Patterns and predictors of change in outcome measures in clinical trials in scleroderma: An individual patient meta‐analysis of 629 subjects with diffuse cutaneous systemic sclerosis

Objective

To examine the range and responsiveness to change of clinical outcome measures and study predictors of clinical response in patients with diffuse cutaneous systemic sclerosis (dcSSc) in the context of clinical trials.

Methods

Data were combined from 629 patients with dcSSc who participated in 7 multicenter clinical therapeutic trials. Trials used common outcome measures: modified Rodnan skin thickness score (MRSS), Health Assessment Questionnaire disability index (HAQ DI), patient's global assessment of disease activity, pulmonary function tests (forced vital capacity, diffusing capacity for carbon monoxide), hand span, and oral aperture.

Results

The combined database included 629 patients (82% women, mean ± SD age 46.5 ± 11.8 years, mean ± SD disease duration 19.4 ± 15.9 months). Outcomes tended to improve during trials for patients with more severe disease at study entry and to worsen for patients with less severe disease at entry. Disease duration was mildly negatively predictive of change in MRSS at 6 months (r = –0.27, P < 0.001), and substantial bidirectional variation in change in MRSS and HAQ DI score was seen across the spectrum of disease duration. Sixty‐three percent of patients with “early” disease (disease duration <18 months) had a decline in MRSS, and 37% had an increase in MRSS. Eighty‐one percent of patients with “late” disease (disease duration ≥18 months) had a decline in MRSS, and 19% had an increase in MRSS. Multivariate mixed models did not demonstrate that any baseline variables were strongly predictive of subsequent outcome.

Conclusion

Among patients with dcSSc enrolled in clinical trials, standard outcome measures tend to improve in those with more severe disease at study entry and to worsen in those with less severe disease at entry. Overall, the MRSS improves during trials, while HAQ DI scores and lung function are mostly static. None of these variables, including disease duration, reliably identifies groups of subjects whose MRSS will predictably increase or decrease in the course of a clinical trial. These findings have important implications for clinical trial design in scleroderma.

     

B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis

Objective

To determine the safety of rituximab, to provide preliminary data regarding the potential efficacy of rituximab, and to investigate the effects of rituximab on autoimmunity and fibrosis in patients with diffuse cutaneous systemic sclerosis (dcSSc).

Methods

Fifteen patients with dcSSc, all of whom experienced their first non–Raynaud's disease–associated disease manifestation within 18 months of trial entry, were recruited to receive 2 intravenous doses of rituximab (1,000 mg), administered 2 weeks apart. Safety, clinical, and exploratory outcomes were evaluated at baseline and at 6 months. The primary outcome was the change in the modified Rodnan skin thickness score (MRSS) at 6 months compared with baseline.

Results

Adverse events included frequent infusion reactions and rare infections (urinary tract infection and dental abscess occurred in 1 patient each). The mean change in the MRSS between baseline and 6 months was not significant. Results of pulmonary function tests and other measures of major organ involvement were stable. The modest B cell infiltrates that were present in most skin biopsy specimens at baseline were completely depleted at 6 months in most patients. Autoantibody titers showed only modest and variable changes after treatment.

Conclusion

In this pilot study, treatment with rituximab appeared to be safe and well tolerated among patients with dcSSc. Rituximab treatment resulted in both depletion of circulating B cells and depletion of dermal B cells but had little effect on the levels of SSc‐associated autoantibodies. Rituximab treatment did not appear to result in a significant beneficial effect on skin disease. The potential efficacy of rituximab in other organs such as the lung could not be clearly evaluated in this small open‐label trial.

     

Clinical subsets,skin thickness progression rate,and serum antibody levels in systemic sclerosis patients with anti–topoisomerase I antibody

Objective

To describe the clinical and laboratory features and natural history of the disease in systemic sclerosis (SSc; scleroderma) patients with anti–topoisomerase I (anti–topo I) antibody who have different skin thickness progression rates (STPRs).

Methods

SSc patients (n = 212) who were anti–topo I antibody positive were divided into 5 subgroups based on STPRs. Skin thickness was measured using the modified Rodnan skin thickness score (MRSS). Anti–topo I IgG antibody levels were determined.

Results

Sixty patients who were anti–topo I antibody positive had diffuse cutaneous SSc (dcSSc) with rapid progression, 82 had dcSSC with intermediate progression, and 29 had dcSSc with slow progression, 14 had limited cutaneous SSc (lcSSc) that became dcSSc, and 27 had lcSSc that did not change throughout. Patients beginning with lcSSc were younger at disease onset and had longer disease duration when diagnosed as having SSc. Interstitial lung disease was common and was equally distributed across the subgroups. Renal crisis occurred most often in patients with rapid progression (22%) and was absent in lcSSc patients. Cardiac involvement was most frequent in the dcSSc subgroups. Both kidney and heart disease occurred most often within 3 years after the onset of skin thickening. The 10‐year cumulative survival rate was <40% for patients with rapid and intermediate progression. Renal and cardiac causes of death were disproportionately frequent in these 2 subgroups. Anti–topo I antibody levels correlated with the STPR and the MRSS.

Conclusion

Anti–topo I antibody–positive patients with SSc with a rapid STPR have reduced survival rates, primarily due to early and often fatal renal and cardiac involvement. Anti–topo I antibody levels parallel the MRSS at the first visit and the STPR. This information is important for managing physicians and researchers planning clinical trials involving patients with early dcSSc.

     

Recombinant human anti–transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter,randomized, placebo‐controlled phase I/II trial of CAT‐192

Objective

To evaluate CAT‐192, a recombinant human antibody that neutralizes transforming growth factor β1 (TGFβ1), in the treatment of early‐stage diffuse cutaneous systemic sclerosis (dcSSc).

Methods

Patients with SSc duration of <18 months were randomly assigned to the placebo group or to 1 of 3 CAT‐192 treatment groups: 10 mg/kg, 5 mg/kg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT‐192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ‐based disease, serum levels of soluble interleukin‐2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFβ1 and TGFβ2.

Results

Forty‐five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT‐192 and 3 deaths in the group receiving 5 mg/kg of CAT‐192. There were more adverse events and more serious adverse events in patients receiving CAT‐192 than in those receiving placebo, although these events were not more frequent in the high‐dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT‐192. Improvement in the MRSS correlated with the disease duration (r = −0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027).

Conclusion

We report the first evaluation of a systemically administered and repeatedly dosed anti‐TGFβ1 drug. In this pilot study, CAT‐192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed.

     

Efficacy of Mycophenolate Mofetil and Oral Cyclophosphamide on Skin Thickness: Post Hoc Analyses From Two Randomized Placebo‐Controlled Trials

Objective

To assess the efficacy of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) on modified Rodnan skin score (MRSS) in participants enrolled in the Scleroderma Lung Study (SLS) I and II.

Methods

SLS I participants received daily oral CYC or matching placebo for 1 year, whereas SLS II participants received daily MMF for 2 years or daily oral CYC for 1 year followed by placebo for second year. We assessed the impact of MMF and CYC on the MRSS in SLS II over a 24‐month period. We also compared the change in MRSS in patients with diffuse cutaneous systemic sclerosis (dcSSc) assigned to CYC and MMF in SLS II and SLS I versus placebo in SLS I over a 24‐month period using a linear mixed model.

Results

In SLS II, the baseline mean ± SD MRSS was 14.0 ± 10.6 units for CYC and 15.3 ± 10.4 units for MMF; 58.5% were classified as dcSSc. CYC and MMF were associated with statistically significant improvements in MRSS from baseline over the period of 24 months in dcSSc (P < 0.05 at each time point), but there were no differences between the 2 groups. In the dcSSc subgroup, the change in MRSS from baseline to all 6‐month visits was similar in SLS II groups (MMF, CYC, pooled cohort [MMF + CYC]) and in the SLS I CYC group and showed statistically significant improvements compared to SLS I placebo at 12, 18, and 24 months (P < 0.05).

Conclusion

In SLS II, MMF and CYC treatment resulted in improvements in MRSS in patients with dcSSc over 24 months. In addition, MMF and CYC treatment resulted in statistically significant improvements in MRSS in patients with dcSSc when compared with the SLS I placebo group.

     

Imatinib in active diffuse cutaneous systemic sclerosis: Results of a six‐month,randomized, double‐blind,placebo‐controlled,proof‐of‐concept pilot study at a single center

Objective

To better understand the feasibility of using imatinib, a tyrosine kinase inhibitor, to treat active diffuse cutaneous systemic sclerosis (dcSSc).

Methods

We performed a 6‐month, randomized, double‐blind, placebo‐controlled, proof‐of‐concept pilot study of imatinib in patients with active dcSSc. Data on safety, modified Rodnan skin thickness scores (MRSS), Health Assessment Questionnaire (HAQ) scores, patient's and physician's global assessments (100‐mm visual analog scale), and biomarkers in serum and skin biopsy samples were collected. We used a 4:1 randomization strategy (imatinib 200 mg administered twice a day versus placebo), stratifying according to current use of methotrexate. The plan was to enroll 20 dcSSc patients.

Results

After enrolling 10 patients (9 receiving active drug and 1 receiving placebo), we found poor tolerability and high rates of adverse events with imatinib, and study enrollment was discontinued. There was no significant difference in the mean MRSS in all patients who took imatinib (31.1 at baseline versus 29.4 at 6 months) or in only those who completed 6 months of imatinib (31.0 at baseline versus 30.3 at 6 months), and there was no difference in the C‐reactive protein level, erythrocyte sedimentation rate, physician's global assessment, patient's global assessment, response to the Health Transition query, or the HAQ scores between those who did and those who did not complete 6 months of therapy. Side effects were edema, fluid retention, fatigue, nausea, cramps/myalgias, diarrhea, alopecia, and anemia. Most side effects occurred within the first week of treatment, and even when imatinib was reintroduced at a lower dosage (200 mg daily), it was poorly tolerated. Two patients were hospitalized because of side effects of the medication. In general, biomarker levels in plasma and skin did not change.

Conclusion

Imatinib was poorly tolerated, and this could limit its application in SSc. The study was too small to form conclusions about the efficacy of imatinib in SSc.

     

Minocycline is not effective in systemic sclerosis: Results of an open‐label multicenter trial

Objective

To determine if minocycline therapy improved skin thickness in early, diffuse systemic sclerosis (SSc) by ≥30%, a level of improvement unlikely to occur in the natural history of the disease as determined by recent controlled trials.

Methods

Subjects with diffuse SSc of ≤5 years' duration were treated with oral minocycline for 1 year. The primary outcome measure was the modified Rodnan skin thickness score (MRSS).

Results

Of 36 subjects initially enrolled, 31 returned for at least 1 followup visit and were included in the analysis (modified intent‐to‐treat analysis). The group consisted of 23 women and 8 men, with a mean age of 51.7 years (range 26–82 years) and a mean disease duration of 23.5 months (range 6–60 months). The mean MRSS at entry was 22.7 (range 12–43), and at the final visit it was 18.6 (range 2–48). There was no statistically significant difference in the change in skin scores between the minocycline‐treated subjects and subjects previously reported in the D‐penicillamine (D‐Pen) trial. In addition, when adjusted for disease duration, a comparison of MRSS in the minocycline trial subjects (including all subjects active at each time point) and the previously reported D‐Pen trial subjects showed no difference and no treatment effect. Fourteen subjects did not complete all 12 months of treatment; 10 of them withdrew due to disease progression. Disease duration was significantly shorter for the noncompleters than for the completers (P < 0.03).

Conclusion

The degree of change in the MRSS was similar to that expected in the natural course of this disease. Based on these data, minocycline is not an effective therapy for SSc.

     

Predicting treatment outcomes and responder subsets in scleroderma‐related interstitial lung disease

Objective

To identify baseline characteristics of patients with scleroderma‐related interstitial lung disease (SSc‐ILD) that could serve as predictors of the most favorable response to 12‐month treatment with oral cyclophosphamide (CYC).

Methods

Regression analyses were retrospectively applied to the Scleroderma Lung Study data in order to identify baseline characteristics that correlated with the absolute change in forced vital capacity (FVC) (% predicted values) and the placebo‐adjusted change in % predicted FVC over time (the CYC treatment effect).

Results

Completion of the CYC arm of the Scleroderma Lung Study was associated with a placebo‐adjusted improvement in the % predicted FVC of 2.11% at 12 months, which increased to 4.16% when patients were followed up for another 6 months (P = 0.014). Multivariate regression analyses identified the maximal severity of reticular infiltrates (assessed as maximum fibrosis scores) on high‐resolution computed tomography (HRCT) at baseline, the modified Rodnan skin thickness score (MRSS) at baseline, and the Mahler baseline dyspnea index as independent correlates of treatment response. When patients were stratified on the basis of whether 50% or more of any lung zone was involved by reticular infiltrates on HRCT and/or whether patients exhibited an MRSS of at least 23, a subgroup of patients emerged in whom there was an average CYC treatment effect of 9.81% at 18 months (P < 0.001). Conversely, there was no treatment effect (a −0.58% difference) in patients with less severe HRCT findings and a lower MRSS at baseline.

Conclusion

A retrospective analysis of the Scleroderma Lung Study data identified the severity of reticular infiltrates on baseline HRCT and the baseline MRSS as patient features that might be predictive of responsiveness to CYC therapy.

     

Modified‐release sildenafil reduces Raynaud's phenomenon attack frequency in limited cutaneous systemic sclerosis

Objective

To examine the effect of sildenafil in patients with Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis (lcSSc).

Methods

In this double‐blind, placebo‐controlled study, 57 patients with RP secondary to lcSSc were randomized to receive modified‐release sildenafil 100 mg once daily for 3 days followed by modified‐release sildenafil 200 mg once daily for 25 days or placebo. The primary assessment was the percentage change in the number of RP attacks per week in the per‐protocol population. Secondary end points included Raynaud's Condition Score, duration of attacks, RP pain score, endothelial dysfunction assessed by a peripheral arterial tonometric (PAT) device, and serum biomarker levels.

Results

The mean percentage reduction from baseline to day 28 in attacks per week was greater for modified‐release sildenafil than for placebo (−44.0% versus −18.1%, P = 0.034); the mean number of attacks per week improved from 25.0 at baseline to 19.3 after placebo treatment and from 30.5 to 18.7 after modified‐release sildenafil treatment (P = 0.244). Decreases from baseline in Raynaud's Condition Score, duration of attacks, and RP pain score were not significantly different between groups. Mean values and changes from baseline in PAT responses and serum biomarker levels were similar between groups. The most frequent adverse events were headache and dyspepsia; the majority of adverse events were mild or moderate.

Conclusion

Our findings indicate that modified‐release sildenafil reduced attack frequency in patients with RP secondary to lcSSc and was well tolerated. Modified‐release sildenafil may be a treatment option in this patient population.

     

MQX‐503, a novel formulation of nitroglycerin,improves the severity of Raynaud's phenomenon: A randomized,controlled trial

Objective

Raynaud's phenomenon (RP) affects 3–9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX‐503, in the treatment of RP in an ambulatory setting.

Methods

We conducted a multicenter, randomized, placebo‐controlled study with a 2‐week single‐blind run‐in period to determine baseline severity, followed by a 4‐week double‐blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX‐503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0–10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run‐in period in terms of ambient temperature) compared with baseline.

Results

The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX‐503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX‐503 had a side effect profile similar to that of placebo.

Conclusion

MQX‐503 is well tolerated and more effective than placebo for the treatment of RP.

     

A four‐gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis

Objective

Improved outcome measures in systemic sclerosis (SSc) are critical to finding active therapeutics for this disease. The modified Rodnan skin thickness score (MRSS) is the current standard for evaluating skin disease in SSc, but it is not commonly used in the clinical setting, in part because it requires specialized training to perform accurately and consistently. The purpose of this study was to investigate whether skin gene expression might serve as a more objective surrogate outcome measure to supplement skin score evaluations.

Methods

Skin RNAs from a group of patients with diffuse cutaneous SSc were studied for expression levels of genes known to be regulated by transforming growth factor β (TGFβ) and interferon (IFN). These levels were correlated with the MRSS, using multiple regression analyses to obtain best‐fit models.

Results

Skin expression of the TGFβ‐regulated genes cartilage oligomeric matrix protein (COMP) and thrombospondin 1 (TSP‐1) correlated moderately well with the MRSS, but the addition of other TGFβ‐regulated genes failed to significantly improve best‐fit models. IFN‐regulated genes were also found to correlate with the MRSS, and the addition of interferon‐inducible 44 (IFI44) and sialoadhesin (Siglec‐1) to COMP and TSP‐1 in multiple regression analyses significantly improved best‐fit models, achieving an R² value of 0.89. These results were validated using an independent group of skin biopsy samples. Longitudinal scores using this 4‐gene biomarker indicated that it detects change over time that corresponds to changes in the MRSS.

Conclusion

We describe a 4‐gene predictor of the MRSS and validate its performance. This objective measure of skin disease could provide a strong surrogate outcome measure for patient care and for clinical trials.

     

Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials

Objective

To assess the effect of vitamin C supplementation on serum uric acid (SUA) by pooling the findings from published randomized controlled trials (RCTs).

Methods

A total of 2,082 publications identified through systematic search were subjected to the following inclusion criteria: 1) RCTs conducted on human subjects, 2) reported end‐trial SUA means and variance, 3) study design with oral vitamin C supplementation and concurrent control groups, and 4) trial duration of at least 1 week. Trials that enrolled children or patients receiving dialysis were excluded. Two investigators independently abstracted trial and participant characteristics. SUA effects were pooled by random‐effects models and weighted by inverse variance.

Results

Thirteen RCTs were identified in the Medline, EMBase, and Cochrane Central Register of Controlled Trials databases. The total number of participants was 556, the median dosage of vitamin C was 500 mg/day, trial size ranged from 8–184 participants, and the median study duration was 30 days. Pretreatment SUA values ranged from 2.9–7.0 mg/dl (Système International d'Unités [SI units]: 172.5–416.4 μmoles/liter). The combined effect of these trials was a significant reduction in SUA of ?0.35 mg/dl (95% confidence interval ?0.66, ?0.03 [P = 0.032]; SI units: ?20.8 μmoles/liter). Trial heterogeneity was significant (I² = 77%, P < 0.01). Subgroup analyses based on trial characteristics indicated larger reductions in uric acid in trials that were placebo controlled.

Conclusions

In aggregate, vitamin C supplementation significantly lowered SUA. Future trials are needed to determine whether vitamin C supplementation can reduce hyperuricemia or prevent incident and recurrent gout.

     

Contribution of activin receptor–like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts

Objective

To use a specific transforming growth factor β receptor type I (TGFβRI; activin receptor–like kinase 5 [ALK‐5]) kinase inhibitor (SD208) to determine the role of activation of the TGFβRI kinase (ALK‐5) in maintaining the profibrotic phenotype of dermal fibroblasts in systemic sclerosis (SSc).

Methods

The effect of SD208 on the expression of key biochemical markers of the fibrotic phenotype was compared in fibroblasts cultured from clinically involved (lesional) and clinically uninvolved skin of patients with diffuse cutaneous SSc (dcSSc) and in fibroblasts from healthy controls matched for age, sex, and anatomic site. Protein expression was compared together with the ability of fibroblasts to adhere to the extracellular matrix and to remodel and contract a free‐floating fibroblast–populated type I collagen lattice.

Results

Inhibiting TGFβRI kinase reduced the expression of a cohort of fibrotic markers by dermal fibroblasts from patients with dcSSc, including type I collagen and β1 integrin. Moreover, inhibition also attenuated the elevated adhesive and contractile abilities of dcSSc fibroblasts.

Conclusion

Our data suggest that some of the key profibrotic features of lesional SSc fibroblasts are dependent upon ALK‐5 activity. Thus, TGFβRI kinase–mediated signaling may contribute to dermal fibrosis in dcSSc.

     

Prevalence of and predictive factors for sustained disease‐modifying antirheumatic drug–free remission in rheumatoid arthritis: Results from two large early arthritis cohorts

Objective

Remission has become an attainable goal of rheumatoid arthritis (RA) treatment, especially since the advent of biologic antirheumatic therapy. Because little is known about patients who achieve disease remission with conventional treatment, we used 2 large independent inception cohorts to study the prevalence of and predictive factors for disease‐modifying antirheumatic drug (DMARD)–free sustained remission after treatment with conventional therapy.

Methods

Remission of disease was assessed in 454 patients from the Leiden Early Arthritis Clinic (EAC) and in 895 patients from the British Early Rheumatoid Arthritis Study (ERAS) who fulfilled the American College of Rheumatology 1987 revised criteria for the classification of RA and were treated with conventional therapy. Sustained DMARD‐free remission was defined as fulfilling the following criteria for at least 1 year: 1) no current DMARD use, 2) no swollen joints, and 3) classification as DMARD‐free remission by the patient's rheumatologist. Predictive factors were identified by Cox regression analysis.

Results

Sustained DMARD‐free remission was achieved by 68 of 454 patients (15.0%) in the Leiden EAC and by 84 of 895 patients (9.4%) in the ERAS. Six factors were associated with sustained DMARD‐free remission in both cohorts: acute onset, short symptom duration before inclusion, not smoking, little radiographic damage at baseline, absence of IgM rheumatoid factor (IgM‐RF), and absence of HLA shared epitope alleles. In the ERAS, low disease activity at baseline was also predictive of remission. Multivariate analyses revealed symptom duration and the absence of autoantibodies (anti–cyclic citrullinated peptide 2 and IgM‐RF) as independent predictors.

Conclusion

Sustained DMARD‐free remission in RA patients treated with conventional therapy is not uncommon. Symptom duration at presentation and the absence of autoantibodies are associated with sustained DMARD‐free remission.

     

A one‐year,phase I/IIa,open‐label pilot trial of imatinib mesylate in the treatment of systemic sclerosis–associated active interstitial lung disease

Objective

Transforming growth factor β (TGFβ) and platelet‐derived growth factor (PDGF) may play a critical role in systemic sclerosis (SSc)–related interstitial lung disease (ILD), and imatinib is a potent inhibitor of TGFβ and PDGF production. In this 1‐year, phase I/IIa open‐label pilot study of imatinib in patients with SSc‐related active ILD, our primary aim was to assess the safety of imatinib; we also explored its efficacy.

Methods

We recruited 20 SSc patients with a forced vital capacity (FVC) of <85% predicted, dyspnea on exertion, and presence of a ground‐glass appearance on high‐resolution computed tomography. Patients received oral therapy with imatinib (up to 600 mg/day) for a period of 1 year. Adverse events were recorded, pulmonary function was tested, and the modified Rodnan skin thickness score (MRSS) was assessed every 3 months. The course of changes in lung function, the Health Assessment Questionnaire (HAQ) disability index (DI), and the MRSS were modeled over the period of study to explore treatment efficacy.

Results

The majority of patients were female (65%), Caucasian (75%), and had diffuse cutaneous SSc (70%). At baseline, the mean ± SD FVC % predicted was 65.2 ± 14.0 and the mean ± SD MRSS was 18.7 ± 10.1. The mean ± SD dosage of imatinib was 445 ± 125 mg/day. Of the 20 SSc patients, 12 completed the study, 7 discontinued because of adverse events (AEs), and 1 patient was lost to followup. Common AEs (≥20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new‐onset proteinuria. Treatment with imatinib showed a trend toward improvement in the FVC % predicted (1.74%; P not significant) and the MRSS (3.9 units; P < 0.001).

Conclusion

Use of high‐dose daily therapy with imatinib (600 mg/day) in SSc patients with ILD was associated with a large number of AEs. Our experience with AEs suggests that dosages of imatinib lower than 600 mg/day may be appropriate and that further dose ranging analysis is needed in order to understand the therapeutic index of imatinib in SSc.

     

Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: A randomized,double‐blind,placebo‐controlled trial

Objective

A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 μg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double‐blind, placebo‐controlled clinical trial to compare placebo with 10 μg/kg/day and 25 μg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate‐to‐severe SSc.

Methods

Men and women ages 18–70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 μg/kg/day or 25 μg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28.

Results

The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo.

Conclusion

Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

     

Living with osteoarthritis: patient expenditures,health status,and social impact

Objective

To determine “out‐of‐pocket” expenditures related to osteoarthritis (OA) and to explore whether demographic details, health status scores (Medical Outcomes Study 36‐item Short Form [SF‐36] and Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), or perception of social effect were expenditure determinants.

Methods

A prospective cohort study of community‐dwelling subjects with OA completed 4 consecutive 3‐month cost diaries. In addition, subjects completed the SF‐36 and WOMAC at baseline and at 12 months. Social impact at baseline was collected. Four groups categorized by age and sex were compared. Patients undergoing joint replacement were excluded.

Results

Differences in health status were defined more by age than by sex, especially for physical function. The costs to the patients were high, particularly for women, who spent more on medications and special equipment. Women also reported receiving more assistance from family and friends. Higher disease‐related expenditures were associated with greater pain levels, poorer social function and mental health, and longer duration of disease. Significant independent predictors of total patient expenditures related to OA were being female and having joint stiffness.

Conclusion

Despite having heavily subsidized health care and access to the Pharmaceutical Benefits Scheme, out‐of‐pocket costs for patients with OA in Australia are considerable. Higher expenditures for patients with OA are related to more advanced disease, especially for women.

     

Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

Objective

T lymphocytes play an important role in systemic sclerosis (SSc), a connective tissue disease characterized by inflammation, fibrosis, and vascular damage. While their precise role and antigen specificity are unclear, T cell–derived cytokines likely contribute to the induction of fibrosis. The aim of this study was to establish the role of cytokine dysregulation by T cells in the pathogenesis of SSc.

Methods

To identify relationships between a specific cytokine, T cell subset, and the disease course, we studied a large cohort of patients with diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc). Using Luminex analysis and intracellular cytokine staining, we analyzed the intrinsic ability of CD4+ and CD8+ T cell subsets to produce cytokines following in vitro activation.

Results

High levels of the profibrotic type 2 cytokine interleukin‐13 (IL‐13) were produced following activation of peripheral blood effector CD8+ T cells from SSc patients as compared with normal controls or with patients with rheumatoid arthritis. In contrast, CD4+ T cells showed a lower and more variable level of IL‐13 production. This abnormality correlated with the extent of fibrosis and was more pronounced in dcSSc patients than in lcSSc patients.

Conclusion

Dysregulated IL‐13 production by effector CD8+ T cells is important in the pathogenesis of SSc and is critical in the predisposition to more severe forms of cutaneous disease. Our study is the first to identify a specific T cell phenotype that correlates with disease severity in SSc and can be used as a marker of immune dysfunction in SSc and as a novel therapeutic target.