Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor alpha inhibitor. METHODS: Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks' follow-up. The patient's assessment of arthritis pain (pain), patient's assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded. RESULTS: At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (> or =0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components. CONCLUSIONS: CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

The long-term outcomes of rheumatoid arthritis: a 23-year prospective, longitudinal study of total joint replacement and its predictors in 1,600 patients with rheumatoid arthritis.

OBJECTIVE: Although total joint arthroplasty (TJA) is a common procedure and an important outcome in rheumatoid arthritis (RA), little is known about its prevalence, failure rate, or predictors over the course of the illness. The current study evaluated these factors in 1,600 consecutive RA patients seen during a period of observation that extended 23 years. METHODS: Beginning in 1974, data from 34,040 RA patient visits were entered prospectively into a computer databank. Data consisted of laboratory, radiographic, physical examination, and self-report questionnaires. At each assessment, we also noted a complete surgical history. Patients were also followed up by questionnaires that were mailed at 6-month intervals. RESULTS: Kaplan-Meier life-table estimates indicated that 25% of RA patients will undergo total joint arthroplasty (TJA) within 21.8 years of disease onset. For patients with 1 TJA, 25% had a TJA in a different joint within 0.92 years and 50% within 7.0 years. Ten years after TJA, approximately 6% of implanted knees and 4% of implanted hips had been replaced with a second TJA, and 12% and 13% of the joints had either a second TJA or a TJA-related operation, respectively. In Cox regressions, a large series of clinical and laboratory variables, which primarily reflected disease activity, predicted TJA. Smoking, either past or present, had a protective effect. Patients with highly abnormal values on the Health Assessment Questionnaire Disability Scale, global severity, and erythrocyte sedimentation rate had a 3-6 times increased risk of TJA. CONCLUSION: TJA, a marker of joint failure and of RA outcome, is predicted by self-report assessments of severity and function, and by a series of laboratory, radiographic, and clinical variables. Prediction improves with the extent of observation, and 2-year observations approach full-study observations in their accuracy. Most TJAs survive for a long time in RA.

Fast food arthritis--a clinico-pathologic study of post-Salmonella reactive arthritis.

OBJECTIVE: To study the clinical presentation, immunogenetics, and serum immune response to lipopolysaccharide (LPS) in a cohort of patients with post-Salmonella reactive arthritis (ReA). METHODS: A validate ReA screening questionnaire (Quest 2) was mailed to 919 individuals reporting symptoms of gastroenteritis to the health department after eating at a single restaurant. Three hundred twenty-one persons returned questionnaires; 170 reported symptoms outside the gastrointestinal tract; 23 of those 170 reporting persistent joint symptoms were seen 4 to 16 weeks after the outbreak and 5 of the 23 were seen in followup 12 to 20 weeks later. Clinical features, HLA Class I typing, serum soluble CD8 levels, and serum antibodies to gram negative LPS by ELISA were determined. RESULTS: Joint complaints were reported more frequently by individuals with a longer duration of diarrhea. Upper extremity joints were frequently involved, and 66% reported one or more extraarticular symptoms of Reiter's syndrome. Three of 5 typed individuals were HLA-B27 positive, including 3 of the 4 most severely involved. Serum soluble CD8 levels correlated poorly with disease activity measured either clinically or by C-reactive protein. Antibodies to Klebsiella and Shigella LPS rose over time, while antibodies to Salmonella LPS fell. CONCLUSION: The clinical picture of post-Salmonella ReA is less stereotyped than often assumed, although severity correlated with HLA-B27 status. The association of joint symptoms with duration of diarrhea and the kinetics of the anti-LPS antibody response support the hypothesis that abnormal gut permeability plays a role in the pathogenesis of post-Salmonella ReA.

Olsalazine in ankylosing spondylitis: a pilot study.

OBJECTIVE: To test the safety and efficacy of olsalazine in men with ankylosing spondylitis (AS) unresponsive to nonsteroidal antiinflammatory drugs and physiotherapy. METHODS: Four patients, including 2 who had not responded to sulfasalazine (SASP) and one who did not tolerate SASP, were treated with olsalazine, up to 3 g/dl for 24 weeks. RESULTS: One patient discontinued olsalazine due to diarrhea at 1 g/day. The other 3 experienced improvement in global spine self assessment by visual analog scale (VAS), 2 of 3 patients, spinal pain (VAS, 3 of 3), night pain (3 of 3), tender joint count (3 of 3) and enthesis score (3 of 3). Changes in Schober's test and chest expansion were minor. Erythrocyte sedimentation rate and C-reactive protein were normal. Loose stools were the only adverse effects observed. CONCLUSION: Olsalazine appears to be well tolerated and effective in men with AS. Further study of olsalazine and direct comparison with SASP in this population may illuminate mechanisms of drug action and add a new therapeutic option.

V alpha gene usage in rheumatoid compared with osteoarthritic synovial tissue T cells.

While many investigators have examined V gene usage by the clonotypic T-cell receptor (TCR) in rheumatoid arthritis (RA) joints, few have reported on arthritic controls. We compared TCR alpha-chain V gene usage in knee synovial tissue specimens from 9 RA and 5 osteoarthritis (OA) patients. There was no significant difference in the number of V gene families used in RA compared with OA synovium. However, there was an increased prevalence of V alpha 28, V alpha 10, V alpha 17, and V alpha 18 and under representation of V alpha 15 in RA compared with OA synovium. Of these, V alpha 28 was also recently described by us as being present in RA synovial tissue early in the course of disease. V alpha 28 associated J region usage, and N-regional diversity was surveyed in T-cell receptors from additional rheumatoid synovial tissue T-cell populations and normal peripheral blood. Oligoclonality was observed in 6/10 rheumatoid specimens either by direct sequencing or where three or more molecular clones were sequenced, compared with 0/5 normal PBMCs. The oligoclonal populations included 2/3 cell lines stimulated with interleukin-2 (IL-2) alone. Several novel J regions were observed, with some recurrent residues observed at N-region positions. These data indicate an increased prevalence of certain TCR V region families in RA versus OA synovium, and suggest an antigen-driven expansion of V alpha 28-expressing T cells in RA synovium.

T cell receptor analysis in rheumatoid arthritis: what have we learnt?

Many clues point to a role for T lymphocytes in the pathogenesis of rheumatoid arthritis (RA), although the importance of these cells and their position within the rheumatoid pathogenic scheme remain unknown. Encouraged by data from animal models of T-lymphocyte-mediated autoimmunity, a major focus of research into the role of T lymphocytes in RA has been the usage of T cell receptor V genes in rheumatoid synovitis. Despite many methodologic problems, involving choice of patients and controls, choice of specimens, and technical factors, several conclusions can be drawn from the published research. In particular, synovial T lymphocyte populations, as a whole, frequently show biased V gene usage and restricted clonality within those T lymphocyte subsets that utilize over-represented V gene families. Continued research into these synovial T lymphocyte subsets should provide important insights into the pathogenesis of RA, particularly if solutions to the identified methodologic problems are implemented.

T-lymphocyte clones responsive to Shigella flexneri.

T lymphocytes from a patient with Shigella flexneri dysentery and postdysenteric reactive arthritis were cloned by limiting dilution with recombinant interleukin-2 and a strain of S. flexneri different from that which had infected her. Five of eight clones produced proliferated in response to the shigellae used to generate the clones. The response required irradiated syngeneic blood mononuclear cells as antigen-presenting cells. One such clone, MC12, proliferated in response to both the shigellae used to generate the clones and the infecting shigellae but not to other shigellae, Salmonella heidelberg, or control Escherichia coli. MC12 was CD3+, CD4+, CD8-, and human histocompatibility leukocyte antigen (HLA)-DR+. The proliferative response to the shigellae was blocked by antibody to HLA-DR but not by antibody to HLA-A,B,C. The response required antigen-presenting cells that shared HLA-DR antigens with the clone and appeared to be restricted by HLA-DR2. The epitope recognized by MC12 was associated with the bacterial membranes. Thus, T-lymphocyte clones that proliferate in response to some shigellae can be isolated from patients with shigellosis.

Treatment of the seronegative spondyloarthropathies with sulfasalazine.

Three patients with reactive arthritis and 2 with ankylosing spondylitis resistant to therapy with nonsteroidal antiinflammatory drugs were treated with enteric coated sulfasalazine in an open trial. Significant toxicity was not observed; 1 patient discontinued sulfasalazine because of gastrointestinal symptoms. As a group, statistically significant improvement was observed in 50 foot walk time, morning stiffness, and hemoglobin concentration. One patient went into complete clinical remission, 2 improved, 1 showed no change, and 1 worsened. Asymptomatic colonic inflammation was found in each of 4 patients examined before beginning therapy. Changes in bowel pathology did not parallel changes in joint symptoms. Sulfasalazine may be a safe and useful therapeutic modality in patients with chronic reactive arthritis or ankylosing spondylitis.

Universal spondylodiscitis in a patient with erosive peripheral arthritis and apatite crystal deposition.

A patient with erosive peripheral arthritis in whom vasculitis and monoclonal IgG kappa paraprotein were associated with sacroiliitis and widespread destruction of intervertebral discs is reported. Crystals resembling apatite were identified in intervertebral disc material, and we postulate that the discitis was accelerated by apatite deposition. Our case illustrates a unique example of axial involvement in rapidly progressive joint disease.

Molecular mimicry in the pathogenesis of rheumatic diseases.

Evidence has been presented to support the conclusion that epitope-specific cross-reactive autoimmunity generated in response to a microorganism can result in an inflammatory sequela. The role of this mechanism in the pathogenesis of the experimental disease, adjuvant arthritis, appears clear. In the case of human rheumatic conditions, such as rheumatic fever and the HLA-B27-associated reactive arthritides, the role is not yet established, but clinical evidence suggests that the hypothesis is an attractive one.

Male hypogonadism and scleroderma.

Two male patients with scleroderma and hypogonadism are described. One patient had Klinefelter's syndrome. The second had normal testosterone but elevated gonadotrophins. Possible relationships between scleroderma and hypogonadism are discussed.