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ID PMID Title PublicationDate abstract
11477276 From bench to bedside: discovering rules for antibody design, and improving serotherapy wi 2001 Jul Anti-T-cell monoclonal antibodies (mAbs) form a unique class of therapeutic agent. Their precise specificity offers tremendous potential for the treatment of autoimmune and inflammatory diseases but also prevents meaningful preclinical animal studies. In particular, adverse reactions to therapy may be unanticipated, and the first administration of a novel T-cell mAb to a patient thus marks the beginning of a unique experiment. By comparing clinical parameters and laboratory measurements, small-scale pilot studies can provide detailed information about mAb biology that both predicts and suggests solutions to the complications of therapy. In this essay I illustrate this concept with reference to three specific areas: lymphocyte depletion, mAb immunogenicity and cytokine-release syndromes. In each case, systematic clinical and laboratory science has improved our understanding of the problem and suggested solutions; most of these solutions have been or are being adopted. Thus, small, open studies are an essential step in the development of novel mAbs, provide an ideal platform for the study of mAb biology, and serve as an early warning system for potential adverse effects.
9222934 Candida infection of a silicone metacarpophalangeal arthroplasty. 1997 Jun Fungal infections following joint arthroplasty are extremely rare. Only 16 cases of Candida prosthetic infections have been reported, involving the hip, knee or shoulder joints. We report a case of a silicone metacarpophalangeal joint replacement complicated by a Candida albicans infection.
9518198 [Arthroscopic surgical measures in the shoulder joint]. 1997 Nov Arthroscopic and open surgery have to be combined for successful surgical therapy of the shoulder joint. A surgeon performing open surgery alone or just using arthroscopic measures cannot cover the full spectrum of modern shoulder surgery. Isolated diagnostic arthroscopy is rarely indicated. Far more common, diagnostic arthroscopy is combined with an operative procedure both to confirm preoperative assessment of pathology and to uncover associated lesions. The results of arthroscopic stabilization of chronic anterior post-traumatic dislocations fail to compare with the high success rates of open procedures. Better patient selection will probably be the key to improving results. In cases of acute traumatic first-time dislocation in young, highly athletic people, arthroscopic repair of the isolated Bankart-Perthes lesion offers the attractive advantage of anatomic reconstruction with minimal soft-tissue dissection. Further indications for arthroscopic measurements of pathologies of the glenohumeral joint are synovectomy in rheumatoid arthritis, capsulotomy in frozen shoulder and tenodesis for lesions of the long head of the biceps. Arthroscopic subacromial decompression according to Ellman is the procedure performed most often and most successfully in the shoulder joint and has overcome the classic Neer open acromioplasty. For smaller tears of the supraspinatus tendon, arthroscopic acromioplasty can be combined with an all arthroscopic suture repair or with mini-open repair. Larger tears of the rotator cuff are still the domain for open reconstructive procedures. In associated or isolated AC joint arthritis, an arthroscopic Mumford procedure can be performed. For chronic calcific tendinitis, isolated arthroscopic excision of the calcium deposit is of great value. Additionally, acromioplasty is needed for true mechanical obstruction of the subacromial space.
11478054 Current concepts regarding pharmacologic treatment of rheumatoid and osteoarthritis. 2001 May Treating patients with osteoarthritis (OA) and rheumatoid arthritis (RA) remains challenging; however, new agents offer the chance for an improved quality of life. As an alternative to traditional nonsteroidal anti-inflammatories, cyclooxygenase-2 inhibitors provide pain relief for OA and RA patients with possible fewer side effects. Otherwise, OA patients may opt for topical agents, injections, or supplements. Rheumatoid arthritis research has led to an improved understanding of the inflammatory cascade and an appreciation of the early tissue destruction. A new treatment philosophy has thus emerged along with the development of new biologic agents; the latter, along with combination therapy and a new disease modifying antirheumatic drug, leflunomide, have greatly expanded the chances for disease control in RA patients.
9973376 IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. 1999 Feb 1 IL-17 is defined as a proinflammatory cytokine and produced by activated CD4+ T cells. In rheumatoid arthritis synovial tissue, high levels of IL-17 contribute to IL-6 production by synoviocytes. The present study was performed to see whether Th cells that produce IL-17 are associated with the Th1, Th2, or Th0 subset. Thirty-three CD4+, alphabeta+ T cell clones were developed from synovial membranes and synovial fluid of rheumatoid arthritis patients. Thirteen clones were defined as Th1 since they produced IFN-gamma but not IL-4, and four clones were defined as Th0 type that produced both IL-4 and IFN-gamma. Sixteen clones were defined as Th2 since they produced high levels of IL-4 and/or IL-10 but not IFN-gamma. IL-17 was measured in a bioassay, where IL-6 production from synoviocytes was a measurement for IL-17 activity in the presence and absence of blocking anti-IL-17 mAb. Three Th1 clones and two Th0 clones produced IL-17. In contrast, none of the sixteen Th2 clones analyzed produced IL-17. In addition, six Th2 clones were further cultured in conditions that induced a switch to Th1 type. Induction of this Th1 phenotype also led to production of IL-17 in two of these clones. The results demonstrate that some cells of the Th1/Th0 phenotype produce IL-17 but not cells of the Th2 phenotype. Thus, IL-17 may define a new subset of T cells, and IL-17 production appears to be a mechanism for Th1/Th0 cells, the most frequent Th subtype present in the rheumatoid synovium, to contribute to the local inflammatory reactions.
11501260 [Inducible nitric oxide synthase expression and nitric oxide production by monocytes in sy 2001 We investigated nitric oxide (NO) production and inducible NO synthase (iNOS) expression by cultured peripheral blood mononuclear cells (PBMC) in systemic sclerosis (SSc). Eighteen patients with SSc were compared to two control groups: 16 rheumatoid arthritis patients (RA) and 23 mechanical sciatica patients. The sum of nitrites and nitrates was determined by fluorimetry in sera and spectrophotometry in supernatants. Inducible iNOS was detected in cultured PBMC by immunofluorescence, immunoblot and flow cytometry with or without IL-1 beta + TNF alpha, IL-4 or IFN gamma from day 1 to day 5. NO metabolite concentrations in the plasma were lower in SSc (34.3 mumol/l +/- 2.63 SEM) than in RA (48.3 mumol/l +/- 2.2; p < 0.02) and sciatica (43.3 mumol/l +/- 5.24; p < 0.03) patients. iNOS was detected in cultured monocytes in the 3 groups but induction occurred on day 1 in RA, day 2 in sciatica and only on day 3 in SSc, whatever the stimulus. The concentrations of NO metabolites are decreased in SSc patients and the induction of iNOS in PBMC is delayed. Low levels of NO, a vasodilator, may be involved in vasospasm, which is critical in SSc. This may suggest therapeutic implications.
11642503 Considerations in the selection of an appropriate conditioning regimen for the treatment o 2001 Oct Autologous hematopoietic stem cell transplantation (HSCT) is becoming more widely accepted as an investigational therapeutic modality for selected patients with severe autoimmune diseases such as rheumatoid arthritis. However, many aspects of the procedure remain controversial--not the least of these is the choice of conditioning regimen. This article briefly reviews the potential advantages and disadvantages of the conditioning regimens commonly employed for the treatment of severe autoimmune diseases in order to facilitate the development of future clinical trials of HSCT for rheumatoid
10356423 Selective cyclooxygenase-2 inhibitors. 1999 May The identification of COX-2 less than a decade ago has been followed by an unprecedented period of discovery and drug development. An awareness of the existence of two COX isoforms has led to potential novel insights into disease pathogenesis (arthritis, Alzheimer's disease, cancer) and the regulation of normal physiology (brain, kidney). The preliminary in vivo experience with COX-2-selective inhibitors has provided evidence for proof of concept for the COX-1 and COX-2 hypothesis, namely that the selective inhibition of COX-2-derived prostaglandins is sufficient to inhibit inflammation and is nonulcerogenic. It may be that we have moved closer to the "better aspirin" envisioned by Sir John Vane for the treatment of degenerative and inflammatory arthritides; however, caution is still warranted. Some toxicities of current NSAIDs may result from COX-2 inhibition, as in the kidney and brain; such side effects may be shared by the selective compounds. In addition, unexpected toxicities may arise simply because new chemical compounds will be widely prescribed. Finally, since the efficacy of traditional NSAIDs derives largely from their capacity to inhibit COX-2, it may be that the COX-2 selective drugs will not prove to be therapeutically superior to available agents. Given the well-recognized toxicity of NSAIDs, however, the availability of COX-2-selective agents promises to provide significant advantage to patients with chronic diseases, such as RA and OA.
9058648 Linkage and association studies of the natural resistance associated macrophage protein 1 1997 Mar OBJECTIVE: To determine if there is any evidence of linkage between the natural resistance associated macrophage protein gene, NRAMP1, and rheumatoid arthritis (RA). METHODS: Two dinucleotide markers, D2S1471, a highly polymorphic marker within 160 kb of NRAMP1, and a less polymorphic marker in the promoter region of NRAMP1, have been analyzed in 115 affected sib-pair RA families (35 with 2 parents, 18 with one parent) from the Arthritis and Rheumatism Council (ARC) National Repository and an additional 85 probands from the ARC National Twin Study and 96 controls. Individuals were typed for both markers by fluorescence based semiautomated polymerase chain reaction analysis. RESULTS: No evidence of increased allele sharing in affected sib-pairs was obtained using identity by descent (IBD), identity by state, and maximum likelihood score (MLS) analysis for the whole data set. A significant increase in allele sharing was observed with marker D2S1471 (LOD 0.74; p 0.05) in the HLA discordant subgroup using IBD and MLS-IBD. No significant differences in allele frequencies were observed for any markers in the association study. CONCLUSION: In a subset of sib-pairs that shared one or zero HLA haplotypes, LOD scores suggestive of linkage were observed. This suggests a role for NRAMP1 polymorphism in a subset of patients who do not possess HLA susceptibility alleles.
9385347 Destruction of the first carpometacarpal joint behaves differently from that of the entire 1997 The aim of our study was to examine the radiographic changes of the wrist and the first carpometacarpal (CMC I) joints in rheumatoid arthritis (RA) occurring over 20 years. The wrists of 83 RF positive RA patients with recent (< or = 6 months) arthritis were evaluated radiographically at onset, at 1, 3, 8, and 15 years and of 68 patients 20 years from entry. In hands where wrist fusion was performed, follow-up continued until the arthrodesis. Larsen grading for the wrist joints and modified grades for the ipsilateral CMC I joints were compared. Larsen grades of both wrists differed highly significantly (p < 0.001) from the grades of the ipsilateral CMC I joints after 3 years and up to end of the study. In conclusion destruction of the CMC I does not proceed uniformly with destruction of the entire carpus and it would be beneficial to classify it separately.
10773969 Intraarticular glucocorticosteroid injection into the lateral atlantoaxial joint under flu 2000 Jan OBJECTIVES: To evaluate the overall efficacy in various disorders of glucocorticoid injection into the lateral atlantoaxial joints, performed via the posterior route under fluoroscopic control. METHODS: Retrospective study of 26 patients including 16 (19 injections) with mechanical disorders and ten (16 injections) with inflammatory disorders. RESULTS: The response rate was 69.3%, the mean pain scale score decrease was 52.3 +/- 40.1%, and the mean duration of pain relief was 8.1 +/- 11.8 months. All three parameters were significantly (P < 0.005) better in the subgroup with inflammatory disorders than in the subgroup with mechanical disorders (response rate, 100% vs 50%; pain scale score decrease, 80 +/- 27% vs 34.2 +/- 40%, and pain relief duration, 16.9 +/- 14.9 months vs 24.5 months). A single patient developed a side effect (moderately severe hypertension). CONCLUSION: Glucocorticoid injection into the lateral atlantoaxial joints is a valid treatment alternative in patients who fail to respond to conventional noninvasive therapy.
10505496 Rigid occipitocervical fusion. 1999 Oct OBJECT: Despite 50 years of neurosurgical experience, occipitocervical fusion continues to present a technical challenge to the surgeon. Traditional nonrigid techniques applied in the occiput and cervical spine often fail secondary to postsurgical cranial settling or rotational deformity. Unlike widely used nonrigid and semirigid techniques, rigid fixation of the craniocervical junction should allow correction of deformity in any plane, provide immediate stability without need for external orthosis, and prevent cranial settling. METHOD: Since 1992, the senior author (D.W.C.) has used a rigid plate and screw fixation system for occipitocervical fusions. The technique proved to be more difficult than expected, and the procedure has evolved as experience was gained. The authors present a series of 24 patients and a technique that now involves the use of a custom-designed T-plate that is attached to the midline occipital "keel" at one end and to the spine at the other end by means of screw-fixed plates. CONCLUSIONS: Although it is still evolving, the current technique for obtaining rigid occipitocervical fixation allows for immediate rigidity and stability of the spine without the use of an external orthosis (that is, in the absence of osteoporosis), may be extended to any level of the spine, may be used in the absence of posterior elements, prevents postsurgical cranial settling and restenosis, facilitates reduction of the spinal deformity in any plane, and sometimes eliminates the need for an anterior (transoral) decompressive procedure.
11263770 Shift toward T helper 1 cytokines by type II collagen-reactive T cells in patients with rh 2001 Mar OBJECTIVE: To investigate the impact of type II collagen (CII)-reactive T cells on the Th1/Th2 cytokine balance in patients with rheumatoid arthritis (RA). METHODS: T cell proliferative responses to bovine CII were examined in synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) by mixed lymphocyte culture. CII-reactive T cell lines were generated from the SFMC and PBMC. Interferon-gamma (IFNgamma), interleukin-12 (IL-12), and IL-4 were measured by enzyme-linked immunosorbent assay in the SF, sera, and culture supernatants of PBMC and SFMC that had been stimulated with CII. RESULTS: The frequency of CII-reactive T cells was higher in the PBMC from RA patients than in that from osteoarthritis patients and healthy control subjects. In RA patients, CII-reactive T cells were more prevalent in SFMC than in PBMC. The mean level of IFNgamma and the ratio of IFNgamma to IL-4 were significantly higher in the culture supernatants of T cells stimulated with CII; these differences were more prominent in SFMC. Levels of IL-12 in the culture supernatants of SFMC and PBMC stimulated with CII were significantly higher than those in unstimulated supernatants. T cell responsiveness correlated well with the level of type 1 cytokines in culture supernatants from RA T cells stimulated with CII. In the CII-reactive cell lines, the increased production of IFNgamma was consistent with clonal expansion. CONCLUSION: CII-reactive T cells are more abundant in SFMC than in PBMC and are strongly associated with a shift toward Thl cytokine in the inflamed joints of RA patients. Our results suggest that a skewing toward type 1 cytokines by CII-reactive T cells may play an important role in the chronic inflammatory process of RA.
10616020 Interaction between tumor necrosis factor microsatellite polymorphisms and the HLA-DRB1 sh 1999 Dec OBJECTIVE: To investigate whether interactions between tumor necrosis factor (TNF) microsatellite polymorphisms and the HLA-DRB1 shared epitope (SE) are associated with disease severity in rheumatoid arthritis (RA), and to determine if such associations are the same in male and female patients. METHODS: Genotyping for the TNFa microsatellite and HLA-DRB1 was carried out on 157 RA patients with established disease (duration >5 years). Disease severity measures included radiographic damage (the Larsen method), functional assessment by the Health Assessment Questionnaire, history of joint surgery, and global appraisal of outcome by means of a visual analog scale score. The association of severity measures with TNFa microsatellite polymorphisms stratified by SE status, and the interaction between TNFa and the SE, were investigated using stratified analyses and multiple or logistic regression analyses. RESULTS: No significant associations were observed between any single TNFa microsatellite polymorphism and disease severity, although preliminary evidence for an interaction between TNFa6 and TNFa11 was obtained. In the presence of the SE, a significantly worse outcome was associated with individuals carrying TNFa6, and a significant interaction (P = 0.04-0.006) was found between these alleles for all the outcome measures examined except history of joint surgery. In the absence of the SE, the TNFa6 allele was associated with significantly better outcome scores. When examined by sex, significant associations between the TNFa6/SE haplotype and disease outcome measures were found only in females. No statistically significant interactions were found in males, although the TNFa6/SE haplotype was still associated with the worst outcome scores. CONCLUSION: The association of the SE with disease severity in RA is influenced by an interaction with the TNFa6 microsatellite polymorphism. This interaction appears to be acting predominantly in female patients, although the trend is similar in the smaller percentage of males carrying the TNFa6/SE haplotype.
11481817 Coverage inequalities of new therapies for rheumatoid arthritis in a managed care setting. 2001 Jul Rheumatoid arthritis (RA) is a progressive disease that leads to functional disability and substantial medical costs. Early treatment with disease-modifying antirheumatic drugs (DMARDs) has been shown to inhibit the progression of RA, with accompanying improvements in functional outcome and long-term medical costs. Biologic response modifiers (BRMs) are a new class of therapeutic agents for RA that offer a more favorable side-effect profile than traditional DMARDs. One BRM, the self-injectable medication etanercept, has demonstrated great potential for improving the long-term prognosis of patients with RA. Unfortunately, patients' access to treatment with etanercept is sometimes limited because of the structure of health-care coverage for self-injectable drugs.
9375862 Soluble interleukin 6 (IL-6) receptor and IL-6 levels in serum and synovial fluid of patie 1997 Nov OBJECTIVE: We studied interleukin 6 (IL-6) and soluble IL-6 receptor (sIL-6R) in serum and synovial fluid (SF) to investigate their role in different arthropathies. METHODS: IL-6 was measured by ELISA and bioassay and sIL-6R by ELISA, in 210 sera and 73 SF samples from 49 patients with rheumatoid arthritis (RA), 20 crystal deposition disease, 17 osteoarthritis (OA), 24 with other inflammatory arthropathies, and 100 controls. In all patients, disease activity was assessed by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); in patients with RA and other arthropathies pain, tender and swollen joints, and Ritchie index were also evaluated. Total leukocyte count in SF was determined. RESULTS: There was good correlation between IL-6 ELISA and bioassay levels both in serum (r = 0.62, p = 0.0001) and in SF (r = 0.72, p = 0.0001). Serum IL-6 was detected only in patients with inflammatory arthritis and SF IL-6 was detected in all patient groups. Serum IL-6 correlated with swollen joints (r = 0.35, p = 0.05), ESR (r = 0.46, p = 0.001), and CRP (r = 0.46, p = 0.001) in RA; and with CRP (r = 0.89, p = 0.0001) in crystal deposition disease. SF IL-6 correlated with ESR (r = 0.54, p = 0.007) and CRP (r = 0.42, p = 0.04) in RA; with SF total leukocyte count (r = 0.61, p = 0.004) in crystal deposition disease; and with SF total leukocyte count (r = 0.61, p = 0.009) in OA. No correlations were found in the group with other inflammatory diseases. No correlations were found between sIL-6R and IL-6 or between sIL-6R and disease activity variables in any group of patients. CONCLUSION: Unlike IL-6, sIL-6R is not produced at the site of inflammation and is not related to clinical or biological disease activity variables. Only in RA are both IL-6 and sIL-6R levels increased, suggesting that sIL-6R may reinforce the systemic effects of IL-6.
11123349 Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center 2001 Jan 1 A unique feature in inflammatory tissue of rheumatoid arthritis (RA) is the formation of ectopic lymphoid aggregates with germinal center (GC)-like structures that can be considered to contribute to the pathogenesis of RA, because local production of the autoantibody, rheumatoid factor, is thought to be a causative factor in tissue damage. However, the factors governing the formation of GC in RA are presently unknown. To begin to address this, the expression of B cell attracting chemokine (BCA-1) (CXCL13), a potent chemoattractant of B cells, was examined in the synovium of patients with RA or with osteoarthritis (OA). Expression of BCA-1 mRNA was detected in all RA samples, but in only one of five OA samples. Lymphoid follicles were observed in four of seven RA samples and in two of eight OA samples, and in most of them BCA-1 protein was detected in GC. BCA-1 was not detected in tissues lacking lymphoid follicles. Notably, BCA-1 was detected predominantly in follicular dendritic cells in GC. CD20-positive B cells were aggregated in regions of BCA-1 expression, but not T cells or macrophages. These data suggest that BCA-1 produced by follicular dendritic cells may attract B cells and contribute to the formation of GC-like structures in chronic arthritis.
10648025 Recent onset arthritis in the elderly: a 5 year longitudinal observational study. 2000 Jan OBJECTIVE: To study the spectrum of diagnoses, course, and outcome of recent onset arthritis after the age of 60, presenting as rheumatoid arthritis (RA)-like disease. METHODS: A 5 year longitudinal observational study enrolled 92 consecutive patients (median age 73 yrs, 54/38 women/men, median duration of arthritis 12 weeks at inclusion). RESULTS: Forty-eight percent were classified as having RA according to the 1987 American Rheumatism Association criteria, 52% as non-RA (41.4% undifferentiated seronegative polyarthritis, 10.8% oligoarthritis with polymyalgic symptoms). Symmetrical involvement of small and medium size joints was more predominant in the RA (91 and 84%, respectively) than the non-RA patients (58 and 52%). The patients with RA compared to non-RA had more active and serious disease at onset, reflected by significant differences in number of swollen joints (median values 18 and 9, respectively), duration of morning stiffness (75 and 10 min), physician's global assessment of disease activity (45 and 28 mm on visual analog scale), and Health Assessment Questionnaire (HAQ) score for functional disability (1.8 and 1.0). Improvement during the course was observed in disease process variables as well as in HAQ disability score for both RA and non-RA patients. Risk factors for a poor 5 year functional outcome were female sex (OR 4.24), diagnosis of RA (OR 3.28), and baseline HAQ score > or =1.4 (OR 3.52). The median change in radiological progression (Larsen-Dale index) was zero. Twenty patients died during followup, the majority from cardiovascular diseases, infections, and malignancies. Mortality compared to the age and sex matched general population was increased for rheumatoid factor (RF) positive patients (standardized mortality ratio 272). Mortality risk factors within the patient cohort were male sex (OR 4.35), age (OR 1.17), and having RF+ RA (OR 11.93). CONCLUSION: Arthritis in the elderly is a heterogeneous group of arthritides with an overall favorable functional prognosis. The subgroup of women with elderly onset RA with functional disability at onset is at risk for a less favorable functional outcome. Mortality was increased for the patients with RF+ elderly onset RA only.
9402864 The rational use of methotrexate in rheumatoid arthritis and other rheumatic diseases. 1997 Nov Methotrexate's mechanism of action affects both the inflammatory and immunosuppressive aspects of response. Its kinetics are defined and include variable absorption, intracellular metabolism, and both renal and biliary excretion. Methotrexate is clearly effective in the treatment of rheumatoid arthritis and may be able to decrease the rate of formation of new bony erosions. It is also effective in psoriatic arthritis and is being used in a multiplicity of other rheumatic diseases. The most common toxicities ascribed to methotrexate are gastrointestinal (e.g. stomatitis) and central nervous system (e.g. headache, fatigue, malaise). Methotrexate-induced hepatic cirrhosis is less common in rheumatoid arthritis than previously thought, although its occurrence in psoriasis is probably higher than in rheumatoid arthritis. Haematological, renal and pulmonary toxicity occur, but are rare, while teratogenicity is well documented. A new and disturbing adverse event, pseudolymphomas are being reported at present.
12212115 [Clinical investigation of effects of bizhongxiao decoction (BZX) on rheumatoid arthritis 2000 Oct 28 Ninety-six patients with rheumatoid arthritis(RA) on active phase were divided into BZX-treated group(BZXG) and methotrexate-treated group(MTXG). The results showed that after 1-month treatment, symptoms and signs, such as joint tenderness, arthralgia, arthroncus, of patients in BZXG improved notably(P < 0.01 or P < 0.05), while those of patients in MTXG did not improve, there was significant difference between these two groups(P < 0.01 or P < 0.05). After 3-month treatment, these symptoms and signs improved in both groups(P < 0.01 or P < 0.05), but BZX had a better effect than MTX. ESR, CRP, RF, C3, IgG, IgA and IgM decreased significantly in both groups after treatment(P < 0.01 or P < 0.05), ESR, CRP in BZXG decreased more and faster than those in MTXG. In BZXG the obviously efficient rat was 70%, the total efficacy rate was 94%, while in MTXG was 52% and 87% respectively. It is indicated that BZX can improve symptoms and signs of patients with RA, has better and faster effects on acute phase reaction than MTX; and it has anti-immunologic effects similar to MTX, and has no obvious side effect.