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Rationale: FVC percent predicted (FVC%) is the primary outcome measure in clinical trials of systemic sclerosis interstitial lung disease. For interpretation of change in the FVC% over time, it is important to define whether these changes are clinically meaningful. Objectives:: To assess the reliability and the minimal clinically important differences (MCID) for FVC% in the Scleroderma Lung Study I and II (SLS-I and -II). Methods: Using data from SLS-I and -II (N = 300), we evaluated the test-retest reliability for FVC% (screening vs. baseline) using intraclass correlation. MCID estimates at 12 months were calculated in the pooled cohort (SLS-I and -II) using two anchors: Transition Dyspnea Index (≥change of 1.5 units for improvement and worsening, respectively) and the Medical Outcomes Short Form-36 Health Transition question (“Compared with one year ago, how would you rate your health in general now”?), where “somewhat better” or “somewhat worse” were defined as the MCID estimates. We next assessed the association of MCID estimates for improvement and worsening of FVC% with patient-reported outcomes (PROs) and computer-assisted quantitation of extent of fibrosis (QLF) and of total interstitial lung disease (QILD) on high-resolution computed tomography. Student’s t test was used to compare the mean difference in outcomes between the MCID improvement/worsening and the “no change” group. Measurements and Main Results: Reliability of FVC%, assessed at a mean of 34 days, intraclass correlation was 0.93 for the pooled cohort. The MCID estimates for the pooled cohort at 12 months for FVC% improvement ranged from 3.0% to 5.3% and for worsening from −3.0% to −3.3%. FVC% improvement by greater than or equal to MCID was associated with either statistically significant or numerical improvements in some PROs, QILD, and QLF, whereas FVC% worsening greater than or equal to MCID was associated with statistically significant or numerical worsening of PROs, QILD, and QLF. Conclusions: FVC% has acceptable test-retest reliability, and we have provided the MCID estimates for FVC% in systemic sclerosis interstitial lung disease–based changes at 12 months from baseline in two clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT00004563 for SLS-I and NCT00883129 for SLS-II).

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.

Few studies exist on sexual activity and functioning in female patients with systemic sclerosis (SSc, scleroderma). We studied the patient-reported impact of SSc on sexual functioning among female patients.101 SSc patients completed the Short Form-36 (SF-36), the Female Sexual Functioning Index (FSFI) and the Female Sexual Function in Scleroderma (FSFS) questionnaires.Sixty patients reported being sexually active (59.4%). Reasons for sexual inactivity included lack of a partner (36.6%), personal choice (31.7%), and health status of the respondent's partner (19.5%). Only 7 subjects (17%) listed scleroderma as the primary reason for sexual inactivity. The mean FSFI score in the sexually active population was 24.9 (SD=6.7, range = 4.5-34.8) which is significantly lower than the mean score of 30.5 reported for the general population. Sexual functioning was significantly correlated with the Mental Component Score of the SF-36 (r=0.54, p0.001) but surprisingly not with the Physical Component Score of the SF-36, age, and disease classification or duration. Several scleroderma-related problems including fatigue, body pain, vaginal dryness, and vaginal discomfort were cited as contributing to sexual difficulties.Women with scleroderma do remain sexually active overall in spite of several disease-related physical and psychological difficulties. Many of their problems are amenable to health interventions and should be addressed during health care visits.

In October of 2007, a group of true experts in diverse areas relevant to scleroderma were invited to Florence, Italy for a 2-day symposium on ‘Controversies in Scleroderma’. As the organizing committee for this activity, we selected the topics and speakers and the format of the meeting which focused on brief cutting-edge presentations followed by intensive group discussions. This Supplement to Rheumatology seemed inescapably important to realize as a summary of the conference and as a compendium for the student of scleroderma everywhere. Each author was asked to write a concise treatise on their individual area of expertise and to follow a uniform format for understandability and accessibility. Full answers are not yet in to critically important questions in scleroderma but progress is considerable. We work in an era of excitement, collaboration and anticipation. The biological platform for considering interventions has never been stronger. We have several plausible molecular targets and the intellectual framework via which we can stratify our approach. As our understanding of the vascular, immunological and fibrotic features of disease evolves, new hypotheses will emerge and hopefully be efficiently and appropriately tested in controlled clinical trials. However, these trials will not be robust unless there is progress in the clinical sciences of trial design and outcome measures. Scleroderma is a remarkably heterogeneous disorder. It is likely that progress in therapy will be focused on both specific features of disease and on overarching approaches to the commonalities of disease pathogenesis that are expressed in all patients. Lung disease remains the leading cause of death with parenchymal and vascular pathologies being of near equal importance. This conference paid particular attention to new knowledge in both areas that will permit efficient study of well-documented cohorts of clinically and pathophysiologically similar patients. There is a lot here but also a lot of work ahead! We have better science and a sophisticated approach to clinical management and trial design. Effective treatments seem within reach. Acknowledgements

This report makes recommendations for standardized techniques of data gathering and collection regarding: 1) skin involvement 2) joint and tendon involvement, and 3) involvement of the skeletal muscles. The recommendations in this report derive from a critical review of the available literature and group discussion. Committee recommendations are considered appropriate for descriptive clinical investigation, translational studies and as standards for clinical practice. Skin involvement should be assessed using the modified Rodnan skin score. Joint involvement, when symmetric synovitis is present, could be best assessed by the DAS-28 as is utilized in rheumatoid arthritis. Clinical assessment should include a routinized evaluation for the presence and number of palpable tendon friction rubs. Muscle involvement should be screened for by performance of the serum creatine phosphokinase assay and assessment of proximal weakness. More specific testing including EMG, magnetic resonance imaging and muscle biopsy should be employed in those patients with clinically significant myopathy only.

Early diffuse scleroderma (systemic sclerosis; SSc) has no proven treatment. This study was undertaken to examine the efficacy of methotrexate (MTX) in improving the skin and other disease parameters in early diffuse SSc.Seventy-one patients with diffuse SSc of3 years' duration were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial. Thirty-five patients were treated with MTX and 36 with placebo. Treatment was administered for 12 months. The primary outcome measures were skin score (as determined with 2 different indices) and physician global assessment.At baseline, there were no statistically significant differences in skin scores, carbon monoxide diffusing capacity (DLco), physician global assessment, or other secondary outcome measurements between the 2 treatment groups. At study completion, results slightly favored the MTX group (mean +/- SEM modified Rodnan skin score 21.4+/-2.8 in the MTX group versus 26.3+/-2.1 in the placebo group [P0.17]; UCLA skin score 8.8+/-1.2 in the MTX group versus 11.0+/-0.9 in the placebo group [P0.15]; DLco in the MTX group 75.7+/-4.6 versus 61.8+/-3.4 in the placebo group [P0.2]). In addition, physician global assessment results favored MTX (P0.035), whereas patient global assessment did not differ significantly between groups. When between-group differences for changes in scores from baseline to 12 months were examined using intent-to-treat methodology, MTX appeared to have a favorable effect on skin scores (modified Rodnan score -4.3 in the MTX group versus 1.8 in the placebo group [P0.009]; UCLA score -1.2 in the MTX group versus 1.2 in the placebo group [P0.02]), but differences in the degree of change in the DLco and physician global assessment were not significant. For the UCLA skin score, these differences in results were not statistically significant after adjustment for baseline differences in sex distribution and steroid use. Dropout rates were similar in the 2 groups.Although results of this trial demonstrated a trend in favor of MTX versus placebo in the treatment of early diffuse SSc, the between-group differences were small and the power to rule out false-negative results was only 50%. Our findings do not provide evidence that MTX is significantly effective in the treatment of early diffuse SSc.

Accelerated nodulosis is a recognized complication of methotrexate (MTX) therapy in rheumatoid arthritis (RA). We describe 3 patients with accelerated nodulosis treated with D-penicillamine (D-Pen) while continuing MTX. The combination of D-Pen with MTX therapy resulted in regression of subcutaneous nodules in all patients, disappearance of pulmonary nodules in one patient, and resolution of vasculitic lesions in 2 patients. Clinical response was observed within the first few weeks of therapy and usually required moderate doses (500 mg/day). Our observations suggest that addition of D-Pen to MTX therapy can be an alternative therapeutic option for accelerated nodulosis in patients with RA.

To test the hypothesis that systemic sclerosis (SSc) patients taking high-dose D-penicillamine (D-Pen) would have greater softening of skin, lower frequency of renal crisis, and better survival than patients taking low-dose D-Pen.Seventeen centers enrolled 134 SSc patients with early (or =18 months) diffuse cutaneous scleroderma into a 2-year, double-blind, randomized comparison of high-dose D-Pen (750-1,000 mg/day) versus low-dose D-Pen (125 mg every other day). All 134 patients were followed up for a mean+/-SD of 4.0+/-1.1 years to assess the frequencies of new-onset scleroderma renal crisis (SRC) and mortality.Sixty-eight patients completed 24 months of drug treatment. The course of the modified Rodnan skin thickness score in the 32 high-dose and the 36 low-dose D-Pen completers was not different at 24 months: the skin score dropped 4.8+/-10.3 (mean+/-SD) units in the high-dose group and 6.9+/-8.4 units in the low-dose group (P = 0.384 by t-test; favoring low-dose D-Pen) from 20.4+/-10.3 in the high-dose and 19.9+/-6.6 in the low-dose D-Pen group at study entry. The incidences of SRC and mortality were not different (P0.38 by Cox proportional hazards and by chi-square test) in the 66 high-dose patients (8 developed SRC and 8 died) compared with the 68 low-dose patients (10 developed SRC and 12 died). Of the 20 adverse event-related withdrawals, 80% occurred in the high-dose D-Pen group.The course of the skin score and the frequencies of SRC and mortality in the high-dose D-Pen group were not different from those in the low-dose D-Pen group. Eighty percent of the adverse event-related withdrawals occurred in the high-dose D-Pen patients. Although this study cannot answer the question of whether low-dose D-Pen is effective, it does suggest that there is no advantage to using D-Pen in doses higher than 125 every other day.

To investigate the safety and pharmacokinetics of a 28 day continuous subcutaneous infusion of recombinant human relaxin in patients with systemic sclerosis with diffuse scleroderma.Thirty patients with stable diffuse scleroderma of moderate severity received recombinant human relaxin at 6, 12, 50, 100, and 200 microg/kg/day or placebo in a double blind, sequential panel, dose escalation study.All patients completed 28 days of study treatment. Steady state concentrations of serum relaxin were achieved by the 3rd day of infusion and were dose proportionate. Patients receiving 200 microg/kg/day achieved levels about 50-fold those of normal pregnancy. Pharmacokinetics of relaxin were nonlinear with hyperbolic increases of both t1/2 and volume of distribution and parallel decrease of elimination rate coefficient. An elimination transport system was suggested with saturation at serum relaxin concentration of 45 ng/ml. Adverse events included local infusion site rash and pain, minor bleeding episodes, and decreased hemoglobin concentration (mean reduction 1.1 g/dl). Standard measures of scleroderma were unchanged, although global assessment favored relaxin over placebo.Recombinant human relaxin in the doses used was safe and well tolerated. Longer term controlled trials are warranted to define the potential efficacy of relaxin in patients with diffuse scleroderma.

To test the ability of the modified Rodnan skin score to reflect skin thickness in skin biopsies from 141 patients with systemic sclerosis (SSc) obtained at entry during a prospective, double blind study of ketanserin versus placebo in SSc.Punch skin biopsies (4 mm) were obtained from the dorsal surface of the distal forearm of 141 patients. Biopsy specimens were trimmed and weighed (wet weight) and then desiccated and reweighed (dry weight). Skin score was recorded for 17 areas, graded 0-4+, while edema was graded 0-4+ in 10 of the same sites using finger pressure.Total skin score correlated with wet weight (r = 0.553) and dry weight (r = 0.517) of the skin biopsies. Local skin score from the biopsied forearm also correlated with wet and dry weight (r = 0.536 and 0.530, respectively). Dry weight as a percentage of wet weight was the same for diffuse cutaneous SSc (dSSc) and limited cutaneous SSc (lSSc) (30.7% for both, NS), despite increased wet weight in patients with dSSc versus lSSc (17.75 vs 13.03 g; p0.001). Edema scores correlated poorly both with wet weight (r = 0.069) and dry weight (r = 0.169).Total and forearm skin score correlates well with both wet and dry forearm skin biopsy weight from forearm biopsies, indicating that skin score reflects the underlying pathology of SSc. Further, the percentage of dry to wet weight is similar for lSSc and dSSc, supporting the usefulness of skin score in differentiating SSc disease subtypes.

GH secretion and the response to GH secretagogues are significantly diminished in obese individuals. Previous studies have shown that L-692,429 (L), a nonpeptide mimetic of GH-releasing peptide, selectively stimulates GH release in normal young men and in the elderly, who also have diminished GH secretion. A paired, two-site study examined the effects of L on GH release in 12 healthy obese (part A; mean +/- SD: age, 26.1 +/- 3.3 yr; body mass index, 35.0 +/- 3.1 kg/m2) and 10 nonobese (part B; age, 22.2 +/- 2.3 yr; body mass index,or = 27.0) young men. In part A, placebo, low dose L (0.2 mg/kg), or high dose L (0.75 mg/kg) was administered iv over 15 min on 3 separate occasions after an overnight fast. Samples for GH, PRL, and cortisol determinations were obtained every 15 min. GH release (mean +/- SE) was significantly increased by both doses of L compared to the effect of placebo: 12.6 +/- 1.8 micrograms/L (low dose), 18.5 +/- 2.7 micrograms/L (high dose), and 0.84 +/- 0.1 microgram/L (placebo), respectively (P0.05). In a subset of 6 obese men, in samples collected every 5 min, the GH response to both doses of L was significantly greater than that to 1 microgram/kg GHRH. To compare the response to low dose L in the obese and to determine the effects of feeding on this response, 0.2 mg/kg L was administered as described in part A to nonobese young men after an overnight fast (fasted) or a standardized breakfast (fed; part B). Low dose L was an effective GH secretagogue in nonobese young men; however, this effect was attenuated with feeding [43.6 +/- 7.9 (fasted) vs. 17.7 +/- 4.8 (fed) micrograms/L]. Of note, the response to low dose L in fasted obese individuals was similar to that in fed nonobese individuals. The administration of L was well tolerated in both groups. We conclude that L is an effective GH secretagogue in obese and nonobese young men and may have therapeutic benefits when administered to relative (obese or elderly) or absolute GH-deficient individuals.

The known intestinal complications of systemic sclerosis (SSc) stem mainly from motor disturbances. Autopsy findings were studied to identify anatomic abnormalities that may be associated with this disease. Descriptions of intestinal organs at autopsy were compared in 16 patients with SSc and 18 patients with systemic lupus erythematosus (SLE), a related disease control. There was a high incidence of perforation in SSc (7 of 16 patients) compared to SLE (1 of 18 patients) (P0.05). In SSc, perforations involved all parts of the bowel: transmural esophageal fibrosis (after heater probe cautery), dehiscence of suture line after gastric resection, perforated duodenal ulcers (N = 2), terminal ileal ischemia, and diverticulitis (N = 2). Two of the perforations in SSc were silent and were discovered at autopsy. The one perforation in SLE was due to full-thickness necrosis from vasculitis. This study suggests that the intestinal walls of patients with SSc are inherently weak; the gastroenterologist should keep this in mind when performing invasive procedures.

Pulmonary arterial hypertension (PAH) related to systemic sclerosis (SSc, scleroderma) is a leading cause of death and disease-related morbidity yet paradoxically is the only complication of disease which has been studied adequately to allow regulatory approval and licensing of specific therapies. PAH (WHO Group 1) is defined by right heart catheterization (RHC) as a mean pulmonary artery pressure ≥ 25 mm Hg in the presence of a normal pulmonary capillary wedge pressure (PCWP) and the absence of significant levels of parenchymal lung disease. However, recent studies have demonstrated frequent elevations of PCWP in response to exercise or fluid challenge during right heart catheterization suggesting that left ventricular diastolic dysfunction or WHO Group 2 type disease is an important confounder. Many WHO Group 1 SSc patients have at least mild parenchymal lung disease and patients with longstanding stable moderate parenchymal disease develop PH as a late feature. WHO Group 3 disease implying microvascular disruption and pulmonary veno-occlusive disorder(PVOD)confound ease of disease categorization. Mixed etiology may be the rule not the exception in SSc. Emerging data suggest markedly improved outcomes associated with early recognition and therapy. Reliance on echocardiography and symptoms alone leads to missed diagnosis in many such subjects. Ancillary testing including measures of pulmonary diffusing capacity or myocardial stress (NT-proBNP assay) become central to screening strategies as does measure of serum uric acid. High resolution chest tomography helps to identify PVOD and to assess the contribution of parenchymal disease whereas ventilation –perfusion radionuclide studies help to exclude thromboembolic disease. Although not yet field validated, the DETECT algorithm suggests that early mild disease can be detected whilst missing only 4% of PAH by employing pulmonary function testing, EKG and echocardiography with assays of NT-proBNP, anticentromere antibody and serum uric acid (see Denton CP et al, EULAR 2013). The majority of randomized controlled trials are of short duration and focused on exercise capacity and quality of life outcomes. SSc has been an under-represented population which further undermines the power of these trials to measure other potential SSc related benefit (Raynaud, digital ulcers, gastrointestinal motility). Thus reliable data on durability of benefit and on therapeutic efficiency are sorely lacking. In the absence of direct drug to drug comparisons, consensus on drug of choice, applications of combined therapy and benefits of “goal-directed” therapy remain unclear in the SSc population. Newer animal models suggest the capacity to foster vascular deremodeling either through antagonism of leukotriene B4 or inhibition of c-abl signaling pathways. Testing our ability to measure disease reversal or to even effectively perform the appropriate trials will require enhanced efforts at aggressive screening and earlier and more frequent use of right heart catheterization. The rheumatologist is the central caregiver in a situation of progressive lung disease wherein outcome is dictated by cardiac status and response. clinical disease features. All data point to the need for vigilance and aggressiveness in diagnostic testing. Disclosure of Interest J. Seibold Shareholder of: Sapientia, Pacific Therapeutics, Consultant for: Actelion, Aries, Bayer, Boehringer-Ingelheim, Celgene, DART, Eiger, Eiccose, FibroGen, Genentech, Novartis, Pfizer, Sanofi-Aventis, Sigma Tau, Speakers bureau: United Therapeutics

An open, randomized, six-way crossover study was conducted in 12 healthy males to assess pharmacokinetics and bioinversion of ibuprofen enantiomers. The mean plasma terminal half-life (t1/2) of R(-)ibuprofen was 1.74 hr when intravenously infused as a racemic mixture and was 1.84 hr when intravenously infused alone. The mean t1/2 of S(+)ibuprofen was 1.77 hr when dosed as S(+)ibuprofen. Examination of values of both the absorption and disposition parameters of R(-)ibuprofen revealed that the kinetics of R(-)ibuprofen were not altered by concurrent administration of S(+)ibuprofen. In this study, there was little or no presystemic inversion of R(-)ibuprofen to its S(+)isomer. Also, 69% of the intravenous dose of R(-)ibuprofen was systemically inverted and 57.6% of the oral dose of R(-)ibuprofen lysinate was bioavailable as S(+)ibuprofen. These results indicate that the bioinversion of R(-)ibuprofen administered orally is mainly systemic. Because bioinversion of R(-)ibuprofen is not complete, S(+)ibuprofen produced higher bioavailability of S(+)ibuprofen (92.0%) than either racemic ibuprofen (70.7%) or R(-)ibuprofen (57.6%). However, bioavailability of R(-)ibuprofen (83.6%) when dosed alone was not significantly different from when dosed as racemic mixture (80.7%).

To determine the safety and efficacy of aminobenzoate potassium (KPAB) in treating the skin manifestations of scleroderma.Via a 48-week prospective, randomized, double blind, placebo controlled trial we compared the efficacy of KPAB 12 g/day with matching placebo. Outcome measures included skin mobility and thickening scores, patient and physician global assessments and, measurements of maximal oral aperture and hand range of motion.Of 146 patients who entered the study, 76 (52%) completed. Demographics of the study population included age 49 +/- 13 years, 83% women, mean (range) disease duration was 104 (7-600) months. There were no differences in the demographics of the KPAB vs placebo nor the group that completed the study compared with the withdrawal group. There were no clinical or statistically significant differences between the KPAB and the placebo treated groups in any of the outcome measures. Subgroup analyses of skin mobility and skin thickening based on age, extent of disease, severity of disease, duration of disease and involved vs uninvolved skin were performed, but no differences were noted. The overall compliance to the medical regimen wasor = 75% in 93% of patients completing the study. Eighteen patients in the KPAB group and 6 placebo patients withdrew due to adverse drug reactions (ADR). The most common withdrawals for ADR were gastrointestinal intolerance and headaches. All ADR resolved following withdrawal of medication.KPAB did not alter the skin changes of scleroderma in a group of patients with relatively longstanding stable disease. KPAB was reasonably well tolerated in this group of patients.

L-692,429, a substituted benzolactam, is a novel nonpeptide mimic of the GH secretagogue, GH-releasing peptide-6. The safety and GH secretory activity of L-692,429 (0.001-1.0 mg/kg, i.v.) were investigated in 24 healthy nonobese young (18-26 yr old) male volunteers who demonstrated a GH response of 7 micrograms/L or more after 1 microgram/kg, i.v. GH-releasing hormone [GH-releasing hormone-(1-29)NH2]. L-692,429 was administered as a 15-min iv infusion in an incremental dose, double blind, placebo-controlled, alternating panel fashion to 3 panels of 8 subjects each. Dose-dependent GH secretion was observed with a threshold dose of 0.05 mg/kg (4 of 6 subjects responded with peak GH > 7 micrograms/L), and 0.2 mg/kg produced a response in all 14 subjects tested (mean +/- SE peak GH, 41.0 +/- 6.3 micrograms/L). The maximum dose of 1.0 mg/kg L-692,429 resulted in a pronounced GH response (peak GH, 82.5 +/- 14.9 micrograms/L; n = 8). The GH peak was seen 30-45 min after initiation of the infusion. Small transient increases in cortical and PRL were observed (increases in cortical averaged 182.1 +/- 33.1 nmol/L and peak PRL was 21 +/- 2.6 micrograms/L after 1.0 mg/kg L-692,429, respectively), whereas no significant changes occurred in LH, FSH, TSH, insulin, or glucose concentrations. Plasma pharmacokinetic analysis revealed dose-related increases in plasma concentrations of L-692,429 and a half-life of 3.8 +/- 0.2 (+/- SE) h, a plasma clearance of 214 +/- 67 mL/min, and a steady state volume of distribution of 14.2 +/- 4.8 L. Facial flushing or a warm sensation were reported in 4 subjects, primarily at dose levels of 0.2 mg/kg L-692,429 or more, but no other clinical or laboratory adverse experiences appeared related to drug treatment. L-692,429, synthesized as a specific nonpeptide mimic of GH-releasing peptide-6, is thus a well tolerated, highly effective, and selective GH secretagogue in man.

We studied the effect of hydralazine, an antihypertensive drug with lupus-inducing side effects, on the conformation of poly(dG-m5dC).poly(dG-m5dC) and a plasmid with a 23 bp insert of (dG-dC)n.(dG-dC)n sequences. Using an e.l.i.s.a. with a monoclonal anti-(Z-DNA) antibody Z22, we found that hydralazine provoked the Z-DNA conformation in poly(dG-m5dC).poly(dG-m5dC) at 250-500 microM concentration. The supercoiled form of hydralazine-treated plasmid bound to Z22 in a gel-retardation assay. To examine further whether Z-DNA could act as an inciting agent in anti-nuclear antibody production in patients, we analysed 65 sera from 25 hypertensive patients taking hydralazine and found anti-(Z-DNA) antibodies in 82% of these sera. Sera from age-matched normal controls showed no binding to Z-DNA. Data on sera drawn sequentially from four hypertensive patients showed that antibodies were present after the drug treatment. These data demonstrate the presence of a high incidence of anti-(Z-DNA) antibodies in patients treated with hydralazine and suggest that a possible mechanism for the production of autoantibodies in drug-related lupus might involve the induction and stabilization of Z-DNA by drugs.

We conducted this study to assess the clinical usefulness and physiologic effects of intravenous iloprost in patients with Raynaud's phenomenon secondary to systemic sclerosis.Thirty-five patients with Raynaud's phenomenon secondary to systemic sclerosis, including 11 with digital ischemic ulcerations, were enrolled in a double blind placebo controlled parallel study in 2 centers. Following a 2 week washout, subjects received intravenous iloprost (0.5-2.0 ng/kg/min) or saline by continuous infusion for 6 h on 5 consecutive days. Clinical assessments, status of digital ulcers, measures of in vivo platelet activation and detailed studies of peripheral vascular response to cold challenge, were performed at entry, at 5 days of therapy and at biweekly intervals for 10 weeks.Complete healing of all cutaneous lesions (ulcers, fissures, and paronychia) was observed 10 weeks after treatment in 6 of 7 patients receiving iloprost versus none of 4 receiving placebo (p = 0.015). Ischemic digital tip ulcers completely healed in all 4 patients with ulcers in the iloprost group, but none in the placebo group (p = 0.029). Patient diaries of frequency, duration and symptoms of Raynaud's phenomenon showed improvement in both groups. Critical ischemic temperature (finger temperature during controlled cold challenge at which Raynaud's or loss of detectable digital blood flow occurred) progressively decreased in the iloprost group from 21.3 +/- 7.3 degrees C at baseline to a minimum of 16.1 +/- 3.2 degrees C at 8 weeks after treatment (p = 0.076), whereas no consistent changes were observed in the placebo group. Treatment was associated with improvement in the rate of skin temperature recovery following cold challenge. No changes were noted in ambient digital skin temperature, total digital blood flow, finger systolic pressure or in measures of in vivo platelet activation. One subject dropped out with chest pain, but adverse effects of nausea, vomiting, headache and jaw pain were otherwise limited to the 5 days of drug infusion.Iloprost appears useful for the treatment of digital ulcers in systemic sclerosis and is associated with evidence of prolonged physiologic improvement although the mechanism of this effect remains unclear.

A 45-yr-old female with mild chronic systemic lupus erythematosus for 20 yr, and with a stroke, digital infarction, and transient vocal cord paralysis during those 20 yr, had severe abdominal pain for 2 wk due to omental infarction associated with the presence of anticardiolipin antibodies. This report suggests that patients with otherwise mild systemic lupus erythematosus may develop severe recurrent thromboembolic events associated with anticardiolipin antibodies, that anticardiolipin antibodies may be associated with mesenteric ischemia, and that mesenteric ischemia associated with anticardiolipin antibodies should be considered in the differential of significant, unexplained abdominal pain in patients with systemic lupus erythematosus.

Plasma levels of soluble interleukin-2 receptors (sIL-2R) were measured by an enzyme-linked immunosorbent assay in 79 patients with systemic sclerosis (SSc). These levels were significantly elevated in SSc patients, compared with normal controls (mean +/- SEM 866.0 +/- 63.6 units/ml versus 293.0 +/- 20.5; P less than 0.001). Soluble IL-2R levels were highest in patients with generalized disease, were strongly associated with mortality (P less than 0.001) and inversely correlated with disease duration (P = 0.003), but were not related to sex, age, specific visceral involvement, serologic status, peripheral lymphocyte count, or therapy. Levels of sIL-2R in the supernatants of peripheral blood mononuclear cells were low in patients and controls, and showed comparable increases following phytohemagglutinin stimulation. Exposure of peripheral blood mononuclear cells to laminin did not induce sIL-2R release. Circulating IL-2 levels were comparably low in patients and controls. Our findings suggest the presence of lymphocyte activation in SSc, and further suggest that measurement of sIL-2R may prove to be a useful laboratory technique for assessing disease activity.

Many excited lines and a remarkable emission in the continuum were observed in the region around the H and K lines during a strong flare.

No single pathophysiologic mechanism explains adequately cold-induced vasospasm in all forms of Raynaud's phenomenon. Local serotonin release from activated platelets is a contributory element in those disorders typified by structural arterial change, e.g., systemic sclerosis (scleroderma). Selective antagonism of S2-serotonergic receptors with ketanserin improves both maximal digital artery flow and cold tolerance. Platelet-derived growth factors, and serotonin itself, may contribute to the fibrotic arteriosclerosis of this disorder. In contrast, in primary (spastic) Raynaud's phenomenon, ketanserin relieves but does not prevent cold-induced vasospasm, which suggests that the role of serotonin is in maintenance of but not provocation of an attack. Antiplatelet therapies could benefit both disorders.

Plasma beta-thromboglobulin (beta TG) levels were measured by radioimmunoassay in 61 patients with systemic sclerosis, 19 with carefully defined primary Raynaud's phenomenon, and 8 with Raynaud's phenomenon in suspected transition to systemic sclerosis. Elevated beta TG was present in 50 (82%) patients with systemic sclerosis but levels could not be correlated with duration or extent of disease nor any particular pattern of visceral involvement. Transitional Raynaud's patients had elevated beta TG in 7 (88%) cases, whereas results in patients with primary Raynaud's phenomenon were comparable to normal controls. beta TG, a sensitive measure of in vivo platelet activation, is useful in the differential diagnosis of Raynaud's phenomenon.

A 75-year-old woman rapidly developed symmetric skin induration with overlying venous furrowing of the inner arms and lateral thighs. This clinical picture and routine histopathologic study with fascial thickening and inflammation suggested a diagnosis of eosinophilic fasciitis. However, elastic tissue stain revealed marked accumulation of irregularly contoured elastin fibers which accounted for the majority of the fascial thickening. This previously undescribed condition is termed fascial elastosis.

Collagen production and collagenase activity were measured in dermal fibroblast cultures obtained from eight patients with diabetes with digital sclerosis and three normal controls. Total collagen synthesis in patients with diabetes was reduced in comparison with controls. DNA replication was also reduced in patients with diabetes. No differences in collagenase activity were noted. Our results suggest that, in contrast to systemic sclerosis, increased synthesis does not contribute to the collagen accumulation of diabetic digital sclerosis. Decreased degradation related to nonenzymatic glucosylation of collagen is a more likely mechanism.

A selective antagonist of S2-serotonergic receptors, ketanserin, was administered intravenously during right heart catheterization to 14 patients with pulmonary hypertension complicating systemic sclerosis. A significant reduction in pulmonary vascular resistance was noted which was accompanied by an increase in cardiac output. Paradoxical increase of pulmonary artery pressure occurred in 3 patients, whereas 2 patients with mild pulmonary hypertension normalized both pulmonary pressure and vascular resistance. Our data support the hypothesis that serotonin, released during in vivo platelet activation, influences pulmonary vascular tone in systemic sclerosis.

Palpable thickening and induration of the skin of the fingers were found in 47 (34%) of 137 children with insulin-dependent diabetes mellitus and in none of 52 normal children. Mild flexion contractures of the interphalangeal joints were seen in 26 (19%), mainly in those children with more extensive and severe skin changes. Such contractures have been linked to microvascular complications of diabetes. The clinical and pathogenic similarities to progressive systemic sclerosis make the digital sclerosis of childhood diabetes a promising model for further rheumatologic study.

In a double blind placebo crossover study, intravenous ketanserin, an antagonist of S2-serotonergic receptors, did not improve plethysmographically monitored digital blood flow during controlled cold challenge in 4 women with carefully defined primary Raynaud's phenomenon. However, ketanserin, if administered at the time of cold induced vasoconstriction, caused prompt vasodilation. These results suggest that serotonin is a contributory element in the maintenance of cold induced vasospasm but that other factors, presumedly adrenergic, initiate the vasoconstrictive response.

A patient is described with pulmonary hypertension complicating rheumatoid arthritis. Anticentromere antibody, a test of high specificity for the CREST syndrome, was present in the serum. Confirmation of this observation may lead to an improved classification of "primary" pulmonary hypertension.

A 55-year-old woman with rheumatoid arthritis in overlap with polymyositis received sulfasalazine for control of synovitis. Cholestatic jaundice, fever, urticaria and agranulocytosis developed after 20 days of treatment and culminated in fatal adult respiratory distress syndrome secondary to Legionella pneumophila. The increasing use of sulfasalazine in the therapy of rheumatoid arthritis mandates that the clinician be aware of this idiosyncratic drug reaction.

Serum eosinophil chemotactic activity was determined by the Boyden chamber technique in 20 patients with eosinophilic fasciitis. Increased eosinophil chemotactic activity (greater than 125% of background) was found in all 20 patients (mean 297% +/- 129), whereas sera of 20 controls with systemic sclerosis and diffuse scleroderma had increased eosinophil chemotactic activity in only 6 (30%) instances (mean 96% +/- 47, P less than 0.001). Although serum eosinophil chemotactic activity decreased over time in all 8 eosinophilic fasciitis patients studied longitudinally, this activity returned to normal in only 3, all of whom received prolonged courses of corticosteroids. Preliminary data suggest the existence of a eosinophilotactic serum factor common to patients with eosinophilic fasciitis.

A patient who presented with primary fibromyalgia syndrome (PFS) was found to have sleep apnea. Since frequent wakening and nonrestorative sleep are prominent clinical complaints in both disorders, we hypothesized an etiologic relationship. A subsequent clinical survey of 11 additional sleep apneics revealed that 3 (27%) fulfilled proposed criteria for PFS. This was significantly greater than local and literature reported studies of nonrheumatologic patients and was comparable to reported prevalence of fibromyalgia in rheumatologic referral populations. A blinded sleep physiology study of 7 patients with PFS revealed a significantly increased percentage of transitional sleep and increased frequency of miniarousals/h, but no significant evidence of occult sleep apnea compared to matched normal controls. The frequent arousals of sleep apnea may be associated with fibromyalgia in some patients but do not explain the sleep disorder of PFS.

Four patients with paraproteinemia and scleredema were studied. Histologic features included marked thickening and fibrosis of the dermis and subcutis. Variable amounts of mucin deposits were detected in the interfibrillar spaces. Serum from one patient significantly stimulated collagen production in normal skin fibroblast cultures, whereas serum from another patient stimulated collagen production in autologous cell cultures. Moreover, serum from one patient stimulated the [35S]sulfate incorporation into the fibroblasts. Circulating serum factors, possibly related to the paraprotein, may enhance the synthesis of extracellular macromolecules by dermal fibroblasts in these patients, thus providing a mechanism for dermal fibrosis.

We studied in vitro platelet aggregation response to serotonin in 19 patients with systemic sclerosis and 18 matched controls. Individuals with early systemic sclerosis had increased % platelet aggregation at 3 minutes over a wide range of serotonin concentrations when compared to individuals with late systemic sclerosis. Patients with generalized disease did not differ from those with limited disease. No significant differences in initial slope of platelet aggregation were detected in any patient subgroup. These data support previous studies suggesting platelet activation in systemic sclerosis and further suggest that future studies of platelet abnormalities in systemic sclerosis should consider the effects of disease duration.