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OBJECTIVE To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm. RESULTS Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only). CONCLUSION In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

To determine, by expert consensus, a definition for early and late fetal growth restriction (FGR) through a Delphi procedure.A Delphi survey was conducted among an international panel of experts on FGR. Panel members were provided with 18 literature-based parameters for defining FGR and were asked to rate the importance of these parameters for the diagnosis of both early and late FGR on a 5-point Likert scale. Parameters were described as solitary parameters (parameters that are sufficient to diagnose FGR, even if all other parameters are normal) and contributory parameters (parameters that require other abnormal parameter(s) to be present for the diagnosis of FGR). Consensus was sought to determine the cut-off values for accepted parameters.A total of 106 experts were approached, of whom 56 agreed to participate and entered the first round, and 45 (80%) completed all four rounds. For early FGR ( 32 weeks), three solitary parameters (abdominal circumference (AC) 3(rd) centile, estimated fetal weight (EFW) 3(rd) centile and absent end-diastolic flow in the umbilical artery (UA)) and four contributory parameters (AC or EFW 10(th) centile combined with a pulsatility index (PI) 95(th) centile in either the UA or uterine artery) were agreed upon. For late FGR (≥ 32 weeks), two solitary parameters (AC or EFW 3(rd) centile) and four contributory parameters (EFW or AC 10(th) centile, AC or EFW crossing centiles by two quartiles on growth charts and cerebroplacental ratio 5(th) centile or UA-PI 95(th) centile) were defined.Consensus-based definitions for early and late FGR, as well as cut-off values for parameters involved, were agreed upon by a panel of experts. Copyright © 2016 ISUOG. Published by John WileySons Ltd.

The aim of this study was to utilise the Quality Enhancement Research Initiative in Systemic Sclerosis (QuERI-SSc) to measure and reduce a perceived gap in the diagnosis of pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc).Rheumatologists enrolled patients with SSc (aged ≥ 18 years) and provided data on a panel of diagnostic tests over 3 years. Pulmonary function testing, echocardiography, 6-minute walk distance, N-terminal pro-brain natriuretic peptide assays, high-resolution computed tomography of the lungs, and ventilation/perfusion scan plus right heart catheterisation (RHC; when appropriate) were emphasised. Exclusion criteria included previously documented PAH, interstitial lung disease, and SSc overlapping with other connective tissue disease.Participating rheumatologists enrolled 207 patients with SSc (90% female; 80% white), with a median age of 57 years and median disease duration of 5 years. A total of 82% of patients were classified as New York Heart Association functional class I and II; of these patients, 177 had an echocardiogram at enrolment and 191 at any time during the study. Of those who met study-specified criteria for RHC at enrolment, only 3 of 7 patients underwent RHC.The screening algorithm was successful in identifying patients with mild impairment. Although specific tools were recommended for screening PAH in patients with SSc, results indicate that significant diagnostic care gaps still exist in the general rheumatology community. Better understanding and adherence to guidelines could improve the care and, ideally, outcomes of these high-risk patients.

Scleroderma (SSc) is an autoimmune connective tissue disorder characterized by progressive fibrosis of the skin and internal organs. The leading cause of death in SSc patients is pulmonary dysfunction as a result of interstitial fibrosis and pulmonary vasculopathy. Our objective was to evaluate histopathological abnormalities associated with the development of pulmonary fibrosis in SSc.Postmortem SSc lung tissue from various stages of fibrosis and tissue from normal lung were analyzed by Masson's trichrome staining and immunohistochemistry. Monoclonal antibodies against smooth muscle-alpha actin (myofibroblast marker), von Willebrand Factor, platelet endothelial cell adhesion molecule-1 (endothelial cell markers), or caldesmon (smooth muscle cell marker) were employed.We found that in the early active stages of SSc lung fibrosis two major types of cellular abnormalities occur. One is the induction of a large number of smooth muscle alpha-actin-positive myofibroblasts in interstitia. The other is the excessive formation of alveolar capillaries (hypervascularity) accompanied by an increase in the number of microvascular endothelial cells. The vascular abnormality also involves the development of microvessels that are irregular in size and shape. However, the population of myofibroblasts and capillary endothelial cells decline as the fibrosis progresses to its most marked, later stages.We conclude that the induction of myofibroblasts and the overdevelopment of capillary microvessels characterize the progression of lung fibrosis in SSc. Using these histological alterations as criteria, therefore we have divided the fibrosis formed in the SSc lungs into four pathological stages. These results suggest that both fibroblast overproliferation and vascular abnormality play an important role in the pathogenesis of lung fibrosis in SSc.

To investigate population hospitalization rates to community hospitals for systemic sclerosis (SSc, scleroderma) and examine whether age, sex, race, and insurance status independently predict length of stay (LOS), hospital charges, and in-hospital death.The 1995 Healthcare Cost and Utilization Project national inpatient sample was used to identify 3,621 SSc hospitalizations. Weighted age, sex, and race-specific frequencies were divided by population estimates to calculate hospitalizations per million people. Regression models were used to model LOS, charges, and in-hospital death with age, sex, race, and insurance serving as the primary independent variables. Covariates included numbers of diagnoses and procedures, whether or not the admission was a transfer from another hospital, and the presence of comorbid conditions.Population hospitalization rates were higher for non-whites compared to whites among those65, while rates were higher for whites compared to non-whites for thoseor =65 years old. On average, non-whites were at least 10 years younger than whites. The mean LOS was 7.5 days, with whites' average LOS being 10% shorter than non-whites', and patients with public health insurance having approximately 9% longer LOS than those with private insurance. Charges averaged almost US$15,000 per hospitalization (median = $8,441), amounting to $280 million in community hospital charges in the U.S. in 1995. The overall in-hospital death rate was 7.1%.These patterns are consistent with a greater burden and increased severity of disease among non-whites under age 65 with Ssc.

Treatment with heparin and low-dose aspirin improves fetal survival among women with antiphospholipid syndrome. Despite treatment, however, these pregnancies are frequently complicated by preeclampsia, fetal growth restriction, and placental insufficiency, often with the result of preterm birth. Small case series suggest that intravenous immune globulin may reduce the rates of these obstetric complications, but the efficacy of this treatment remains unproven. This pilot study was undertaken to determine the feasibility of a multicenter trial of intravenous immune globulin and to assess the impact on obstetric and neonatal outcomes among women with antiphospholipid syndrome of the addition of intravenous immune globulin to a heparin and low-dose aspirin regimen.This multicenter, randomized, double-blind pilot study compared treatment with heparin and low-dose aspirin plus intravenous immune globulin with heparin and low-dose aspirin plus placebo in a group of women who met strict criteria for antiphospholipid syndrome. All patients had lupus anticoagulant, medium to high levels of immunoglobulin G anticardiolipin antibodies, or both. Patients with a single live intrauterine fetus at/=12 weeks' gestation were randomly assigned to receive either intravenous immune globulin (1 g/kg body weight) or an identical-appearing placebo for 2 consecutive days each month until 36 weeks' gestation in addition to a heparin and low-dose aspirin regimen. Maternal characteristics, obstetric complications, and neonatal outcomes were compared with the Student t test and the Fisher exact test as appropriate.Sixteen women were enrolled during a 2-year period; 7 received intravenous immune globulin and 9 were given placebo. The groups were similar with respect to age, gravidity, number of previous pregnancy losses, and gestational age at the initiation of treatment. Obstetric outcomes were excellent in both groups, with all women being delivered of live-born infants after 32 weeks' gestation. The rates of antepartum complications such as preeclampsia, fetal growth restriction, and placental insufficiency (as manifested by fetal growth restriction or fetal distress) were similar between the 2 groups. Gestational age at delivery (intravenous immune globulin group, 34.6 +/- 1.1 weeks; placebo group, 36.7 +/- 2.1 weeks) and birth weights (intravenous immune globulin group, 2249.7 +/- 186.1 g; placebo group; 2604.4 +/- 868.9 g) were similar between the 2 groups. There were fewer cases of fetal growth restriction (intravenous immune globulin group, 0%; placebo group, 33%) and neonatal intensive care unit admission (intravenous immune globulin group, 20%; placebo group, 44%) among the infants in the intravenous immune globulin group than those in the placebo group, but these differences were not significant.A multicenter treatment trial of intravenous immune globulin is feasible. In this pilot study intravenous immune globulin did not improve obstetric or neonatal outcomes beyond those achieved with a heparin and low-dose aspirin regimen. Although not statistically significant, the findings of fewer cases of fetal growth restriction and neonatal intensive care unit admissions among the intravenous immune globulin-treated pregnancies may warrant expansion of the study.

To examine whether those participating in solvent oriented hobbies (SOH) are at greater risk of developing systemic sclerosis (SSc), and if the association is modified by the presence of the anti-Scl70 antibody.Patients with SSc and controls were recruited from a university hospital rheumatology clinic. Recreational hobby and occupational histories were obtained along with blood samples. Cumulative scores were created for participation in SOH. Logistic regression was used to calculate odds ratios associated with SOH exposure after adjustment for sex, age at diagnosis, and occupational solvent exposure, and to examine the association between SOH exposure and the presence of anti-Scl70.Solvent exposure based on hobbies and occupations was determined for 178 cases (141 women, 37 men) and 200 controls (138 women, 62 men). Overall participation in SOH was not associated with SSc. However, odds of high cumulative SOH exposure was 3 times greater in those patients with SSc testing positive for the anti-Scl70 antibody compared to patients testing negative (OR 2.9, 95% CI 1.1, 7.9), and twice as great as controls (OR 2.5, 95% CI 1.1, 5.9).While patients with SSc did not participate more often in SOH than controls over all, odds of high cumulative SOH exposure was greater among patients with SSc testing positive for anti-Scl70 compared to those testing negative and compared to controls. These results provide further evidence that environmental agents may play a role in the development of Ssc.

The primary objective was to determine whether occupational exposure to organic solvents is related to an increased risk of systemic sclerosis (SSc; scleroderma).Occupational histories were obtained from 178 SSc patients and 200 controls. Exposure scores were computed for each individual using job exposure matrices, which were validated by an industrial expert.Among men, those with SSc were more likely than controls to have a high cumulative intensity score (odds ratio [OR] 2.9, 95% confidence interval [95% CI] 1.1-7.6) and a high maximum intensity score (OR 2.9, 95% CI 1.2-7.1) for any solvent exposure. They were also more likely than controls to have a high maximum intensity score for trichloroethylene exposure (OR 3.3, 95% CI 1.0-10.3). Among men and women, significant solvent-disease associations were observed among SSc patients who tested positive for the anti-Scl-70 autoantibody; these trends were not observed among the men and women who tested negative for anti-Scl-70.These results provide evidence that occupational solvent exposure may be associated with an increased risk of SSc.

Beta(2)glycoprotein I (beta(2)GPI) physiologically binds to negatively charged phospholipids (PLs) and is a natural regulator of the coagulation cascade. Thrombotic clinical complications and recurrent fetal loss associated with autoimmune antiphospholipid (aPL) antibodies are thought to be related to their binding to Beta(2)GPI-PL complex and interference with the physiological function of Beta(2)GPI.To investigate the effect of aPL on beta(2)GPI-PL interaction, we studied the binding of biotinylated Beta(2)GPI to cardiolipin (CL) by enzyme-linked immunosorbent assay (ELISA) in the presence and absence of purified aPL immunoglobulin G (IgG) antibodies.Adding five different aPL IgG antibodies with different levels of aPL activity isolated from the sera of five patients with aPL-associated recurrent fetal death greatly increased the binding of biotinylated beta(2)GPI to CL-coated plates. The optical densities (ODs) were 0.635, 0.890, and 1.265 in the presence of three aPL IgG antibodies, compared to 0.425 in the absence of aPL IgG. In contrast, normal human IgG had no enhancing effect. The OD was 0.480 and 0.425, respectively. The enhancement of beta(2)GPI binding to CL by aPL IgG correlated with the titers of aPL antibodies. The use of phosphate-buffered saline with increasing salt concentrations as a washing buffer for the ELISA resulted in more stable binding of beta(2)GPI to PL in the presence of aPL IgG.These findings suggest that the binding of autoimmune aPL antibodies to beta(2)GPI-PL complex results in abnormally tighter interaction between beta(2)GPI and PLs, which may lead to physiological dysfunction of beta(2)GPI as a regulator of coagulation.

To determine whether ceramide regulates prostaglandin (PG) production by cultured human amnion cells and decidual cells independently of interleukin-1 beta (IL-1 beta).Cells were grown in monolayer culture and then incubated with varying concentrations of ceramide, IL-1 beta, ceramide in the presence and absence of IL-1, and control media. Production of PGE2 was determined using a specific radioimmunoassay.Ceramide induced a significant concentration-dependent increase in PGE2 production by amnion cells and decidual cells. However, PGE2 production induced by IL-1 beta was significantly more than with ceramide alone, and there was no potentiation of PGE2 production with coincubation of ceramide and IL-1 beta.We suggest that term human amnion cells and decidual cells are responsive to ceramide independent of IL-1 beta and that generation of these substances in response to an infection in the uterus may lead to increased PG production by human gestational tissues, indicating that there are several mechanisms leading to PG production by these cells.

Autoimmune diseases occur most commonly in women of childbearing age. Over 70% of individuals with autoimmune diseases are women, though some conditions (e.g., ankylosing spondylitis) are more common in men. Many authorities have focused on sex hormones as an explanation for the relatively high proportion of females affected by autoimmune diseases. This article covers systemic lupus erythematosus, the prototypical autoimmune disease, and antiphospholipid syndrome, which is associated particularly with pregnancy loss.

We describe 2 cases of diffuse fasciitis with eosinophilia (DFE) associated with prolonged exposure to the industrial solvent trichloroethylene (TCE). The medical and personal histories, examinations, and laboratory and pathological investigations were reviewed and summarized. The 2 case reports, representing the first and 2nd cases of DFE associated with TCE, were compared with 8 reported cases of systemic sclerosis associated with TCE and suggest a direct association between TCE exposure and the development of fasciitis (DFE).

Lipopolysaccharide (LPS) administration has been known to cause murine fetal death for over 50 years, but the responsible mechanism(s) remains unclear. We used the LPS-hyporesponsive murine strain, C3H/HeJ, to 1) establish whether LPS-induced fetal death is due to a maternal or fetal response to LPS and 2) to investigate the involvement of tumor necrosis factor alpha (TNF alpha) in fetal death caused by LPS. C3H/HeJ (LPS-hyporesponsive) or C3H/HeN (LPS-responsive) females were mated with C57B1/6 or C3H/HeN males (both LPS-responsive). Administration of 10 micrograms LPS caused fetal death in C3H/HeN mothers. However, up to 1000 micrograms LPS did not result in the death of LPS-responsive fetuses when administered to C3H/HeJ mothers. Systemic administration of TNF alpha was able to cause fetal death in both C3H/HeN and C3H/HeJ strains of mice. Pretreatment of pregnant C3H/HeN mice with anti-TNF alpha antibodies significantly reduced fetal death caused by LPS administration. The administration of a sublethal dose of TNF alpha plus 10 micrograms LPS to pregnant C3H/HeJ mice restored abortifacient activity. These results indicate that LPS-induced fetal death is due to a maternal response as opposed to a direct fetal response to LPS and that TNF alpha appears to be an important mediator of fetal death caused by LPS.

To determine the risk of antiphospholipid antibody-related disorders in women with elevated levels of these antibodies.We used an historic cohort study design. Surveys of medical and obstetric histories for the interval from initial antibody testing to the time of patient interview were used to calculate age-adjusted rates for the development of medical disorders associated with antiphospholipid antibodies. The cohort included 130 women with lupus anticoagulant, medium to high levels of immunoglobulin G anticardiolipin antibodies, or both.The median interval of study was 3.2 years (range 0.7-9.5, mean 3.7). Sixty-three subjects (48%) developed at least one new disorder during the study interval. The age-adjusted rates (per 1000 patient-years; +/- standard error) for the development of the disorders studied were as follows: thrombosis (156.8 +/- 30.0), cerebrovascular accident (93.8 +/- 25.1), amaurosis fugax (57.1 +/- 23.2), transient ischemic attack (170.4 +/- 27.6), systemic lupus erythematosus (9.8 +/- 3.8), and autoimmune thrombocytopenia (56.0 +/- 22.2). Of the 34 thrombotic events that occurred during the study interval, eight were associated with pregnancy and eight occurred while the patients were taking anticoagulant medications.Our subjects developed complications associated with antiphospholipid antibodies at a substantial rate, and almost half suffered at least one new event during the study interval. The high rate of thrombosis in individuals with antiphospholipid antibodies, especially associated with pregnancy, underscores the need to evaluate long-term anticoagulation in these patients.

To determine whether unexplained elevations of maternal serum alpha-fetoprotein (MSAFP) in women with antiphospholipid antibodies are associated with adverse pregnancy outcomes.A retrospective cohort study was used to compare pregnancy outcomes between women with second-trimester MSAFP values equal to or greater than 2.5 multiples of the median (MoM) and less than 2.5 MoM. The cohort included 60 pregnancies in 47 women with medium to high positive levels of immunoglobulin (Ig) G anticardiolipin antibodies, lupus anticoagulant, or both.Thirteen pregnancies (22%) had elevated MSAFP values (median 3.6 MoM, range 2.5-12.6). Of these, amniotic fluid AFP was normal in seven and elevated in one. None of the elevated MSAFP levels were explained by fetal anomalies, current fetal death, multiple gestation, incorrect dates, or vaginal bleeding. Pregnancies with elevated MSAFP values had a significantly higher incidence of fetal death (eight of 13, 62%, versus three of 47, 6%) and perinatal loss (ten of 13, 77%, versus seven of 47, 15%) than those with normal MSAFP (P.001, Fisher exact test). In these women, the sensitivity and specificity of an unexplained elevated MSAFP level in ascertaining fetal death were 73 and 90%, respectively. For perinatal loss, the sensitivity was 59% and the specificity was 93%. Of the placentas studied, infarction occurred in eight of nine (89%) among the women with elevated MSAFP.Unexplained second-trimester elevations of MSAFP are common in women with antiphospholipid antibodies and are significantly associated with fetal loss. Abnormalities in the fetoplacental barrier are implicated as part of the pathophysiology of antiphospholipid antibody-mediated pregnancy loss.

Fourteen patients with systemic sclerosis (SSc, scleroderma) and interstitial lung disease were treated with oral cyclophosphamide (1-2 mg/kg/day) and low dose prednisone (10 mg/day). There was a significant improvement in FVC after 6 months compared to entry values (2.21 +/- 0.19 l vs. 2.03 +/- 0.15 l, p0.02). Improvement was maintained at 12 months (2.27 +/- 0.27 l, p0.05) and 18-24 months (2.60 +/- 0.28 l, p0.001). In 12 cases followed for 18-24 months, FVC was stable or improved. No significant improvement or decline was noted for the DLCO. Side effects included cytopenia (2), infection (1), and hemorrhagic cystitis (2), and one possible related malignancy. A controlled prospective trial of cyclophosphamide is warranted in patients with SSc and active interstitial lung disease.

Silica, Silastic, and silicone (any organic compound in which silicon replaces carbon) have been associated with a number of connective-tissue diseases, most commonly systemic sclerosis (scleroderma). Silicone is known to leak from breast implants and spread to surrounding tissues, including lymph nodes, but silicone's role in the origin and pathogenesis of the inflammation and fibrosis related to such conditions remains controversial. Synovial tissue, alveolar macrophages, and skin, each from three different patients with silicone-gel implants, plus the breast implant capsules from each of the three patients, were examined by light microscopy, transmission electron microscopy, and electron probe microanalysis for the presence of silicon-containing material.Silicon was identified within the fibrous breast capsule of each case, associated with a chronic inflammatory cell infiltrate. Silicon was also identified within tissues involved by chronic inflammation and fibrosis, namely, synovium, skin, and alveolar macrophages, in association with clinical, serologic, and histologic evidence of connective tissue disease. All three patients improved after removal of the silicone-gel breast implants.The presence of silicon-containing material within sites of connective-tissue disease supports a role for silicon in the origin or pathogenesis of such conditions in patients with silicone-gel breast implants. All patients with connective-tissue disease should be questioned about exposure to various forms of silicon. In those patients with known exposure, tissue specimens should be examined carefully for silicon-containing material and, if found, the source should be removed.

We describe the detection and the growth of fibroblasts with human smooth muscle cell differentiation features from bronchoalveolar lavage (BAL) fluid of 53% of patients with scleroderma, but not from healthy controls. The binding of alpha-actin, vimentin and desmin antibodies by scleroderma lung fibroblasts exceeded that of normal adult lung fibroblasts, indicating that scleroderma lung fibroblasts express some markers of human smooth muscle cell differentiation (myofibroblasts), which may account for differences in biological behavior. A mesenchymal cell phenotype was documented by mRNA analysis, showing high expression of collagen type I and fibronectin in these cells. Fibronectin is also released in significantly higher amounts by scleroderma alveolar macrophages than by macrophages from healthy donors.

To determine the outcome of treated pregnancies in women with well-characterized antiphospholipid syndrome.We reviewed 82 consecutive pregnancies in 54 women with antiphospholipid syndrome who were treated during pregnancy with the following: 1) prednisone and low-dose aspirin; 2) heparin and low-dose aspirin; 3) prednisone, heparin, and low-dose aspirin; or 4) other combinations of these medications or immunoglobulin.The overall neonatal survival rate was 73%, excluding spontaneous abortions, but treatment failures (fetal and neonatal deaths) occurred in all treatment groups. Patients with successful treated pregnancies had fewer previous fetal deaths than those with unsuccessful treated pregnancies. There were no significant differences in outcome among the four treatment groups. Preeclampsia and fetal distress occurred in half of all pregnancies, and fetal growth impairment occurred in nearly one-third. Preterm delivery due to maternal or fetal indications was required in 37% of the pregnancies. Four pregnancies were also complicated by postpartum thrombosis during treatment.Pregnancy in women with antiphospholipid syndrome appears to be improved by treatment, but fetal loss may occur despite treatment. Preeclampsia, fetal distress, fetal growth impairment, and premature delivery are common. Because of the clinically significant risk of thrombotic episodes, thrombosis prophylaxis should be considered in these patients.

We describe two patients with life-threatening puerperal infection due to group A beta-hemolytic streptococcus. Each patient had bacteremia, shock, and multi-organ involvement. Both cases were compatible with a recently described streptococcal toxic shock-like illness. Both women failed to improve despite vigorous medical and antibiotic therapies, and each required hysterectomy. Obstetricians should be alert to the importance of early diagnosis and treatment of this potentially lethal infection.

Seventeen patients with early systemic sclerosis (SSc) underwent high resolution computed tomography (HRCT) of the chest to evaluate dyspnea and/or abnormal pulmonary function tests (PFT). All patients were assigned a dyspnea score and each had routine chest radiography (CXR). Bronchoalveolar lavage (BAL) was performed on 10 patients. HRCT was abnormal in 15 patients (88%), while CXR was abnormal in only 10 patients (59%). Mediastinal lymphadenopathy was detected in 7 patients (41%). Disease duration, dyspnea score, and forced vital capacity (FVC) did not correlate with HRCT score. However, trends toward higher total BAL cell counts and higher BAL neutrophil counts were noted in patients with ground glass opacities on HRCT, and BAL lymphocyte counts were significantly higher in such cases. HRCT is superior to CXR for detecting early interstitial lung disease in SSc, but patient history and FVC correlate poorly with HRCT findings. Ground glass opacities on HRCT may reflect active alveolitis, and mediastinal lymphadenopathy associated with SSc lung disease may be a consequence of pulmonary inflammation.

Lymphokine activated killer (LAK) cells, which arise from interleukin-2 (IL-2) activation of natural killer (NK) cells, are capable of lysing NK-resistant cell targets, including endothelial cells (EC). Since EC cytotoxicity is postulated to play a role in the pathogenesis of systemic sclerosis (SSc), experiments were performed to measure LAK activity in the peripheral blood lymphocytes (PBL) of 10 SSc patients and 10 normal controls. SSc patients had no significant spontaneous cytotoxicity against NK-resistant cell targets, including EC. After IL-2 stimulation in vitro, SSc patients and normal controls demonstrated cytotoxicity toward NK-resistant cell targets, including EC. This LAK-mediated EC cytotoxicity was actually lower for SSc patients than for normal controls. These studies do not preclude a role for LAK-mediated EC cytotoxicity in the pathogenesis of SSc, but demonstrate that LAK cells are not spontaneously present in circulating PBL.

Elastosis perforans serpiginosa is a rare complication of D-penicillamine therapy. It has been reported to occur in Wilson's disease and cystinuria, usually after many years of high-dose therapy. We report a case of D-penicillamine-induced elastosis perforans serpiginosa with unique clinical features occurring in a 10-year-old child with juvenile rheumatoid arthritis who received only 71 gm of the drug over 9 months. The case is also unusual because of the short course and low cumulative dose of drug received and because of the calcification of elastic fibers. The calcification of elastic fibers suggests that this case may represent an unusual variant of elastosis perforans serpiginosa or an overlap with pseudoxanthoma elasticum. All reported cases of D-penicillamine-induced elastosis perforans serpiginosa are reviewed, and histopathologic and electron microscopic findings are presented. The theoretic mechanisms of action of D-penicillamine on elastic tissue synthesis and morphology are discussed.

Childhood dermatomyositis is an inflammatory condition affecting the skin and muscles that is often associated with a small vessel vasculopathy. According to previous retrospective studies, it is suggested that the severity of the vasculopathy is related to the course of the disease. Sequential in vivo nailfold microscopy was used to assess the frequency and the degree of vasculopathy in nine children with dermatomyositis. The degree of morphologic changes in the nailfold capillary bed was shown to correlate with the clinical course. The technique of nailfold capillaroscopy may prove to be a clinically useful, noninvasive means of early prognosis.

Immunofluorescence (IF) data from three different biopsy sites (nailfold, forearm, buttock) were studied in 18 patients with scleroderma (SD, systemic sclerosis) and the results compared with those obtained from 10 normal controls (NC) and 7 patients with systemic lupus erythematosus (SLE). Immunoglobulin (Ig) deposits were detected by direct IF technique at the dermo-epidermal junction (DEJ) in 8/14 nailfolds, 6/15 forearms and in none of the buttock specimens of SD patients. Epidermal nuclear staining was present in 6/14 nailfolds, and in 6/15 forearms and buttocks. The most prominent finding was the observation of multiple Ig deposits in the cuticle of 9/14 patients with SD. NC group was negative in all sites for epidermal nuclear staining and the only DEJ deposit occurred in the forearm of one subject. In conclusion, this study demonstrates that Ig deposits in SD, both at the DEJ and in the epidermal nuclei, occur more often than previously reported and are especially frequent in the nailfoldcuticle area.

Synovial fluid lymphocytes (SFL) and peripheral blood lymphocytes (PBL) from patients with rheumatoid arthritis were compared for their response to lectin stimulation and for their behavior in the autologous mixed lymphocyte reaction (AMLR). The SFL proliferative response to phytohemagglutinin (PHA), as measured by tritiated thymidine incorporation at 72 hr, was lower than that of PBL (P less than 0.001). When T-cell growth factor (TCGF) was added to the medium, there was an increase in the SFL proliferative response to PHA (P less than 0.05). In contrast, TCGF did not alter significantly the PBL proliferative response to PHA. Mixing experiments were performed to determine whether the poor SFL proliferative response was due to passive absorption and removal of in situ-generated TCGF by "suppressor" cells. When cultured together, SFL did not suppress the PBL proliferative response to PHA, suggesting that decreased production of TCGF rather than competitive binding of TCGF results in the poor SFL proliferative response to lectin stimulation. In the AMLR, synovial fluid non-T cells were found to be more stimulatory to peripheral blood T cells than were peripheral blood non-T cells (P less than 0.001). In comparison to peripheral blood T cells, synovial fluid T cells were poor responders in the AMLR. Repetitive in vitro autologous stimulation of peripheral blood T cells resulted in proliferative responsiveness analogous to that of SFL, i.e., a relatively poor proliferative response in the AMLR and a poor response to PHA. The latter could be augmented by TCGF. The SFL requirement for exogenous TCGF is consistent with a state of immune activation. In vivo stimulation by non-T cells may play an important role in the immune activation which characterizes rheumatoid SFL.