and limited subtypes of SSc were significantly associated with DRB1*0803 (47% vs 15% in controls; Pcorr < 0.05) and DRB1*1501 (50% vs 17% in controls; Pcorr < 0.01), respectively. These HLA associations have not been reported in other ethnic groups and possible associations with certain autoantibody subsets remain to be confirmed. CONCLUSION: HLA-DR gene has a primary association with anti-topo I response, and HLA-DR 38V-67FLEDR71 group alleles including DRB5*0102 (in linkage disequilibrium with DRB1*1502) show the strongest association with anti-topo I response in Korean patients with SSc.     

Autoantibodies to leucocyte antigens in hydralazine-associated nephritis.

Clinical and laboratory findings and drug history were studied in 17 patients with suspected hydralazine-associated nephritis, five of whom only had renal disease, while twelve also had extrarenal manifestations. Renal biopsies revealed extracapillary proliferative or focal segmental proliferative glomerulonephritis in 10 patients, and tubulo-interstitial nephritis in five patients. Antinuclear antibody (ANA) was found in 16 patients, but none of the 14 patients tested had antibodies to DNA. Tests for antibodies to myeloperoxidase (anti-MPO) and antibodies to neutrophil cytoplasm antigen (ANCA) were performed by ELISA. Twelve of the 14 patients tested had anti-MPO; five of these 14 patients had ANCA, while one had borderline levels. These findings suggest that hydralazine facilitates the induction of a systemic disease with multiple autoantibody production.     

Loss of epidermal Langerhans' cells and endothelial cell HLA-DR antigens in the skin in progressive systemic sclerosis

Skin biopsies from the volar aspect of the forearm were studied in 26 patients with progressive systemic sclerosis (PSS) (16 diffuse, 10 CREST) and 4 controls using monoclonal antibodies against Langerhans' cells, T lymphocytes, macrophages, B lymphocytes, NK/K cells and HLA-DR antigen(s). Langerhans' cells were reduced or absent (anti-T6, anti-HLA-DR) in 19 of 20 clinically involved and in all 6 uninvolved PSS skin biopsies. Electron microscopic studies of 3 PSS patients indicated a reduction in the number of Langerhans' cells, with normal morphology of the remaining. HLA-DR antigen(s) on dermal endothelial cells were absent or reduced in 8 of 20 involved and 5 of 6 uninvolved PSS skin biopsies, but were present on the surface of dermal mononuclear cells presumably representing activated T lymphocytes. Increased numbers of dermal macrophages were found in 19% of PSS biopsies compared with controls. Absence of Langerhans' cells appears to represent the most widespread immunopathological feature of PSS. It is also associated with absent endothelial HLA DR surface antigens and activated T lymphocytes within the dermis.