Pollinator-mediated selection on floral morphology: evidence for transgressive evolution in a derived hybrid lineage.

Hybridization between closely related lineages is a mechanism that might promote substantive changes in phenotypic traits of descendants, resulting in transgressive evolution. Interbreeding between divergent but morphologically similar lineages can produce exceptional phenotypes, but the potential for transgressive variation to facilitate long-term trait changes in derived hybrid lineages has received little attention. We compare pollinator-mediated selection on transgressive floral traits in both early-generation and derived hybrid lineages of the Piriqueta cistoides ssp. caroliniana complex. The bowl-shaped flowers of morphotypes in this complex have similar gross morphologies and attract a common suite of small insect pollinators. However, they are defined by significant differences in characters that generate pollinator interest and visitation, including floral area and petal separation. In common garden experiments, patterns of pollen deposition in early-generation recombinant hybrids indicate that Piriqueta's pollinators favour flowers with greater area and reduced petal separation. Changes in floral morphology in derived hybrid lineages are consistent with predictions from selection gradients, but the magnitude of change is limited relative to the range of transgressive variation. These results suggest that hybridization provides variation for evolution of divergent floral traits. However, the potential for extreme transgressive variants to contribute to phenotypic shifts may be limited due to reduced heritability, evolutionary constraints or fitness trade-offs.

Translational mini-review series on immunology of vascular disease: inflammation, infections and Toll-like receptors in cardiovascular disease.

Cardiovascular disease, in which atherosclerosis is the major underlying cause, is currently the largest cause of death in the world. Atherosclerosis is an inflammatory disease characterized by the formation of arterial lesions over a period of several decades at sites of endothelial cell dysfunction. These lesions are composed of endothelial cells, vascular smooth muscle cells, monocytes/macrophages and T lymphocytes (CD4(+)). As the lesions progress some can become unstable and prone to disruption, resulting in thrombus formation and possibly a myocardial infarction or stroke depending upon the location. Although the exact triggers for plaque disruption remain unknown, much recent evidence has shown a link between the incidence of myocardial infarction and stroke and a recent respiratory tract infection. Interestingly, many reports have also shown a link between a family of pattern recognition receptors, the Toll-like receptors, and the progression of atherosclerosis, suggesting that infections may play a role in both the progression of atherosclerosis and in inducing the more severe complications associated with the disease.

RISK-SENSITIVE ANTIPREDATOR BEHAVIOR IN THE TRINIDADIAN GUPPY, POECILIA RETICULATA.

The comparative approach has become a powerful tool for understanding how predation has shaped prey behavior. In this study we recorded the occurrence of common aquatic predator species and their densities in seven natural populations of Trinidadian guppies, Poecilia reticulata. We then exposed shoals of guppies from each of these populations to a series of predator treatments. Predator treatments differed in the species of predator used (pike cichlids, Crenicichla frenata; rivulus, Rivulus hartii; and freshwater prawns, Macrobrachium carcinus) and thus in the level of risk posed. We recorded the antipredator responses of guppies in each of these predator treatments. The strength of antipredator behavior shown by guppies was affected by both the type of predator they were exposed to and the level of predation risk they experienced naturally in the wild. Importantly, we found that guppies from high-risk populations showed a heightened response, compared to those from lower risk populations, only when exposed to the predator species that posed the greatest risk. Our results show the importance of individual predator species in shaping the behavioral traits of prey species at the population level. This has implications for prey movement between habitats that are geographically close but differ greatly in predator fauna.

Coral diversity and disease in Mexico.

Field studies and empirical tests of the 'diversity-disease hypothesis' demonstrate the effects of species richness on disease transmission and severity in plant systems. Yet the converse, i.e. effects of disease on diversity, is rarely considered in either relatively well-studied plant systems or marine ecosystems. We investigated these effects along the Mexican Yucatan Peninsula to (1) quantify the relationship between disease prevalence and coral diversity, (2) test the hypothesis that octocoral and scleractinian disease prevalence are associated with one another, and (3) establish a long-term dataset. Aspergillosis of sea fans and 6 scleractinian diseases were documented. Prevalence of aspergillosis declined from 12.85% in 2002 to 5.26% in 2004, while prevalence of scleractinian diseases remained relatively constant at 5.7 +/- 0.8% in 2002 and 7.96 +/- 0.7% in 2004. Sites were relatively rich (71 species of octocoral and scleractinian corals) and even (E5 > 0.5). Sea fan disease prevalence was not associated with scleractinian disease prevalence, nor were there consistent associations between disease and measures of diversity. However, the most abundant octocoral and scleractinian species are susceptible to infection with several diseases, and disease may alter coral diversity in complex ways. These data represent the first in what will become a long-term dataset monitoring disease prevalence and associated changes in coral diversity.

Monophosphoryl lipid A enhances mucosal and systemic immunity to vaccine antigens following intranasal administration.

The induction of protective immunity stemming from vaccines delivered by mucosal routes is dependent on the development of safe and effective mucosal adjuvants. The immunostimulant monophosphoryl lipid A (MPL(R)) was evaluated for its ability to enhance both systemic and mucosal immunity to three distinct antigens. Vaccines formulated with MPL(R) and hepatitis B surface antigen, tetanus toxoid or influenza antigens were administered by intranasal delivery to mice. In each case the vaccines formulated with MPL(R) resulted in enhanced IgA titers from mucosal samples. Enhanced IgA concentrations were detected in samples from both local and distal mucosal sites. In addition, the MPL(R) formulated vaccines induced systemic immunity characteristic of a Th1-type of response. Serum IgG2a antibody titers were elevated and cytotoxic T cell activity was enhanced.

3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant activities.

The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific antibodies in mice.

Synthesis and biological evaluation of a new class of vaccine adjuvants: aminoalkyl glucosaminide 4-phosphates (AGPs).

A novel series of acylated omega-aminoalkyl 2-amino-2-deoxy-4-phosphono-beta-D-glucopyranosides (aminoalkyl glucosaminide 4-phosphates) was synthesized and screened for immunostimulant activity. Several of these compounds enhance the production of tetanus toxoid-specific antibodies in mice and augment vaccine-induced cytotoxic T cells against EG.7-ova target cells.

Early undifferentiated connective tissue disease (CTD). VI. An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated CTD.

OBJECTIVE: (1) To review the diagnoses after 10 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD). (2) To examine the death rates and disease remissions in these patients. METHODS: This inception cohort of 410 patients had less than one year of signs and/or symptoms of CTD. Diagnoses of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and poly/dermatomyositis (PM/DM) were made in 197 patients using accepted diagnostic and classification criteria. Diagnoses of undifferentiated CTD were made in 213 patients. These latter patients were placed in 3 categories: isolated Raynaud's phenomenon (RP), unexplained polyarthritis (UPA), and undifferentiated CTD (UCTD), defined as meeting at least 3 of 11 specific manifestations of CTD. The diagnoses and remissions in all patients after 10 years were determined. RESULTS: Patients with well established CTD tended to remain with the original diagnosis. The 10 year survival was at least 87% in all diagnostic categories, with the exception of SSc, in which it was 56%. The progression of UPA to RA occurred infrequently. The presence of antinuclear antibodies suggested that UPA may develop additional symptoms and/or a specific diagnosis, and RP in these patients increased the likelihood of progressing to UCTD or a specific well established CTD. Ten percent of patients with RP progressed to SSc. In patients with UCTD, joint pain/tenderness and swelling counts were associated with progression to other diagnoses including RA, while either serositis, malar rash, or discoid lupus suggested the eventual diagnosis of SLE. CONCLUSION: The survival of patients with SSc was poor, with most dying early in the course of their disease. Remissions were seen in all groups of patients except SSc. The remissions were sometimes transient in SLE. Undifferentiated disease at initial examination within 12 months of onset usually remains undifferentiated.

Concurrent medical disease in work-related carpal tunnel syndrome.

BACKGROUND: Work-related carpal tunnel syndrome (CTS) now accounts for more than 41% of all repetitive motion disorders in the United States. Carpal tunnel syndrome is also associated with obesity and many different medical diseases. PATIENTS AND METHODS: Two hundred ninety-seven patients medically certified with a work-related upper extremity industrial illness underwent a systematic search for concurrent medical diseases. Diagnoses of CTS were made using 4 separate case definitions. RESULTS: One hundred nine separate atraumatic illnesses (mainly hypothyroidism, diabetes mellitus, and various arthropathies) capable of causing arm pain or CTS were diagnosed in a third of all patients. Using record reviews and patient histories alone, 68% of these conditions would have been missed. One hundred ninety-eight patients had been diagnosed as having CTS 420 times in more than 1000 office visits, but diagnostic laboratory studies were ordered only 25 times. Every case definition of CTS was significantly associated with a related medical condition. Two definitions yielded more than 41% prevalence of concurrent disease (odds ratio, > or = 2.36; P < or = .004), and up to two thirds of these patients had either a medical disease or were obese (odds ratio, > or = 3.15; P < or = .001). Two cohorts totaling 114 patients (38%) working for companies employing nearly 19,000 people included all CTS claims filed during 2 evaluation periods. They did not differ from the other patients with CTS with respect to age, concurrent disease, or obesity. CONCLUSIONS: Routine patient histories and record reviews are inadequate for proper evaluation of work-related CTS. Unrecognized medical diseases capable of causing CTS are common. Studies asserting an association between occupational hand usage and CTS are of questionable validity unless they prospectively account for confounding disease and obesity.

Early undifferentiated connective tissue disease. V. An inception cohort 5 years later: disease remissions and changes in diagnoses in well established and undifferentiated connective tissue diseases.

OBJECTIVE: To review the diagnoses after 5 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD); to examine death rates and disease remissions in these patients. METHODS: This inception cohort of 410 patients was identified in 10 academic rheumatology practices. They had less than one year of signs and/or symptoms of CTD. Diagnoses of specific well established CTD were made using accepted diagnostic and classification criteria. The diagnoses after 5 years were determined. RESULTS: Patients with well established CTD tended to remain with the original diagnosis. The progression of unexplained polyarthritis to rheumatoid arthritis occurred infrequently. Ten percent of patients with isolated Raynaud's phenomenon progressed to systemic sclerosis (SSc). The 5 year survival was over 90% in all diagnostic categories, with the exception of SSc, in which it was 64%. CONCLUSION: Patients with a well established CTD usually continued with the same diagnosis. Patients with undifferentiated CTD tended to remain undifferentiated or to remit.

Effective adjuvants for the induction of antigen-specific delayed-type hypersensitivity.

Vaccines utilizing poorly immunogenic subunit antigens are dependent upon adjuvants to drive the appropriate T cell responses. In an effort to determine the ability of several adjuvants to promote cell-mediated immunity (CMI), we assessed delayed-type hypersensitivity (DTH) in mice inoculated with heat-killed Listeria monocytogenes (HKLM) vaccines. The vaccines were formulated as oil-in-water emulsions containing one or more of the following bacterial-derived immunostimulators: MPL immunostimulant, a monophosphoryl lipid A preparation, synthetic trehalose dicorynomycolate (TDCM) and Mycobacterium phlei cell wall skeleton (CWS). Oil-in-water emulsions containing HKLM without adjuvants did not induce DTH responsiveness in mice. The incorporation of TDCM, or MPL plus TDCM and/or CWS to the formulation enabled the HKLM vaccine to stimulate CMI characterized by DTH responsiveness. Following antigen challenge the resulting increases in footpad thickness ranged from 15-20% and were comparable to the DTH driven by complete Freund's adjuvant. Adjuvants composed of MPL/TDCM and MPL/TDCM/CWS induced responses equivalent to those measured in mice immunized with viable L. monocytogenes, and the responses remained at these levels for at least 2 months. Furthermore, in vivo depletion of CD4+ T cells, but not CD8+ T cells, abrogated the induction and expression of DTH, indicating that the response is mediated by CD4+ T cells.

Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active ankylosing spondylitis (AS) that is not controlled with nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred sixty-four patients with AS were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on morning stiffness, back pain, and physician and patient global assessments. RESULTS: While longitudinal analysis revealed a trend favoring SSZ in the middle of treatment, no difference was seen at the end of treatment. Response rates were 38.2% for SSZ and 36.1% for placebo (P = 0.73). The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). AS patients with associated peripheral arthritis showed improvement that favored SSZ (P = 0.02). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints. CONCLUSION: SSZ at a dosage of 2,000 mg/day does not seem to be more effective than placebo in the treatment of AS patients with chronic, longstanding disease. SSZ is well tolerated and may be more effective than placebo in the treatment of AS patients with peripheral joint involvement. This effect is more pronounced in treatment of the peripheral arthritis in this subgroup of AS patients.

Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active psoriatic arthritis (PsA) resistant to nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred twenty-one patients with PsA were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on joint pain/ tenderness and swelling scores and physician and patient global assessments. RESULTS: Longitudinal analysis revealed a trend favoring SSZ treatment (P = 0.13). At the end of treatment, response rates were 57.8% for SSZ compared with 44.6% for placebo (P = 0.05). The Westergren erythrocyte sedimentation rate declined more in the PsA patients taking SSZ than in those taking placebo (P < 0.0001). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints, including dyspepsia, nausea, vomiting, and diarrhea. CONCLUSION: SSZ at a dosage of 2,000 mg/day is well tolerated and may be more effective than placebo in the treatment of patients with PsA.

Early undifferentiated connective tissue disease. IV.Musculoskeletal manifestations in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of patients with well-established connective tissue diseases: followup analyses in patients with unexplained polyarthritis and patients with rheumatoid arthritis at baseline.

OBJECTIVES: To examine the musculoskeletal manifestations in a large cohort of patients (n = 410) diagnosed with either a well-established connective tissue disease (CTD) (n = 197) or an early undifferentiated CTD (n = 213) with a symptom duration of <1 year. This study was aimed at determining the predictive value of demographic, clinical, and laboratory features on outcome in patients with unexplained polyarthritis (UPA) (from the early undifferentiated CTD cohort; n = 67) or rheumatoid arthritis (RA) (from the well-established CTD cohort; n = 57), over a 5-year followup period. METHODS: Patients from both cohorts were assessed at years 1, 3, and 5. At the study visits, clinical data were collected in a standardized manner, and sera were obtained and stored. A priori criteria were established for patient ascertainment and diagnosis over the duration of the study. Standard statistics were used for comparisons of baseline characteristics in patients diagnosed as having systemic lupus erythematosus, RA, undifferentiated CTD, and UPA at entry into the cohorts. Baseline features in patients with UPA were examined according to the different subsequent outcomes (RA, CTD, or undifferentiated CTD, remission [nonpersistent], or persistent or active UPA). Baseline features in patients with RA whose disease remained active versus those in whom remission was attained were also examined. Two multivariable analyses, classification trees and polychotomous logistic regression, were performed to predict disease outcomes over time. RESULTS: The overall rate of ascertainment for the 410 patients ranged from 90 % at year 1 to 71 % at year 5. Patients with established CTDs showed a tendency for more stable diagnoses than those with early undifferentiated CTDs (90-100% versus 45-70%). Consistent baseline predictors of persistent active disease among patients with RA, in both univariate and multivariable analyses, were higher joint counts for pain and tenderness and higher erythrocyte sedimentation rate (ESR). In approximately 20% of patients who were classified as having RA when they originally entered the cohort, the disease was in remission at 5 years. Twenty percent of the patients originally classified as having UPA developed RA over the duration of the study. These patients tended to be older and to have swelling of small joints at baseline. However, a consistent pattern of predictive variables could not be identified in the multivariable analyses, other than at year 1 (higher small joint counts for swelling and higher ESR). CONCLUSION: Baseline features (joint counts, and ESR) among RA patients were variously predictive of persistently active disease at years 1-5. Consistent baseline predictors of outcome among patients with UPA only emerged at year 1. Remission occurred in approximately 20% of RA patients, whereas a similar percentage of patients with UPA developed RA. These findings have implications with regard to treatment decisions in patients with early RA and/or UPA.

Serum phospholipase A2 activity in patients with rheumatoid arthritis before and after treatment with methotrexate, auranofin, or combination of the two.

OBJECTIVE: (1) To confirm a previous observation that serum phospholipase A2 (PLA2) activity correlates with disease activity in rheumatoid arthritis (RA); and (2) to determine whether serum PLA2 activity changes after treatment with methotrexate (MTX), auranofin (AF), or a combination of the 2 (COMBO). METHODS: Sera obtained at baseline and after treatment from 100 patients with RA (40 MTX, 32 AF, and 28 COMBO) who participated in a multicenter, double blind trial were tested for PLA2 activity using an assay that measures the release of radiolabeled 14C oleic acid from the cell membrane of Escherichia coli. Detailed statistical analysis was performed using previously collected clinical data to determine whether correlations exist between RA disease activity and serum PLA2 activity; whether baseline serum PLA2 activity predicted a therapeutic response in any treatment group; and whether there was a significant change in serum PLA2 activity after treatment in patients who responded to the various drugs. RESULTS: Baseline serum PLA2 activity was significantly increased in patients with RA compared to healthy controls. No correlation between serum PLA2 activity and RA disease activity was noted at baseline. Mean serum PLA2 activity did not change significantly after treatment with MTX, AF, or COMBO in either treatment responders or nonresponders. CONCLUSION: Serum PLA2 activity is increased in patients with RA compared to healthy controls, but does not correlate with disease activity in patients, nor does it predict a response to treatment with MTX, AF, or COMBO. Serum PLA2 activity also did not change significantly after treatment with any of the above agents.

TJ-114 (Sairei-To), an Herbal Medicine in Rheumatoid Arthritis.

The search for better treatments for malignancies has been enhanced by use of a relatively inexpensive clinical protocol that encourages the preliminary screening of a large number of potential anticancer drugs with early elimination of those that are clearly ineffective, preserving resources for more intensive evaluation of those that show some evidence of benefit. We adapted this method to determine whether the herbal medicine TJ-114 was worthy of further study for the treatment of rheumatoid arthritis (RA) patients. TJ-114 is a traditional herbal medicine that has been used extensively in Japan for the treatment of RA, Reports suggest that it may be a useful second-line agent, well-tolerated and safe. For these reasons, a 6-month, open prospective pilot study to evaluate the efficacy, safety and tolerability of TJ-114 in United States RA patients was undertaken. Thirty patients were enrolled; 18 completed the study. There were five responders by predefined composite criteria. Twelve patients withdrew from the trial, six for lack of efficacy, four for non-compliance, one for diarrhea and one for constipation and abdominal pain. The anti-cancer drug screening protocol stipulates that the drug be discarded if there are no responders among the first 14 patients and only 1 or 2 among the first 30 patients. Using this approach, the response rate found in this study justifies placebo-controlled, double-blind studies to determine the relative efficacy and toxicity of TJ-114 in a more definitive manner.

Reliability and validity of the CSSRD functional assessment survey in rheumatoid arthritis. Cooperative Systematic Studies of Rheumatic Diseases.

OBJECTIVE: To demonstrate the reliability and validity characteristics of a fast, intensively focused functional assessment questionnaire that has been used in rheumatoid arthritis clinical trials by the Cooperative Systematic Studies of Rheumatic Diseases group (CSSRD). METHODS: Data from three double-blind, controlled clinical trials by CSSRD were used to examine the properties of the Functional Assessment Survey as a measure of physiologic function. RESULTS: The Functional Assessment Survey has reasonable test-retest reliability and convergent validity with the Steinbrocker et al. functional class. It demonstrated appropriate divergent validity with other clinical measures of response, as well as discriminant validity. CONCLUSIONS: The CSSRD Functional Assessment Survey is brief, intensive, and focused. Reliability and validity characteristics have been documented.

Endocrine responses and body composition changes during feed restriction and realimentation in young bulls.

Changes in serum metabolic hormones, carcass composition, and body weight gains were examined in 21 Angus bulls (9 mo old) subjected to feed restriction and realimentation. They were allotted to three feeding regimens: 1) control (CON); 2) restricted (REST); and 3) realimented (REAL). The CON group was fed 3.2% of their body weight; the REST group was fed 1.5%. The REAL group was fed the restricted diet (1.5% BW) for 84 d then fed the control diet (3.2% BW) until slaughter. The CON and REAL groups were slaughtered at approximately 400 kg and the REST group at 346 kg. For the experiment, average daily gains (kg/d) were different (P < .05) (CON = 1.60; REAL = 1.35; REST = .64). Bulls were bled every 20 min for 6 h on d 14, 70, 98, and 127 of the experiment. Overall carcass characteristics (yield grade, muscle area, marbling) and chemical analysis of 9-10-11 rib sections indicated changes in quantity and percentages of protein and fat commensurate with the dietary intake treatments. The REST group had the least lean and fat (P < .05); the REAL group had less fat than (P < .05) but the same amount of lean (P > .05) as the CON group. Serum GH was higher in the REST than in the CON group (P < .05). In the REAL group, serum GH values rose to a level similar to that of the REST group; realimentation lowered serum GH (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Cognitive distortion, helplessness, and depressed mood in rheumatoid arthritis: a four-year longitudinal analysis.

Cognitive models of depression have been invoked to explain the development of depressive symptoms and disorders in patients with chronic pain. However, few long-term, prospective studies have examined A. T. Beck's (1967, 1987) model in this context. Seventy-two patients with rheumatoid arthritis completed the Beck Depression Inventory, the Cognitive Errors Questionnaire, and the Arthritis Helplessness Index during an initial assessment and again 4 years later. Initial levels of cognitive distortion were significantly related to follow-up levels of depressed mood, controlling for initial depression levels. This was also true for perceptions of helplessness. In contrast, initial depression levels did not predict changes in these cognitive processes. These results suggest that cognitive distortion and helplessness contribute to depressed mood among patients with arthritis.

Comparison of aminobenzoate potassium and placebo in the treatment of scleroderma.

OBJECTIVE: To determine the safety and efficacy of aminobenzoate potassium (KPAB) in treating the skin manifestations of scleroderma. METHODS: 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. RESULTS: 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 was > or = 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. CONCLUSION: 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.