Thyroid dysfunction in a prospectively followed series of patients with progressive systemic sclerosis

Thirty-nine patients with progressive systemic sclerosis (PSS) in stable clinical conditions were extensively evaluated for the presence of thyroid disease. Two patients had previously undetected hypothyroidism while 7 additional patients had normal serum thyroid hormone levels but an exaggerated TSH response to thyrotropin-releasing hormone (TRH) administration, consistent with subclinical hypothyroidism. Four of the 9 subjects with abnormal TRH responses had positive antithyroid antibodies and of the remaining 5, 4 had been on chlorambucil or prednisone. Basal TSH and TSH response to TRH were significantly higher in PSS patients as a group when compared to a control group and increased with increasing duration of PSS. Serum antithyroid antibodies (antithyroglobulin and/or antimicrosomal antibodies) were positive in 18% and thyroid scans were abnormal in 18% of the patients. The euthyroid sick syndrome was not seen. Our findings indicate an increased frequency of, sometimes previously unsuspected, clinical and subclinical hypothyroidism in stable PSS patients which appears to be autoimmune in nature and becomes more prevalent with increased PSS duration. Careful and regular monitoring of the thyroid function in PSS patients is advisable.     

Primary Sjögren’s syndrome and risk of ischemic stroke: a nationwide study

Few studies are available on the risk of ischemic stroke after a diagnosis of primary Sjögren’s syndrome (PSS). This study investigated whether PSS increased the risk of ischemic stroke in a large, nationwide cohort. Data for 4,276 patients who were newly diagnosed with PSS from 2000 to 2006 and who did not have a stroke prior to diagnosis of PSS were obtained from the Registry of Catastrophic Illness in Taiwan. For each PSS patient, data for ten controls (matched by age, gender, comorbidities, and enrollment date) without systemic autoimmune disease or previous stroke were obtained from the Longitudinal Health Insurance 2000 database. All study subjects were followed up from the date of enrollment until they developed ischemic stroke, died, or until the end of 2006, whichever was earliest. To investigate if PSS was an independent factor in determining the risk of developing ischemic stroke, a Cox regression model was used with adjustment for age, gender, and comorbid disorders. Among 4,276 PSS patients and 42,760 controls, 669 subjects (51 PSS patients and 618 controls) developed ischemic stroke during the mean 3.7-year follow-up period (interquartile range 2.2–5.2 years). Patients with PSS and controls had a similar incidence of ischemic stroke occurrence (3.17/1,000 vs. 3.90/1,000 person years). Multivariate analysis adjusted for baseline covariates indicated that PSS did not increase the risk of ischemic stroke (adjusted hazard ratio: 0.84, 95 % confidence interval: 0.63–1.12, P?=?0.244). PSS is not associated with an increased risk of ischemic stroke subsequent to diagnosis.     

The relationship of arrhythmias and conduction disturbances to other manifestations of cardiopulmonary disease in progressive systemic sclerosis (PSS)

Disorders of rhythm and conduction are characteristic of the cardiac involvement in progressive systemic sclerosis (PSS), but their over-all frequency in PSS is not well established. Therefore, 46 ambulatory patients with PSS underwent several tests of cardiopulmonary function, including a 24-hour continuous electrocardiogram (Holter monitor). Conduction disturbances (sinus node dysfunction, first-degree heart block, pre-excitation), supraventricular arrhythmias (supraventricular tachycardia, atrial fibrillation, premature contractions of atrial or junctional origin) and ventricular arrhythmias (ventricular tachycardia, multifocal premature contractions) were observed on Holter monitoring in 26 subjects. Although these arrhythmias and conduction disorders were predictably observed in patients who complained of palpitations or syncope, or who had an electrocardiogram which showed first-degree heart block, ventricular bigeminy, left anterior superior hemiblock, prolonged p wave, right or left axis deviation, right or left ventricular hypertropy, pathologic Q waves or low voltage, they were often found in patients who lacked other clinical evidences of heart disease. Arrhythmias and conduction disturbances were not significantly more frequent among patients with cardiomegaly or interstitial change on chest roentgenogram nor were they related to the presence or severity of abnormal lung function. This study suggests that Holter monitoring may be a valuable adjunct in evaluating heart disease in PSS.     

Longitudinal changes in lung function and respiratory symptoms in progressive systemic sclerosis. Prospective study

Most patients with progressive systemic sclerosis (PSS) exhibit lung involvement. However, the natural history of lung disease in PSS remains poorly defined. To evaluate lung function over time in PSS, a battery of lung function tests were prospectively performed serially between 1973 and 1982 in 61 patients with PSS. Functional indexes of restriction (vital capacity and total lung capacity) and diffusion impairment (diffusing capacity) showed greater-than-expected annual rates of change. Male subjects showed a trend toward faster declines in forced vital capacity, forced expired volume in one second, total lung capacity, and functional residual capacity and a more rapid increase in static recoil pressure at 90 percent of total lung capacity than did female subjects. Nonsmokers had greater rates of decline in total lung capacity and static lung compliance (but not in forced vital capacity or diffusing capacity) and a greater rate of increase in static recoil pressure than did current and former smokers. Level of lung function at initial study visit, age, race, and chlorambucil therapy had no significant effect on the annual rates of change in lung function, whereas longer duration of disease prior to study entry was associated with a slower annual decrease in lung volumes. Between the first and last visits (mean interval 3.1 years, maximum nine years), the frequency of abnormality in pulmonary function test results showed significant change only in the diffusing capacity (60 percent increasing to 82 percent) and static lung compliance (40 percent increasing to 54 percent), whereas the frequency of respiratory symptoms showed little change. These findings indicate an overall indolent progression of PSS-related lung disease, with substantial individual variability.     

Insulin resistance is a risk factor for progression to Type 1 diabetes

Aims/hypothesis Glucose homeostasis is determined by an interplay between insulin secretion and insulin action. In Type 1 diabetes, autoimmune destruction of pancreatic beta cells leads to impaired insulin secretion. However, the contribution of impaired insulin action (insulin resistance) to the development of Type 1 diabetes has received little attention. We investigated whether insulin resistance was a risk factor for progression to Type 1 diabetes.Methods Islet-antibody-positive first-degree relatives of Type 1 diabetes probands were followed for 4.0 years (median). Insulin secretion was measured as first-phase insulin response (FPIR) to intravenous glucose. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-R). We compared subjects who progressed (n=43) and subjects who did not progress (n=61) to diabetes, including 21 pairs matched for age, sex, islet antibodies and FPIR.Results Progressors had higher insulin resistance relative to insulin secretion at baseline (median HOMA-R : FPIR 0.033 vs 0.013, p<0.0001). According to Cox proportional hazards analysis, islet antibody number, FPIR, fasting plasma glucose, fasting serum insulin, HOMA-R and log(HOMA-R : FPIR) were each predictive of progression to diabetes. However, log(HOMA-R : FPIR) (hazard ratio 2.57 per doubling, p<0.001) was the only metabolic variable independently associated with progression. In the matched comparison, progressors had higher fasting glucose, fasting insulin, HOMA-R and HOMA-R : FPIR, both at baseline and during the follow-up pre-clinical phase.Conclusions/interpretation Relatives positive for islet antibodies who progress most rapidly to diabetes have a subtle disturbance of insulin–glucose homeostasis years before the onset of symptoms, distinguished by greater insulin resistance for their level of insulin secretion. Taking steps to reduce this insulin resistance could therefore delay the development of Type 1 diabetes.An erratum to this article can be found at     

Evaluation of thrombotic children with malignancy

The purpose of this study was to evaluate inherited and acquired prothrombotic risk factors among children with malignancies who have thrombosis and emphasize the importance of inherited prothrombotic risk factors. Thirty-seven consecutive children with thrombosis and malignancy were included in this study. The patients were evaluated separately for time of development of thrombosis, insertion of a central venous line (CVL), history of l-asparaginase usage, and recent infections. Prothrombotic risk factors such as factor V G1691A and prothrombin G20210A mutation, protein C, protein S, antithrombin III deficiencies, factor VIII and lipoprotein(a) elevation, and antiphospholipid antibodies were analyzed for all patients. Of 387 children with thrombosis, 37 (9.5%) had a malignancy. Thrombosis was detected in 9 patients at the time of diagnosis, during maintenance therapy in 25 patients, and after the discontinuation of treatment in 3 patients. One or two additional prothrombotic risk factors other than l-asparaginase therapy and insertion of central venous lines were present in 20 of these patients (54%). It was found that eight patients had the factor V G1691A mutation in the heterozygote state. One of them had the factor V G1691A mutation associated with a history of infection and one patient had the factor V G1691A mutation associated with factor VIII elevation. One had the the prothrombin G20210A mutation in the heterozygote state, four had lipoprotein(a) elevation, two had factor VIII elevation, one had a decreased protein S level, one had a decreased protein C level, one had antiphospholipid positivity, and two had histories of infection. Malignancy is an important risk factor for the development of childhood thrombosis. However, the risk of thrombosis increases when accompanied by additional prothrombotic risk factors. For this reason, especially children with malignancy and at high risk for the development of thrombosis, such as those who have received l-asparaginase or a replaced CVL during their therapy, might be screened for additional prothrombotic risk factors and appropriate measures might be taken to prevent the development of thrombosis.     

TET2 mutations in secondary acute myeloid leukemias: a French retrospective study

Ten-eleven translocation 2 (TET2) mutations have been involved in myeloid malignancies. This retrospective study aims at evaluating the frequency and impact of TET2 mutations in 247 secondary acute myeloid leukemia cases referred to as myelodysplasia-related changes (n=201) or therapy-related (n=46) leukemias. Mutation of at least one copy of the TET2 gene was detected in 49 of 247 (19.8%) patients who presented with older age, higher hemoglobin level, higher neutrophil and monocyte counts, and lower platelet count. TET2 mutations were significantly less frequent in therapy-related (8.7%) than myelodysplasia-related changes (22.3%; P=0.035) leukemias and strongly associated with normal karyotype (P<0.001). TET2 mutations did not significantly associate with NPM1, FLT3-ITD or FLT3-D835, WT1, or N- or K-RAS mutations. Complete remission was achieved in 57% of evaluable patients who had received intensive chemotherapy. In this group, TET2 mutations did not influence the complete remission rate or overall survival.     

Ungueal capillaroscopy in fasciitis with eosinophilia: a distinctive feature of systemic scleroderma. Apropos of 15 cases

Eosinophilic fasciitis (EF) is a recently described disease whose distinction from progressive systemic sclerosis (PSS) is still being discussed. PSS has a characteristic microcirculation pattern. We performed nailfold microscopy on 15 patients with EF and compared the results to those of 98 PSS patients and 75 normal control subjects. EF patients have a normal microcirculation pattern (13/15) or discrete, non-specific anomalies: none had the typical capillary pattern associated with PSS and associated diseases. The findings of this study justify making a distinction between EF and PSS and demonstrate that nail fold microscopy can be a useful tool for an early differential diagnosis between these two disorders.     

Comparing functional results one year and ten years after ileal pouch-anal anastomosis for chronic ulcerative colitis

Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice for most patients with chronic ulcerative colitis. Long-term results, however remain undefined; the major concern is that function may deteriorate. PURPOSE: The aim of this study was to assess functional outcome in a subgroup of patients who have an IPAA for chronic ulcerative colitis for >10 years. METHODS: Among 1400 IPAA patients, 75 consecutive subjects (31 females and 44 males; median age 31 at operation) were identified who had the procedure prior to 1982. All patients had functional results recorded 1 year and 10 years following ileostomy closure. RESULTS: There were four deaths during the follow-up period; none were pouch related. Two patients refused ileostomy closure. Of the remaining 69 patients, there were 8 (11 percent) failures, leaving 61 subjects available for study. Stool frequency (7±3, mean±SD) remained unchanged. Of the 50 subjects with initially excellent daytime continence, 39 (78 percent) remained the same, 10 (20 percent) developed minor incontinence, and 1 developed poor control after 10 years. Four of 10 subjects (40 percent) with initial minor daytime incontinence remained unchanged, 4 (40 percent) improved, and 2 (20 percent) worsened. The one subject with poor control at one year was unchanged. Nocturnal fecal spotting increased over the 10-year period but not significantly (38 percent vs.52 percent;P=0.08). CONCLUSIONS: After IPAA, functional results in terms of stool frequency and rate of fecal incontinence did not deteriorate with time.Read at the meeting of The American Society of Colon and Rectal Surgeons, Chicago, Illinois, May 2 to 7, 1993.     

Measurement of endogenous plasma thrombopoietin in patients with acquired aplastic anaemia by a sensitive enzyme-linked immunosorbent assay

We measured the endogenous plasma concentration of thrombopoietin (TPO) in 76 patients with acquired aplastic anaemia (AA) by a sensitive sandwich enzyme-linked immunosorbent assay (ELISA). The plasma TPO concentrations were significantly higher in AA patients when compared to healthy control subjects ( P  < 0.0001) and there was a significant negative correlation between plasma TPO concentrations and platelet counts in 54 AA patients who had not received any platelet transfusions prior to sampling. On the other hand, there was no statistically significant correlation between the TPO concentrations and platelet counts in 22 AA patients who had previously received platelet transfusions.
We studied serial changes of plasma TPO concentration in 24 patients who showed an increase in their platelet counts following bone marrow transplantation or immunosuppressive (IS) therapy. Although a decrease in plasma TPO concentration was observed, levels remained above the range of normal healthy controls even in the patients who attained normal platelet counts following therapy. A decrease in TPO concentrations was observed in only half of the responders to IS therapy. Whether exogenous TPO will result in increased platelet counts in AA patients with high TPO levels remains to be determined.     

Herpes zoster and impaired cell-associated immunity to the varicella-zoster virus in patients with Hodgkin's disease.

Thirty-two patients with Hodgkin's disease and 12 normal donors were studied for their in vitro lymphocyte responsiveness to a membrane-associated varicella-zoster (VZ) antigen. When compared to the normal donors, patients with Hodgkin's disease in whom radiotherapy was recently completed and those with active, recurrent disease had markedly impaired cell-associated immunity to VZ antigen. In addition, there was a suggestion that patients in long-term remission who had received primary combined modality therapy (radiotherapy plus chemotherapy) had an impaired response when compared to normal persons or to patients who had received single modality therapy. Newly diagnosed, untreated patients with Hodgkin's disease did not differ significantly from normal persons as a group but two of six were unresponsive to the VZ antigen whereas all normal subjects were responsive. Most patients in remission for at least one year following therapy had normal in vitro responsiveness. In two patients herpes zoster developed after the demonstration of absent in vitro lymphocyte reactivity to the VZ antigen.     

Exhaled nitric oxide is elevated in patients with progressive systemic sclerosis without interstitial lung disease

BACKGROUND: Progressive systemic sclerosis (PSS) is a multisystem disorder of unknown etiology. Interstitial lung disease (ILD) is a major cause of mortality in this condition, and a major challenge in this regard is to identify parameters that would predict the onset or progression of ILD in patients with PSS. Abnormal cellularity of BAL fluid (BALF) has been demonstrated in patients with PSS without ILD. STUDY OBJECTIVES: We investigated exhaled nitric oxide (NO) as a noninvasive marker of pulmonary inflammation in patients with PSS with and without clinical and radiologic evidence of ILD. This was compared with the cellularity of BALF. Our hypothesis was that exhaled NO was elevated in patients with PSS without ILD who had abnormal BALF cellularity. SETTING: Pulmonology and rheumatology units of a university-based, tertiary referral hospital in Durban, South AFRICA: STUDY METHODS: Exhaled NO was measured using a chemiluminescence analyzer in 12 patients with PSS and ILD and in 12 patients without clinical or radiologic evidence of ILD and in 30 healthy control subjects. BAL was performed in patients with PSS with and without the presence of ILD and in six healthy control subjects. RESULTS: Subclinical inflammation was confirmed by increased inflammatory cell counts in BALF from patients with PSS without ILD. Exhaled NO (mean [SEM]) was elevated in patients with PSS without ILD at 9.6 (0.7) parts per billion (ppb) compared to patients with PSS and ILD at 6.2 (0.6) ppb (p < 0.001) and healthy control subjects at 6.3 (0.2) ppb (p < 0.001). CONCLUSION: Exhaled NO may therefore be an important noninvasive surrogate marker of inflammation in patients with PSS without ILD.     

Edrophonium Provocative Testing During Electrogastrography (EGG) (Effects on Dyspeptic Symptoms and the EGG)

The aim of this study was to determine whetheredrophonium induces dyspeptic symptoms and/or gastricmyoelectric changes in normal subjects and patients withfunctional dyspepsia. Eighteen normal controls and 28 patients with functional dyspepsiaunderwent electrogastrography (EGG) with edrophoniumadministration. After EGG recording with 1-hr fastingand 2-hr postprandial periods, subjects received anintravenous infusion of saline (placebo) followed byedrophonium 10 mg. After each injection, the EGG wasrecorded for 15 min and symptoms scored. Patients withfunctional dyspepsia had significantly more frequent gastrointestinal symptoms in response toedrophonium than normal controls. Edrophonium had noeffect on EGG dominant frequency, but increased thepower of the dominant frequency in both controls anddyspeptic patients. In the dyspeptic patients,reproduction of the patient's symptoms was associatedwith an increase in the power of the dominant frequency,whereas when no symptoms were produced, there was nochange in power. Overall, 21 of 28 dyspeptic patients(75%) had either an abnormal baseline EGG (N = 10) or anormal EGG and positive edrophonium test (N = 11). Inconclusion, edrophonium administration can reproduce symptoms in some dyspeptic patients.Symptoms after edrophonium administration may be relatedto either more vigorous gastric contractions and/orincreased visceral perception of normal gastric contractions.     

Fecal lactate and short bowel syndrome

In patients with short bowel syndrome (SBS), the carbohydrate overload to the colon may disturb the normal pattern of colonic fermentation with production ofd-lactic acid and subsequent development of a metabolicd-lactic acidosis. We measuredd-lactic acid in blood, urine, and feces, as well as the composition of fecal water and fecal reducing substances from 11 patients with SBS, comparing the results with those from normal subjects. The fecal water from patients with SBS was characterized by low pH, potassium, and volatile fatty acids, high osmotic gap, and high concentration ofl- andd-lactic acid. Five of 11 had abnormal amounts of fecal reducing substances. Fecald-lactic acid was increased in nine of 11 patients. However, none of these patients showedd-lactic acid in urine, and only one had a very low concentration in plasma. These results show thatd-lactic acid was overproduced in the colon of most of the patients with SBS. However, other factors such as absorption or impairedd-lactic acid metabolism may be necessary for a plasmatic increase ofd-lactic acid.Unidad de Terapia Nutricional, Hospital de Niños Sor Maria Ludovica, La Plata, Provincia de Buenos Aires, Argentina.Part of this work was presented at the International Symposium on Short Chain Fatty Acids, Strasbourg, France, September 1993.     

Response of patients with Hodgkin's disease to pneumococcal vaccine.

Postsplenectomy, 41 patients previously treated for Hodgkin's disease were given pneumococcal vaccine, and type-specific antibody levels were measured before and after immunization. Postimmunization antibody levels in patients with Hodgkin's disease were significantly lower than those in normal control subjects for 10 of the 12 serotypes measured. Mean postimmunization antibody level for patients (587 +/- 427 ng of antibody nitrogen/mL) was much lower than that for control subjects (1787 +/- 694). Antibody levels tended to increase with time from therapy for Hodgkin's disease, and several patients who had not received therapy for more than 3 years had normal responses to immunization. Despite vaccination, one patient developed pneumococcal meningitis and another, pneumococcal bacteremia. Both infected patients had low postimmunization mean antibody levels (282 and 137 ng/mL, respectively). Postsplenectomy sepsis in patients with Hodgkin's disease is related to a humoral immune deficiency probably induced by radiation and chemotherapy, and this immune deficiency persists for several years.     

Manometric asymmetry of the lower-esophageal high-pressure zone

The lower-esophageal high-pressure zones (LEHPZ) of 10 normal subjects, 8 patients with hiatus hernia and one patient with progressive systemic sclerosis (PSS) were investigated using a special 8-lumen recording catheter, the lateral orifices of which were spaced at 45° intervals around the circumference of the catheter. While similar pressures were recorded from all orifices within the stomach and esophageal body, pressures within the LEHPZ were found to be related to spatial orifice position. In normal subjects, but not in patients with hiatus hernia, a significantly higher localized pressure was detected by orifices directed toward the left posterior quadrant of the circumference of the distal esophagus, while a lesser, rather uniform, pressure was recorded from the other three quadrants. From the PSS patient, who had severe gastroesophageal reflux, a LEHPZ was detected only in the left posterior quadrant. The results suggest that the recorded LEHPZ represents the summation of two factors: an intrinsic force possibly due to a physiologic loweresophageal sphincter and an extrinsic force possibly resulting from compression of the distal esophagus by the lateral margin of the diaphragmatic hiatus.Partial support of this work was provided by the Gastro-Intestinal Research Foundation, Chicago, Illinois.     

Abdominal rectopexy for complete prolapse: Prospective study evaluating changes in symptoms and anorectal function

The effect of abdominal rectopexy on bowel function is difficult to assess in retrospective studies because preoperative bowel habit cannot be determined accurately. This study examined bowel symptoms and physiologic tests of anorectal function prospectively in 23 patients before and at three months after rectopexy. Rectopexy eliminated complete prolapse in all and stopped bleeding in 16 of 18 patients. Incontinence improved significantly. Constipation (<3 bowel actions per week or straining for more than 25 percent of defecation time) was relieved in 4 of 11 affected patients but developed in 5 of the 12 who were not constipated preoperatively. Since the median bowel frequency was 21 motions per week before surgery and 17 afterward, the main determinant of constipation was straining. Abdominal pain was relieved after rectopexy in 6 of 12 patients but developed in 3 of 13 who were pain-free before surgery. Three patients (13 percent) had a first-degree relative with rectal prolapse. Perineal descent decreased significantly. Maximal anal resting pressure increased significantly, but this did not correlate significantly with improved continence. Twenty-one patients (91 percent) could expel a 50-ml balloon preoperatively; 18 of those 21 could still do so postoperatively. The two patients who could not expel the balloon preoperatively were able to do so postoperatively. This study shows that rectal prolapse is associated with profoundly abnormal defecation and abdominal pain. While abdominal rectopexy improved continence, it may improve or worsen other bowel symptoms, including constipation.Support for this study was received from the Imperial Cancer Research Fund, ICI Pharmaceuticals (SA) Ltd., the St. Mark's Research Foundation, and the Medical Research Council of South Africa.     

Esophageal motility in progressive systemic sclerosis (PSS)

The evaluation of structural and functional abnormalities of the esophagus by manometry (using perfused tubes) and cine-radiography were compared in 25 subjects with progressive systemic sclerosis (PSS). Motility by both procedures was definitely abnormal in 19 subjects and normal in 3. The remaining 3 subjects had abnormal motility on manometry, coupled with cine-esophagrams interpreted as normal. Many structural abnormalities not demonstrated by manometry were identified by cine-radiography. Therefore, the initial diagnostic examination of motility in PSS should be the cine-esophagram.     

Urinary excretion of antinuclear antibodies

The frequency of antinuclear antibodies (ANA), the immunoglobulin class of ANA and their specificity for known nuclear antigens were determined in 24-h urine collections from patients with systemic lupus erythematosus (SLE) and progressive systemic sclerosis (PSS). Sixteen % of SLE patients had detectable urine ANA by indirect immunofluorescence using mouse kidney substrate. A higher incidence, 32% of SLE and 28% of PSS patients, had detectable ANA in a titer greater than or equal to 1:16 using HEp-2 cell substrate. IgG ANA was the most frequent immunoglobulin class of antibodies present in the urine; 56% of SLE and 29% of PSS patients with urine ANA had more than one immunoglobulin class of antibodies. Antibodies to Sm, nRNP, SS-A and dsDNA were detected in SLE urine; antibodies to SS-A and centromere were detected in PSS urine. Urine ANA detected on mouse kidney substrate and urine dsDNA antibodies correlated with diffuse proliferative glomerulonephritis in patients with SLE. Sixty-two% of SLE patients with urine ANA had proteinuria. In the remaining SLE patients and in all the PSS patients with urine ANA however, protein excretion was normal. SDS-PAGE revealed heavy and light immunoglobulin molecules in both SLE and PSS patients with urine ANA. The intact immunoglobulin was shown to have ANA activity. ANA present in the urine of SLE and PSS patients with apparently normal renal function may be an early sign of altered glomerular capillary membrane permeability.