Frank A. Wollheim

Early rheumatoid arthritis —onset, course, and outcome over 2 years

SummaryEighty-nine patients, 33 men and 56 women, with early definite rheumatoid arthritis were followed for 2 years. Two-thirds were seropositive. About 1/3 were eventually treated with second line drugs. The disease mostly had an insidious onset initially involving the finger joints. Early remission occurred in 16%. Patient relevant measures such as pain, patients overall assessment of disease activity and anxiety decreased significantly. Disability evaluated by the HAQ disability index remained at a low level. The joint damage score (JDS) in hands and feet increased steadily and only 18% were nonerosive after 2 years. One-third developed hand deformities which was associated with higher JDS. A joint function index (SOFI) correlated significantly with JDS. Twenty-eight percent had a slower rate of joint damage progression the second year. There was no significant correlation between JDS and disease duration. Six patients developed rapidly progressive damage in larger joints, five in the hip joints and one in the shoulder joint, all requiring joint replacement. The ability to predict outcomes with clinical and laboratory variable obtained at entry was of limited clinical usefulness. By applying discriminant analyses 67%–80% of the cases who fared worst regarding clinical, functional, and radiological features could be correctly classified.

Therapeutic effects on cartilage metabolism in arthritis as measured by release of proteoglycan structures into the synovial fluid

Proteoglycans are molecules that are degraded and released from the articular cartilage into the synovial fluid early in an arthritic process. Such released proteoglycans were quantified by an enzyme linked immunosorbent assay (ELISA). The proteoglycan content in synovial fluid from patients with various knee joint arthritides was constant in two samples withdrawn five days apart. To determine if therapeutic measures were paralleled by effects directly on the articular cartilage the patients were treated with local injections of glucocorticoids. In all patients the glucocorticoids induced a reduction of the proteoglycan content in the synovial fluid, reflecting their effects on the cartilage. In two patients with spontaneous remission of their arthritis a reduction in the proteoglycan content in the synovial fluid was also noted. The quantification of proteoglycans in synovial fluid appears to have potential as a useful tool for monitoring the effects of therapy on cartilage metabolism.

Associations of HLA-DRB and HLA-DRQ genes with two and five year outcomes in rheumatoid arthritis.

OBJECTIVE--To evaluate the clinical usefulness of genomic HLA typing during the first five years of established rheumatoid arthritis (RA). METHODS--The HLA-DRB and -DQB alleles were determined by restriction length polymorphisms and polymerase chain reaction amplification with sequence specific primers in 99 Swedish patients with RA. Clinical features after two and five years disease duration were related to the genetic pattern. Seventy four patients were seropositive, 25 had nodules, 90 developed erosions, and 15 required joint replacements. Twelve patients were in remission after five years. Disability was assessed by health assessment questionnaire, and radiographic damage in hands and feet by the Larsen method. RESULTS--Eighty seven per cent of the patients carried the conserved third hypervariable region sequence (HVR3), 32% had DRB1*04 on one allele, and 26% had DRB1*04 on both alleles (all frequencies significantly greater than in controls). Frequencies of DRB1*04 associated DQB*0301 and *0302 were normal. Patients carrying DRB1*04 on both alleles tended to have more radiographic changes after two years, but this difference had diminished after five years. Disability did not vary with regard to the genotype. Homozygous HVR3 patients had about three times greater risk of undergoing joint replacement. Homozygosity for HVR3 and presence of DQB*0302 both tended to be associated with erosive disease. CONCLUSIONS--We confirmed a strong association of disease with the presence of the shared epitope on one or two alleles. However, genotype was not strongly associated with disease severity after two and five years disease duration, and thus the value of genomic typing to select patients for early aggressive therapy is questionable.

Inhibition of type I collagen production by dermal fibroblasts upon contact with activated T cells: Different sensitivity to inhibition between systemic sclerosis and control fibroblasts†

OBJECTIVE To assess the role of T lymphocyte-fibroblast contact in type I collagen production by cultured dermal fibroblasts from normal individuals and from patients with diffuse systemic sclerosis (SSc). METHODS Cell membranes were prepared from activated CD4+ and CD8+ T cells, or type 1 T helper (Th1) clones, and added to confluent fibroblast monolayers. Type I collagen production was measured in culture supernatants, and messenger RNA (mRNA) levels of type I procollagen alpha1 (pro alpha1[I]) and matrix metalloproteinase 1 (MMP-1) were evaluated by Northern hybridization analysis. RESULTS Dose-dependent inhibition of type I collagen production was observed with CD4+ and CD8+ T cells from both SSc patients and controls. Inhibition of type I collagen was significantly less pronounced in fibroblasts from SSc patients than in fibroblasts from controls (P < 0.02). Inhibition was not reversed by the addition of exogenous transforming growth factor beta, interleukin-4, interleukin-1 receptor antagonist, anti-tumor necrosis factor, anti-CD40, or indomethacin, whereas anti-interferon-gamma (IFNgamma) reversed Th1-mediated inhibition. This inhibitory activity was specific for type I collagen, since mRNA levels of pro alpha1(I) were decreased, whereas mRNA levels of MMP-1 were strongly increased. CONCLUSION The production of type I collagen by skin fibroblasts is specifically down-regulated by membranes from activated T cells. The contact-dependent regulatory activity exerted by T cells on fibroblasts depends, at least in part, on the presence of membrane-associated IFNgamma. However, SSc fibroblasts are more resistant to inhibition than are fibroblasts from normal individuals.

Tumour necrosis factor microsatellites and HLA-DRB1*, HLA-DQA1*, and HLA-DQB1* alleles in Peruvian patients with rheumatoid arthritis

OBJECTIVE To study the association between rheumatoid arthritis (RA) and HLA and tumour necrosis factor (TNF) polymorphism in Peruvian mestizo patients in comparison with ethnically similar controls. METHODS Seventy nine patients with RA and 65 ethnically matched healthy controls were genotyped for HLA-DRB1, HLA-DQA1, HLA-DQB1, and TNFα and TNFβ alleles using PCR amplification. Clinical severity was assessed as mild, moderate, or severe in 35 of the patients. RESULTS TNFα6 showed the strongest association with disease susceptibility. The TNFα6 allele was more common in patients than in controls (p<0.0076) and the proportion of patients with at least one copy of this allele was greater (p<0.015, relative risk 2.35). Among the HLA-DRB1* alleles with the shared epitope sequence, only the DRB1*1402 allele was significantly increased in patients compared with controls (p<0.0311), as was the proportion of patients with at least one copy of this allele (p<0.0232, relative risk 2.74). In contrast, the overall frequency of alleles with the shared epitope was not different in patients and controls. The haplotype HLA-DRB1*1402-DQB1*0301-DQA1*0401 was significantly more common in patients. TNFα6 was more common in patients whether or not they had this haplotype. None of the 11 patients lacking the TNFα6 allele had severe disease. CONCLUSIONS This study shows for the first time that TNF gene polymorphism is associated with susceptibility to RA in a non-white population. TNFα6 and HLA-DRB1*1402 independently conferred significantly increased risk in Peruvian mestizo patients.

Disease activity and joint damage progression in early rheumatoid arthritis: relation to IgG, IgA, and IgM rheumatoid factor.

The clinical and biochemical correlations with joint damage progression over two years in a consecutive group of 68 patients with rheumatoid arthritis with disease duration of less than two years are reported. Joint damage was assessed with Larsens severity scale and a measure of change in progression rate constructed. Initial haemoglobin concentration, Ritchie index, and Waaler-Rose titre in combination accounted for one third of the variance in joint damage progression. Rheumatoid factor (RF) concentrations were followed with enzyme linked immunosorbent assays (ELISAs) for IgG RF, IgA RF, and IgM RF. The RF concentrations, except IgG RF, decreased with time; significant correlations between RFs and disease activity were few and barely clinically useful. After two years IgG RF correlated significantly with a radiological score if early non-erosive changes were omitted. All RFs tended to correlate better with this radiological score at all three observation points. Analyses of the change in progression rate indicated a time delay between development of radiographic changes and increase of IgG RF. These results suggest an indirect relation between RFs and joint damage. Clinical and biochemical improvements in early RA occur despite joint damage progression, and conventional markers have insufficient predictive value.

Predictors of joint damage in rheumatoid arthritis

Rheumatoid arthritis (RA) is the dominant form of destructive chronic arthritis with the potential to cause substantial disability and permanent functional impairment. The final extent and progression rate with time, however, varies markedly. In order to study effects of intervention and to support early aggressive and atoxic therapy in selected cases, predictive disease markers are needed. Recent advances regarding joint tissue composition and pathophysiology have defined a number of biological marker candidates which need to be explored for possible prognostic information. Some markers are characteristic for RA, such as rheumatoid factors and certain autoantibodies, which although they are more prevalent among patients with aggressive disease are not sensitive as predictors in early disease. Genetic susceptibility markers have been claimed to be good predictors of persisting arthritis in early synovitis clinics, but their role as severity markers in established disease is limited. Unspecific markers of inflammation, notably ESR or CRP when persistently elevated, are useful to monitor disease course and newer markers need to document their superiority over these. Another group of markers are attractive because of enriched or exclusive occurrence in joint tissue, and altered metabolism in joint disease. Thus, collagen type III propeptides, hyaluronates, and neopterin originating in the synovium could be useful, and, in particular, hyaluronate levels indeed do provide some predictive information. Highly tissue‐specific cartilage metabolites include aggrecan fragments, collagen II fragments, cartilage oligomeric matrix protein (COMP) and the extraarticular cartilage matrix protein (CMP). When used alone or in combination in early disease some information can be obtained which may in the future facilitate prognostication. Bone metabolism can be monitored and there are different markers for synthesis and resorption. Meanwhile, whilst the new markers are essential research tools, their routine clinical usefulness remains to be proven.

Factors Related to the Progression of Joint Destruction in Rheumatoid Arthritis

In 103 (M = 25, F = 78) of 150 consecutive RA patients, values of the following variables were obtained at the start and end of a 2-year follow-up period: radiographic destruction score of hands and feet according to Larsen (Larsen index), Ritchie index, B-hemoglobin, ESR and plasma proteins (alpha 1-antitrypsin, ceruloplasmin, CRP, fibrinogen, haptoglobin, orosomucoid, IgA, IgG, IgM, C3 and C4). 60% of the values of delta LI (final minus initial value of Larsen index) were significantly larger than zero (11-44 units, p less than 0.05). delta LI was larger in females than in males (p = 0.11). Comparing women with duration of disease (DoD) 1-6 years versus 7-52 years. delta LI was larger in the former group (p = 0.005). Comparing women with the largest delta LI (19-44 units) with the remainder ones (delta LI = -9-18 units), CRP and haptoglobin was higher and IgM lower in the former group (p = 0.03, 0.02 and 0.03 respectively). In women with DoD 1-6 years (and only in this interval) significant linear relationships were found between delta LI and hemoglobin (r = 0.52, p less than 0.01) Ritchie index, haptoglobin, CRP (r = 0.41-0.46, p less than 0.05) and IgM (r = -0.43, p less than 0.05). The mean of repeated hemoglobin values correlated even more strongly with delta LI (r = 0.70, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum IL-15 in patients with early systemic sclerosis: a potential novel marker of lung disease

The pathogenesis of systemic sclerosis (SSc) is characterized by autoimmunity, vasculopathy and fibrosis. IL-15 is a pleiotropic cytokine that has impact on immune, vascular and connective tissue cells. We therefore investigated IL-15 in the circulation of patients with early SSc and explored possible associations of serum IL-15 with vasculopathy and fibrosis. Serum levels of IL-15 were analysed in 63 consecutive patients with SSc of disease duration less than 4 years and without disease-modifying treatment. Thirty-three age-matched healthy control individuals were enrolled. Serum IL-15 levels were increased in the sera of SSc patients compared with that of healthy control individuals (P < 0.01). Serum IL-15 levels correlated with impaired lung function, assessed both by the vital capacity (P < 0.05) and by the carbon monoxide diffusion capacity (P < 0.05). The association between IL-15 and the vital capacity remained after multiple linear regression analysis. Patients with intermediate serum IL-15 levels had a higher prevalence of increased systolic pulmonary pressure compared with patients with either low or high serum IL-15 levels (P < 0.05). Moreover, increased serum IL-15 levels were associated with a reduced nailfold capillary density in multivariable logistic regression analysis (P < 0.01). Serum IL-15 levels also correlated inversely with the systolic blood pressure (P < 0.01). We conclude that IL-15 is associated with fibrotic as well as vascular lung disease and vasculopathy in early SSc. IL-15 may contribute to the pathogenesis of SSc. IL-15 could also be a candidate biomarker for pulmonary involvement and a target for therapy in SSc.

Computer based quantitative analysis of capillary abnormalities in systemic sclerosis and its relation to plasma concentration of von Willebrand factor.

OBJECTIVES--To evaluate an objective and quantitative method for assessment of capillary abnormalities in systemic sclerosis (SSc). METHODS--Nailfold capillaries were investigated by capillary microscopy and photographed in 17 consecutive SSc patients (five with diffuse cutaneous systemic sclerosis (dSSc) and 12 with limited cutaneous systemic sclerosis (lSSc)) and in 17 healthy controls. Investigators having no access to clinical data made drawings from magnified projections of coded photographs and analysed them using a computer program. Capillary density (capillary loops/mm in the distal row) and median capillary loop area were calculated. Presence of functional or organic arterial changes was evaluated by measurement of finger pressure with finger cooling. Plasma concentration of von Willebrand factor (VWF) was analysed using an enzyme linked immunosorbent assay (ELISA). RESULTS--In 16 of 17 SSc patients and 13 of 17 controls the technical quality of the photographs was sufficient for computer analysis. Capillary density was decreased in dSSc (median 6.9 loops/mm) and in lSSc (median 3.8 loops/mm) compared with healthy controls (8.9 loops/mm) and median capillary loop area was increased in dSSc (7.3 x 10(-3) mm2) and in lSSc (8.5 x 10(-3) mm2) compared with healthy controls (5.0 x 10(-3) mm2). An inverse relation was found between capillary density and median capillary loop area in SSc patients. Plasma VWF was increased in patients (median 401 IE/l in dSSc and 409 IE/l in lSSc) compared with controls matched for age and sex (median 276 IE/l). Computer based analysis showed capillary density below the control range and median capillary loop area above the control range in 14 of 16 SSc patients. Measurement of finger pressure with finger cooling showed organic vascular changes in nine of 13 SSc patients. CONCLUSION--Computer based quantitative analysis has low interobserver variability and is a quantitative and sensitive method of assessing capillary abnormalities in SSc.