Influence of variations across the MMP-1 and -3 genes on the serum levels of MMP-1 and -3 and disease activity in rheumatoid arthritis.

Matrix metalloproteinases (MMPs) are involved in joint destruction in rheumatoid arthritis (RA), and are strongly associated with levels of inflammation. To understand the relationship between MMP-1 and -3 variants and MMP levels in RA, we investigated the genotypic and haplotypic relationships of the MMP-1 and -3 genes with circulating levels of these MMPs. The genotypes of single-nucleotide polymorphisms (SNPs) rs1799750 (1G/2G, MMP-1 promoter), rs495366 (G/A, intergene), rs679620 (A/G, MMP-3 coding region) and rs3025058 (5A/6A, MMP-3 promoter) were determined in 430 RA patients. Each polymorphism was associated with serum levels of MMP-1 (P trend <0.0001 for each SNP), with haplotype 1G-G-A-5A associated with the highest level. The intergenic and MMP-3 SNPs were associated with MMP-1 levels independent of the MMP-1 promoter SNP. The MMP-3 SNPs were associated with serum MMP-3 level (P trend <0.0001 for each SNP), and were each associated with mean time-averaged disease activity (DAS28) in patients followed up for 2 years (P=0.003). Our findings indicate that several closely linked polymorphisms in the MMP-1-MMP-3 loci have an important role in determining the circulating levels of these MMPs in RA, and that MMP-3 polymorphism is associated with the level of disease activity over time.

Antinuclear antibodies are associated with tumor necrosis factor receptor I gene polymorphism in patients with rheumatoid arthritis.

OBJECTIVES: Antinuclear antibodies (ANA) are a common feature of autoimmune diseases such as rheumatoid arthritis (RA). Herein, we investigate the relationship between ANA and polymorphism in the tumour necrosis factor receptor (TNFR) genes. METHODS: Serum titers of ANA at diagnosis were measured in 267 patients with RA and a single nucleotide polymorphism (SNP) in each of the TNFR-I (36A/G) and TNFR-II (676T/G) genes was genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Circulating levels of soluble TNFR (sTNFR) and TNF-α were also measured in some patients. RESULTS: Our initial analyses revealed the presence of ANA was associated with the TNFR-I 36A/G SNP, with a trend of increasing ANA frequency with G allele dosage (p=0.004). ANA status was also associated with lower sTNFR-I levels and a raised sTNFR-II/sTNFR-I ratio. The TNFR-II 676T/G SNP and circulating levels of sTNFR-II and TNF-α were not associated with ANA status. In an adjusted multivariate regression model the TNFR-I 36 GG genotype (OR 7.8, p=0.008) and levels of sTNFR-I (p=0.018) were independently associated with ANA status. CONCLUSIONS: Our findings suggest a possible link between the production of ANA and the TNF-α/TNFR-I signalling system, which may be related to the apoptosis-inducing ability of this cytokine.

Measurement of natural killer cell cytotoxicity by area under a cytotoxic curve. A method suitable for rheumatoid arthritis.

Calculation of the area under a curve derived from a 51Cr cellular release assay gives a reproducible expression of cellular cytotoxicity and correlates well with results at fixed lymphocyte-to-target cell ratios and with lytic units at 20% and 30% cytotoxicity. This method is suitable for quantifying the low cytotoxicity seen in rheumatoid arthritis. The area under the cellular cytotoxic curve may be calculated using a simple mathematical formula or by computer analysis.

A disease activity index: its use in clinical trials and disease assessment in patients with rheumatoid arthritis.

Measuring disease activity is important in the assessment of patients with rheumatoid arthritis (RA). The value of composite indices in determining activity is discussed. A validated index, the Stoke index, has been used in clinical trials of combination therapy in patients with RA, both to evaluate efficacy and to stratify response to single-agent therapy before randomization to combination treatment. Disease activity determines the use of disease-modifying antirheumatic drugs. Should these drugs be used in mild RA when disease activity is low? Results of a study comparing hydroxychloroquine with placebo in this situation suggest that they should. Finally, the outcome of suppressing disease activity over a 5- to 10-year period is unknown. Measured either radiologically or functionally, preliminary data suggest that the lower the mean disease activity over time, the more favorable the outcome.

Clinical value of ELISA assays for IgM and IgG rheumatoid factors.

The clinical value of enzyme linked immunosorbent assays (ELISA) assays for IgM and IgG rheumatoid factors was assessed in a series of studies using rabbit IgG as antigen. The tests were reproducible with intra-assay coefficients of variation of 6% and could be simply and rapidly performed. Normal ranges were established using 106 sera from healthy controls. In a cross sectional study of 208 rheumatoid patients these assays were compared with the Rose-Waaler and laser nephelometric assessments of rheumatoid factor. In some patients there were discrepancies between rheumatoid factor positivity determined by one method or another. IgM ELISA and Rose-Waaler titres showed a significant correlation (r = +0.58; p less than 0.001), but there was a low correlation between IgM and IgG ELISA (r = +0.27; p less than 0.001). There was no evidence to show that the measurement of IgM or IgG rheumatoid factor gave significantly more clinical information than traditional tests such as the Rose-Waaler or latex agglutination tests.

Development and preliminary assessment of a simple measure of overall status in rheumatoid arthritis (OSRA) for routine clinical use.

We describe the development and initial assessment of a simple measure of overall status in rheumatoid arthritis (OSRA) for use in the routine clinical setting. The measure is constructed in four parts: demographic details, activity score, damage score and treatment category. It requires no laboratory tests and uses details collected routinely during a clinic visit. It was validated in a series of 488 patients. The measure proved acceptable and demonstrated face, content, construct and discriminant validity. OSRA will be useful as an audit tool in the serial follow-up of RA patients and in describing the characteristics of a population of such patients.

Treatment of early rheumatoid arthritis: a review of current and future concepts and therapy.

This review contrasts the difficulty of differentiating early rheumatoid arthritis (RA) from the many other causes of inflammatory polyarthritis and emphasizes the need for early treatment of RA with drugs that are present considered inappropriate for a mild, self-limiting disease. Pointers to help establish a definitive diagnosis of RA include the use of the American College of Rheumatology (ACR; formerly the American Rheumatism Association) diagnostic criteria, the presence of rheumatoid factor (RF), a raised erythrocyte sedimentation rate (ESR), raised serum levels of C-reactive protein (CRP) and low concentrations of serum sulphydryl (SH) groups. More sophisticated tests that are helpful and indicative of erosive-type disease are genetic markers such as the human leukocyte antigen HLA DR4 (especially the third allelic variable of DR beta 1) as well as an impaired sulphoxidation status. Similarly, the presence of the shared epitope alleles 0401 and 0404 quantitatively increases disease susceptibility and severity as their penetration increases. Experience with treatment indicates that control of the inflammatory process of RA reduces the progression of radiological damage. It is concluded that antimalarials are effective in mild disease, as is auranofin, whilst sulphasalazine is more effective than hydroxychloroquine in patients with disease diagnosed as definitive or classical RA. Intramuscular gold also lessens the development of erosions. The role of corticosteroids has not been defined. A number of combinations of drugs have been used, although they are probably not indicated as the first choice treatment for very early disease. Attitudes towards early treatment are changing; these are briefly reviewed and the authors' opinions on the management of early disease are outlined. Finally some new ideas, both theoretical and practical, on future development are summarized.

Rheumatoid arthritis and chronic lymphatic leukaemia.

There is evidence for an increased incidence of lymphoproliferative disorders in patients with rheumatoid arthritis (RA). We present the clinical features of 4 patients with RA and chronic lymphatic leukaemia (CLL) which, occurring in a population of 1505 RA patients, represents a significantly increased prevalence of CLL (p less than 0.05) compared to the general population. These patients had significantly lower natural killer cell activity than matched rheumatoid controls (p less than 0.05) or normal controls (p less than 0.01) and we discuss this as a possible mechanism of association.

Raised endothelial cell stimulating angiogenesis factor in ankylosing spondylitis.

Endothelial cell stimulating angiogenesis factor (ESAF) is important in the neovascularisation that precedes new bone formation, and raised levels are found in association with healing fractures and osteoarthritis. We investigated its relevance to the new bone growth that is found at inflammatory sites in ankylosing spondylitis (AS). Forty-one patients with AS were studied clinically and radiographically and had their serum ESAF levels measured. In comparison to age-matched controls the AS patients had significantly raised ESAF levels (p < 0.0001). Within the AS group, patients with relatively higher ESAF levels had no characteristic clinical or radiological features.

Use of the Stoke Index to differentiate between disease-modifying agents and non-steroidal anti-inflammatory drugs in rheumatoid arthritis.

The Stoke Index is a validated composite algorithm that has been designed to give a global measure of disease activity in rheumatoid arthritis (RA). The use of this single measure of disease activity in RA simplifies the critical evaluation of drug therapy. 368 patients with RA of varying duration and severity, entered into comparative drug trials between 1980 and 1987, had the algorithm calculated four weeks prior to therapy, at the start of treatment, and bi-monthly to six months. The index score was significantly improved by drugs with known slow acting anti-rheumatic drug (SAARD) activity and improvement could be seen as early as two months after the beginning of treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) did not improve the score. The index differentiates between treatments in patients with minor or major disease activity. We conclude that this composite index of disease activity provides a sensitive, meaningful measure for the evaluation of therapy in RA.

Raised epidermal phospholipase A2 activity in rheumatoid arthritis.

Epidermal phospholipase A2 (PLA2) in RA patients was significantly higher than in normals (p less than 0.0001) but lower than in psoriatic patients (p less than 0.05). No relationship was observed between PLA2 activity and commonly used measures of rheumatoid disease activity in a cross-sectional study. However, in a longitudinal study change in PLA2 activity correlated strongly with changes in disease activity.

Improving the response to gold or D-penicillamine by addition of sulphasalazine. A pilot study in 25 patients with rheumatoid arthritis.

In a 6-month open pilot study 25 patients with Rheumatoid Arthritis (RA) whose disease was refractory to Gold or D-Penicillamine (DPA) were given Sulphasalazine (SAS) in addition. Three patients withdrew because of nausea. Twenty-two patients who completed therapy showed significant improvement in clinical and laboratory measures of disease activity.

Antibodies to neuroblastoma cells in rheumatoid arthritis: a potential marker for neuropathy.

OBJECTIVE: To investigate the prevalence of antibodies to neuroblastoma cells in patients with rheumatoid arthritis (RA) complicated by peripheral neuropathy (PN), and to determine whether there is any relationship of these antibodies with the severity of neuropathy. METHODS: The study was carried out on 28 patients with RA complicated by PN, 29 RA patients without PN and 28 healthy volunteers (HV). A cell-based ELISA method was used to test sera for the presence of IgG and IgM anti-neuroblastoma cell antibodies. Localisation and characterisation of neuroblastoma antigens recognised by patients' sera was carried out by immunofluorescent microscopy and Western blotting. RESULTS: Elevated levels of IgG anti-neuroblastoma cell antibodies were found in 10 (36%) neuropathic patients and in 1 (3%) RA control (chi 2 = 9.53, P = 0.002), while significant levels of IgM anti-neuroblastoma cell antibodies were demonstrated in 10 (36%) neuropathic patients and in 2 (7%) RA controls (chi 2 = 7.12, P = 0.008). Overall, the levels of antibodies in healthy volunteers were significantly lower than in RA controls and patients with PN. No significant relationship was found between the level of anti-neuroblastoma cell antibodies and severity of RA or neuropathy. Immunofluorescence staining of neuroblastoma cells with sera from 18 neuropathic patients demonstrated cytoplasmic and/or nuclear patterns. Western blotting demonstrated reactivity with a heterogeneous group of neuroblastoma antigens. Little or no reactivity was seen with RA control or HV sera. CONCLUSION: Antibodies against neuroblastoma cells are more prevalent in RA patients with peripheral neuropathy than in RA patients without peripheral nerve involvement. Such antibodies may be useful diagnostic markers for peripheral neuropathy in RA.

Prevalence of antibodies to neurofilament polypeptides in patients with rheumatoid arthritis complicated by peripheral neuropathy.

OBJECTIVE: Neurofilaments are essential components of the axon cytoskeleton. Neurofilament defects are suspected in several neurodegenerative conditions, and antibodies to neurofilaments have been found in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Our main objectives were: (i) to determine the prevalence of anti-neurofilaments antibodies in patients with rheumatoid arthritis (RA) complicated by peripheral neuropathy; and (ii) to relate the clinical features of RA and peripheral neuropathy to anti-neurofilament antibodies. METHODS: In this study we used an ELISA technique to measure IgG antibody levels against three neurofilament polypeptides (NF-L, 70 kD; NF-M, 150 kD; and NF-H, 200 kD) in RA patients with peripheral neuropathy, and compared them with the antibody levels in uncomplicated RA controls and healthy volunteers. RESULTS: Abnormal antibody levels to one or more of the neurofilament polypeptides were found in 9 (32%) of the peripheral neuropathy patients, but only in 3 (9%) of the RA and healthy controls. There were significant correlations between the levels of antibodies against the different neurofilaments; the cross-reactivity of some sera with different neurofilament proteins was also observed. There was no significant correlation between the levels of anti-neurofilament antibodies and measures of RA disease activity. CONCLUSIONS: We conclude that a significant proportion of our RA patients with neuropathy had abnormal antibody levels to one or more neurofilaments and that the measurement of these antibodies may provide a useful diagnostic test.

Septic polyarthritis due to bacteroides fragilis in a patient with rheumatoid arthritis.

A case of septic polyarthritis is described in a patient with severe RA who had not received steroid therapy. The organism involved, Bacteroides fragilis, was sensitive to metronidazole.

Saline washout for knee osteoarthritis: results of a controlled study.

Twenty patients with persistent symptoms due to osteoarthritis of the knee were randomly allocated to a saline washout or control group. Both groups showed improvement. Knee washout conferred no more benefit than intra-articular saline injection.

Polyarthritis, rash and lymphadenopathy: case reports of two patients with angioimmunoblastic lymphadenopathy presenting to a rheumatology clinic.

Two patients presented with a symmetrical inflammatory polyarthropathy. Both patients fulfilled the diagnostic criteria for angioimmunoblastic lymphadenopathy. We present the two case histories and review the current literature. Although an uncommon disease, the diagnosis of angioimmunoblastic lymphadenopathy should be considered in a patient presenting with polyarthritis and skin rash.

Prediction of radiographic damage in hands and feet in rheumatoid arthritis by clinical evaluation.

Radiography of hands and feet is a standard measure of outcome in rheumatoid arthritis. We hypothesised that this radiological information can be reproduced by clinical evaluation. A rheumatologist examined 78 patients with rheumatoid arthritis and tried to predict the radiological Larsen score, for the proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, ankle, and metatarsophalangeal (MTP) joints. Spearman correlation between clinical Larsen and X-ray Larsen was 0.79 for hands and 0.66 for feet. There was no significant difference in scores for PIP, MCP, wrists, or ankles, but MTP joints were underscored by clinical Larsen relative to X-ray Larsen (median of 20 vs 22 respectively, p = 0.04). Categorical data for index finger MCP joints showed significant proportional agreement of 37% (Kappa 0.24, p < 0.0001). In conclusion, the Larsen X-ray score can be predicted by clinical examination with surprising accuracy in the small hand joints but less so in the feet. Although the favourable agreement shown in this study does not make X-rays redundant, we suggest that clinical examination of the hands should be further refined and standardised as a measure of outcome.

ELISA assays for IgM and IgG rheumatoid factors: their clinical correlations during therapy with slow-acting anti-rheumatic drugs.

A longitudinal study of changes in rheumatoid factor levels and their correlations with other clinical and laboratory assessment of disease activity followed 45 rheumatoid arthritis patients during 12 months continuous therapy with gold and penicillamine. Rheumatoid factors were measured by the titred latex assay and by ELISA assays for IgM and IgG rheumatoid factor. The IgM ELISA assay correlated strongly with the titred latex assay and weakly with the IgG rheumatoid factor assay at 0, 6 and 12 months. All showed significant falls with treatment, and ELISA assays were not more sensitive indicators than the latex assay. Correlations of initial rheumatoid factor levels by all 3 assays to 34 other clinical and laboratory assessments showed that only a small number of weak correlations existed; there were more at 6 and 12 months, but still not many. Changes in rheumatoid factor levels over 0-6 months showed no significant correlation to changes in other variables. There were no more correlations with ELISA assays than with titred latex rheumatoid factor. We conclude that ELISA rheumatoid factor assays have no clinically relevant advantage over the titred latex assay when following rheumatoid patients treated with gold or penicillamine.

Capillaritis: a manifestation of rheumatoid disease.

We present seven cases of capillaritis arising in patients with rheumatoid arthritis and suggest that it is primarily related to disease activity and not drugs. In the majority, the rash resolved spontaneously with the use of a topical steroid to treat the symptom of itch.