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ID PMID Title PublicationDate abstract
10788533 Analysis of p53 tumour suppressor gene somatic mutations in rheumatoid arthritis synovium. 2000 Mar OBJECTIVE: In order to study the role of the p53 tumour suppressor gene in the proliferation of rheumatoid arthritis (RA) synovium, we analysed the mutation of p53 in the synovial fibroblast-like type B synoviocyte from RA patients. METHODS: Synovial fibroblast-like type B synoviocytes were prepared from the synovial tissues from nine Japanese patients with RA. The p53 cDNA region from exons 4-11 was screened for mutations by the streamlined mutation detection method in which polymerase chain reaction (PCR) products are post-labelled and are analysed by automated capillary electrophoresis using single-strand conformation polymorphism conditions, followed by direct sequencing of the subclones of the PCR products. RESULTS: p53 mutation with possible functional alteration was detected in four of the nine RA patients (44.4%). Of a total of 262 p53 cDNA subclones, 10 subclones were carrying 10 p53 mutations, eight of which were associated with amino acid alterations or protein truncation. Of the p53 functional mutations, a substitution of Gly at amino acid residue 245 to Asp (G245D) was identified in two patients in three subclones. G245D was the first mutation that was recurrently identified in different RA individuals. G245D is also one of the relatively common mutations in human cancers. CONCLUSIONS: In some patients with RA, dysfunction of p53 might play a role in the proliferation of the synovial tissue. G245D mutation might especially need further study as it is the first recurrently identified p53 mutation in RA and is also one of the frequently identified mutations in human cancers.
10568423 Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with 1999 Sixty-six rheumatoid arthritis (RA) patients were analyzed retrospectively to assess the incidence and risk factors for elevation of serum hepatic aminotransferases during methotrexate (MTX) therapy. The effect of folate supplementation on serum ALT and RA activity was evaluated prospectively in 14 patients who showed a sustained high serum level of ALT. The frequency of elevation of serum AST or ALT was 4-5 times greater than in patients taking other DMARDs. Multivariate linear regression analysis demonstrated that elevation of ALT was independently associated with sex (female), obesity, baseline ALT, MTX dose, and gastrointestinal side effects. Folate supplementation caused ALT levels to decrease in all patients within 3 months. Eleven patients showed no change of RA activity, but 3 patients dropped out of the study because of the exacerbation of RA. These results suggest that careful monitoring of serum hepatic aminotransferases is necessary in patients with predisposing factors, especially those receiving more than 0.15 mg/kg of MTX weekly. Folate supplementation can reverse the sustained elevation of ALT, but might cause exacerbation of RA in some patients.
9213787 [A new approach to rheumatoid arthritis]. 1997 Apr 12 Slow-acting antirheumatic drugs (SAARDs) are usually prescribed in rheumatoid arthritis only when non-steroid anti-inflammatory drugs can no longer suppress the inflammation or when articular damage is radiologically apparent. It was established recently that articular damage occurs in an early phase of RA. This damage is linked to subsequent disability; to prevent it is the purpose of SAARDs. In view of the short-term reduction of arthritis activity and improvement of function as well as the meanwhile established fact that the side effects of SAARDs are not different from those of other antirheumatic agents, SAARDs should be prescribed in an early phase of RA.
11680919 A comparison of the Canadian Occupational Performance Measure and the Health Assessment Qu 2001 Oct The Canadian Occupational Performance Measure (COPM) is receiving international attention as an important assessment for directing occupational therapy interventions and measuring client-centred outcomes. The COPM measures individuals' perceptions of disability by identifying those tasks that are important to them and difficult to perform. The Health Assessment Questionnaire (HAQ) has been used extensively with persons with arthritis and measures individuals' perceived difficulty in performing predetermined tasks of daily living. The HAQ has been shown to correlate with actual performance and has reported concurrent validity with a number of similar scales. In this study, 13 participants diagnosed with rheumatoid arthritis were assessed with the COPM and the disability dimension of the HAQ. Participants scored performance limitations on both the COPM and the HAQ; the correlation coefficient between the scores was not statistically significant. However, when the COPM and the HAQ scores for similar activities were compared, a statistically significant correlation was found. These findings support the use of the COPM as a valid measure of self-reported performance.
9811046 No increased risk of malignancies and mortality in cyclosporin A-treated patients with rhe 1998 Nov OBJECTIVE: To evaluate the cyclosporin A (CSA)-attributed risk of developing malignancies in general and malignant lymphoproliferative diseases (LPDs) and skin cancers in particular, as well as the CSA-attributed incidence of mortality in patients with rheumatoid arthritis (RA). METHODS: In a retrospective, controlled cohort study, the incidence of malignancies and mortality was evaluated in 208 CSA-treated patients with RA compared with 415 matched control patients with RA between 1984 and 1995. Patients were followed up for a median of 5.0 years (range 1.4-12.0). RESULTS: Forty-eight cases of malignancy (8 in the CSA group and 40 in the control group; relative risk [RR] 0.40, 95% confidence interval [95% CI] 0.19-0.84) were identified, of which 8 were malignant LPDs (2 CSA versus 6 control; RR 0.67, 95% CI 0.14-3.27) and 14 were skin cancers (2 CSA versus 12 control; RR 0.33, 95% CI 0.08-1.47). Seventy-three patients died (16 CSA versus 57 control; RR 0.56, 95% CI 0.33-0.95) due primarily to cardiovascular diseases (4 CSA versus 22 control; RR 0.36, 95% CI 0.13-1.04) or a malignancy (3 CSA versus 8 control; RR 0.67, 95% CI 0.18-2.43). Proportional hazards regression analysis with correction for potential confounding factors did not significantly change the results. CONCLUSION: The study findings suggest that CSA treatment in RA patients does not increase the risk of malignancies in general or the risk of malignant LPDs or skin cancers in particular. Moreover, the incidence of mortality in CSA-treated RA patients was comparable to that in matched control RA patients.
9645414 Destruction and arthroplasties of the metatarsophalangeal joints in seropositive rheumatoi 1998 Destruction and arthroplasties of the metatarsophalangeal (MTP)joints and interphalangeal (IP) joint of the big toe were evaluated in 103 seropositive rheumatoid arthritis (RA) patients in a prospective follow-up study at onset and at 1, 3, 8, 15, and 20 years from entry. A total of 83 patients attended the 15-year follow-up and 68 attended the 20-year follow-up. Data on the forefoot synovectomies and reconstructions performed were obtained from patient documents and radiographs. The radiographs were assigned by the Larsen method; in the end point analysis the last or preoperative radiograph was used. Erosions of Larsen grade > or =2 were present in 6%/ of the investigated 1236 joints at onset and after 20 years in 62%, respectively. At the end point, 24% of the joints were severely damaged (Larsen grade 4-5). The MTP I and IP joints showed the lowest grade of destruction during follow-up, and MTP V the worst destruction. Synovectomies were performed in 24 MTP joints; a total of 75% of these joints were later resected. MTP II-V head resections were performed in 21% and the Keller procedure in 12% of the MTP I joints. Erosive changes occur early in the MTP joints, and their grade of destruction is high; therefore they should be included in radiographic criteria and scores. MTP synovectomies are insufficient treatments for RA without concomitant immunosuppression of the disease.
10643276 [The colonization resistance of the mucous membrane of the large intestine in patients wit 1999 Sep Specific and quantitative compositions of the colon mucous microflora in 36 patients with rheumatic arthritis (RA) in the remission period were studied. The mucous membrane of healthy people is colonized by bifidobacteria, lactobacilli, Bacteroides, Escherichia and enterococci. The mucous membrane in such people is mainly colonized by aerobic opportunistic conventionally pathogenic enterobacteria (enteropathogenic Escherichia, Citrobacter [correction of cytobacter], Enterobacter, Klebsiella, etc.), staphylococci, enterococci and anaerobic bacteria (Bacteroides, peptococci, peptostreptococci, etc.). Taking into account significant changes of colonization resistance in the colon mucous membrane in remission period of RA, it is necessary to apply bacteriotherapy, using bacterial drugs containing bifidobacteria and lactobacteria.
9224239 Arthroplasty of rheumatoid metatarsophalangeal joints. An outcome study. 1997 Jul Deformity of the forefoot is a common disabling problem in chronic rheumatoid arthritis. The most common deformifies are hallux valgus, cockup toes, and depressed metatarsal heads. Resection arthroplasty has been improved by adding reconstructive procedures, for example, medial capsular arthroplasty in the great toe and plantar plate arthroplasty of the lesser toes with longitudinal pinning of all toes for 4 weeks. Results were compared with a series of silicone double hinge implants without grommets in the great toe and resection of lesser metatarsal heads and pinning. Patients were evaluated by questionnaire to evaluate outcome. There was no significant difference in the two series of patients. Overall good results were 85% to 95% and slightly favored the group without implants. These results were equal to those reported in the literature for patients who underwent fusion of the great toe and resection arthroplasty of lesser toes.
11665968 Expression of recombination-activating genes and terminal deoxynucleotidyl transferase and 2001 Oct OBJECTIVE: Lymphocytic infiltrates in rheumatoid arthritis (RA) synovium often resemble lymphoid follicles and contain clonally related Ig transcripts, suggesting in situ antigen-dependent B cell selection. Recent reports have shown expression of recombination-activating genes (RAGs) and concurrent secondary rearrangement of Ig genes in normal peripheral lymphoid organs (receptor revision). We sought to determine if RAG-mediated receptor revision of Ig kappa light chains occurs in B cells within the RA synovium. Because we previously reported enhanced N-region addition at V(L)-J(L) joins in clonally expanded light-chain transcripts from RA synovium, we also sought expression of terminal deoxynucleotidyl transferase (TdT), which is normally expressed only in B cell precursors or immature B cells. METHODS: Reverse transcription-polymerase chain reaction (PCR) was used to detect RAG and TdT transcripts from unselected and B cell-enriched synovial and peripheral blood mononuclear cells obtained from 12 RA patients. Activity of RAG protein was sought using ligation-mediated PCR to detect recombination intermediates, and immunohistochemistry was performed to identify RAG+ cells within synovia. RESULTS: We found evidence of RAG-mediated secondary Ig kappa light chain rearrangements in about one-third of RA synovia. TdT expression was found in several samples, but did not correlate with RAG expression. CONCLUSION: RAG-mediated secondary Ig rearrangements of kappa light chains may contribute to the local production of antibodies to autoantigens (e.g., rheumatoid factor) or exogenous antigens, or it may represent a failed attempt at immune tolerance. TdT expression suggests the presence of immature B cells in RA synovia. These findings have important implications for the local generation of antibodies in RA and other chronic inflammatory diseases.
10328578 Apomodulation as a novel therapeutic concept for the regulation of apoptosis in rheumatoid 1999 May Fas-mediated apoptosis is observed in synoviocytes of patients with rheumatoid arthritis (RA). This process may be involved in the pathophysiology of RA. We have recently found that Fas-mediated apoptosis of RA synoviocytes is associated with activation of two signaling pathways, the c-Jun amino-terminal kinase (JNK)/activator protein-1 (AP-1) pathway, and the FADD (Fas-associated death domain protein)/Caspase-8/Caspase-3/PARP (poly(ADP-ribose)polymerase) pathway. The latter appears to be one of the major signaling pathways required for Fas-mediated apoptosis in RA synoviocytes. Interestingly, Fas-mediated apoptosis in synoviocytes may be induced at least in part by tumor necrosis factor-alpha. Paradoxically, tumor necrosis factor-alpha also causes proliferation of synoviocytes. Employing these molecular processes in the treatment of RA, we have recently shown that ex vivo gene transfer of human Fas ligand (hFasL) induced apoptosis of synoviocytes and infiltrated mononuclear cells of RA synovial tissue through cell-to-cell interaction via the Fas/FasL system. We believe that further understanding of the complex regulatory mechanisms of apoptosis in RA synoviocytes would uncover further aspects of the pathophysiologic mechanisms of RA and contribute to the development of new and effective therapies for RA.
10561480 Liposome encapsulated aurothiomalate reduces collagen-induced arthritis in DBA/1J mice. 1999 Sep 21 Collagen-induced arthritis (CIA) generated in rats or mice has long been a model system for the study of rheumatoid arthritis in humans. In particular, this system has been used to study the mechanisms and effects of anti-arthritic drugs in the treatment of the disease. Sodium aurothiomalate (ATM) is an agent often used to treat rheumatoid arthritis in humans; however, it possesses inherent toxicities which limits its usefulness. Liposome-encapsulated drugs are currently being developed to minimize the toxicities associated with a variety of potentially beneficial drugs. We have chosen to encapsulate ATM into small unilamellar vesicles (SUVs) to determine whether greater efficacy would be achieved in treating CIA with SUV ATM as compared to using the free drug. SUVs were prepared from hydrogenated egg phosphatidylcholine and cholesterol. These SUVs were very stable. Vesicles stored at 4 degrees C lost only 0.09% of encapsulated ATM (SUV ATM) after 14 days and were able to reduce collagen-induced arthritis in these mice. Animals treated by i.m. injections of SUV ATM exhibited a 50% reduction in symptoms. More importantly, histological examination of knee joints of the affected animals verified that SUV ATM treatment prevented cellular infiltration of lymphocytes into the synovia of the collagen-sensitized mice. Conditioned media from spleen cell cultures was assayed for the presence of inflammatory lymphokines that might be affected by SUV ATM to account for the success in suppressing collagen-induced arthritis.
10776690 Influence of cyclosporin A on radiological progression in early rheumatoid arthritis patie 2000 The aim of this study was to evaluate whether cyclosporin A (CsA) influences the radiological disease progression in early rheumatoid arthritis (RA) patients in comparison with other disease-modifying drugs (DMARDs). A total of 103 early RA patients, without prior use of DMARDs, were randomized to receive CsA (3 mg/kg per day) or methotrexate (MTX) (0.15 mg/kg per week). In addition, all patients received prednisone (7.5 mg/day). After 42 months of treatment, pairs of hand and wrist radiographs of 41 patients treated with CsA and 42 treated with MTX were evaluated blindly and separately by two investigators, using reference radiographs for scoring. A scale scoring similar to Larsen's standard radiographs with minor modifications was used. The studied radiographs were obtained at the beginning and 42 months after therapy in both groups. Patients in both groups responded beneficially to the above treatment regimens. In the CsA group, 37 patients (71 %) remained radiographically stable and 4 worsened, while in the MTX group 39 patients (76%) remained stable and 3 deteriorated. No significant radiological worsening was found in the CsA-treated patients as compared to those treated with MTX. Early immuno-intervention in RA patients appears to be crucial for the future development of joint damage: CsA can delay radiological disease progression and may inhibit joint damage deterioration in early RA patients.
9370878 Intractable diarrhoea associated with secondary amyloidosis in rheumatoid arthritis. 1997 Sep OBJECTIVE: To examine the clinical characteristics of intractable diarrhoea associated with secondary amyloidosis in rheumatoid arthritis (RA). METHODS: Of 179 RA patients with biopsy confirmed secondary amyloidosis, 24 cases (23 women and one man) with intractable diarrhoea lasting for more than one month were retrospectively evaluated. RESULTS: The mean (SD) duration of diarrhoea was 87 (64) days. Prodromal symptoms of gastrointestinal dysfunction (n = 21) and impaired peristalsis (n = 16) were observed. Laboratory data showed hypoproteinaemia (4.7 (0.85) g/dl) caused by malabsorption or protein loss and high values of C reactive protein (17.0 (9.3) mg/dl). Recurrence of intractable diarrhoea (n = 4) and transition from intractable diarrhoea to other gastrointestinal problems of amyloidosis (ischaemic colitis (n = 2) and intestinal pseudo-obstruction (n = 4)) were observed. In 19 patients (25 episodes) the duration of intravenous hyperalimentation at remission (18 episodes) was 68 (52) days. Corticosteroid pulse therapy was administered to 10 patients (11 times) and the time elapsed from the end of corticosteroid pulse therapy to the end of diarrhoea was 18 (14) days. One and five year survival rates after the onset of intractable diarrhoea were 73.4% and 38.9%. Seven of 13 patients (54%) had died as a result of infectious diseases. CONCLUSION: Intractable diarrhoea associated with secondary amyloidosis in RA is a serious clinical entity and the prognosis is poor. Although it is assumed that intravenous hyperalimentation treatment and corticosteroid pulse therapy are favourable regimens for intractable diarrhoea, the patients should be monitored for possible infectious complications.
10527397 IDDM9 and a locus for rheumatoid arthritis on chromosome 3q appear to be distinct. 1999 Sep Markers near a locus for type 1 diabetes on chromosome 3q22-q25 (IDDM9) demonstrate linkage to rheumatoid arthritis, however it is not clear whether these two loci overlap. Sex-specific linkage analysis may be of interest for rheumatoid arthritis on chromosome 3q since linkage of type 1 diabetes to IDDM9 derives predominantly from affected female sibpairs, and rheumatoid arthritis is more common in females than males. Using data from a recent genome scan for rheumatoid arthritis and sex-specific linkage analysis we show that linkage of rheumatoid arthritis to chromosome 3q peaks approximately 30 cM centromeric to IDDM9. Furthermore, there is no evidence for linkage to IDDM9 in females with rheumatoid arthritis.
11109612 [Immunological aspects of early stage rheumatoid arthritis diagnosis]. 2000 AIM: To study immune status of patients with rheumatoid arthritis (RA) to improve immunodiagnosis at early stage of the disease. MATERIALS AND METHODS: Immunological examination covered 28 patients with rheumatoid arthritis (RA) aged 16 to 72 years. The duration of RA varied from 1.5 months to 1.5 years. Lymphocyte population and T-lymphocyte subpopulation were measured using monoclonal antibodies. Serum Ig were measured in Reafarm plates. RESULTS: Patients with stage II articular function insufficiency (AFI) demonstrated a significant lowering of the absolute number of lymphocytes, natural killers, elevated concentration of IgA compared to patients with less severe AFI. Patients with systemic symptoms had significantly decreased percentage of T-lymphocytes vs patients with isolated articular syndrome. Natural killers' levels were elevated in all the patients in early RA. A significant rise in the percentage of B-lymphocytes and serum IgG concentrations were also seen. In T-lymphopenia, relative amount of T-helpers and T-suppressors was significantly elevated while the ratio T-helpers/T-suppressors was reduced. CONCLUSION: Changes found in the immune status allows diagnosis of early RA, characterize immune disorders, help to select adequate immunomodulating therapy supporting function of the suppressor cells.
11764204 Ability of hand radiographs to predict a further diagnosis of rheumatoid arthritis in pati 2001 Dec OBJECTIVE: To evaluate the ability of hand radiographs collected at study inclusion to predict a diagnosis of rheumatoid arthritis (RA) 2 years later, in a cohort of patients with early arthritis. METHODS: We evaluated 270 patients with arthritis of less than one year duration. At the first visit, all patients underwent a standardized evaluation including laboratory tests and radiographs. Followup was 30+/-11.3 mo. The hand radiographs were read by observers blinded to patient data who looked for item 7 of the 1987 ACR criteria for RA and used Sharp's method to score erosions and joint space narrowing. RESULTS: The kappa coefficient for ACR item 7 was < 0.65 for bony decalcification and > 0.8 for erosions. Intra and interobserver correlation coefficients for Sharp score ranged from 0.90 to 0.95. The "erosion" component of ACR item 7 was more specific than the full item 7 (96% versus 87.5%; p = 0.02). Sharp erosion score was not better than the erosion component of item 7 (sensitivity 17%; specificity 96%). CONCLUSION: Regardless of the criterion used, hand radiographs were of limited value to predict which patients would be considered as having RA 2 years later. Diagnostic performance was similar for the "erosions" component of the 1987 ACR item 7 and for Sharp erosion score. The full 1987 ACR item 7 (erosions or bony decalcification) performed less well.
11302865 Outcome of cervical spine surgery in patients with rheumatoid arthritis. 2001 May OBJECTIVES: Cervical spine instability in patients with rheumatoid arthritis (RA) may lead to cervical myelopathy or occipital neuralgia, or both. Morbidity and mortality in patients with RA treated with cervical spine surgery during two years of follow up were evaluated. METHODS: Between 1992 and 1996 55 patients with RA underwent cervical spine surgery because of occipital neuralgia or cervical myelopathy, or both. Patients were classified according to the Ranawat criteria for pain and neurological assessment before operation and three months and two years postoperatively. For occipital neuralgia a successful operation was defined as complete relief of pain and for cervical myelopathy as neurological improvement. RESULTS: Occipital neuralgia was present in 17 patients, cervical myelopathy in 14 patients, and 24 had both. Surgical treatment in the patients with symptoms of occipital neuralgia who were still alive two years after surgery was successful in 18/29 (62%). In the surviving patients with cervical myelopathy neurological improvement of at least one Ranawat class was seen in 16/24 (67%). Postoperative mortality within six weeks was 3/51 (6%). Within two years after the operation 14 /51 (27%) of the patients had died; in most patients the cause of death was not related to surgery. The highest mortality (50%) was found in the group of six patients with quadriparesis and very poor functional capacity (Ranawat IIIB). CONCLUSION: Cervical spine surgery in patients with RA performed because of occipital neuralgia or cervical myelopathy, or both, is successful in most patients who are alive two years after surgery. However, the mortality rate during these two years is relatively high, which seems to be largely related to the severity of the underlying disease and not to the surgery itself.
9214427 The AIMS2-SF: a short form of the Arthritis Impact Measurement Scales 2. French Quality of 1997 Jul OBJECTIVE: To develop a short form of the Arthritis Impact Measurement Scales 2 (AIMS2) questionnaire, preserving content validity as the priority criterion. METHODS: A 2-step reduction procedure was used: 1) Delphi technique, with 1 panel of patients and 1 panel of experts each selecting 1 set of items independently; and 2) nominal group technique, where members of both panels reached consensus on the final selection of items, using information derived from item analysis. Psychometric properties of the AIMS2-Short Form (AIMS2-SF) and AIMS2 were compared using data from a cohort of 127 rheumatoid arthritis patients who completed the AIMS2 twice prior to the initiation of methotrexate (MTX) treatment and 3 months post-initiation of MTX treatment. RESULTS: The 2 panels reached consensus on a 26-item AIMS2-SF (54.4% reduction from the AIMS2). Factor analysis showed preservation of the 5-component structure. Convergent validity (Physical and Symptom components with clinical variables: r = 0.24-0.59), test-retest reproducibility (intraclass correlation coefficient >0.7), and sensitivity to change at 3 months (standardized response mean 0.36-0.8, except Social Interaction component [0.08]) were very close to the values for the original AIMS2. CONCLUSION: The AIMS2-SF is a shorter version of the AIMS2 (i.e., available in 2-page format) and has psychometric properties similar to those of the AIMS2.
9266623 Availability of iron and degree of inflammation modifies the response to recombinant human 1997 Forty-six patients with rheumatoid arthritis (RA) and documented anemia of chronic disease (Hb < 100/110 g/l) were randomized to receive either human recombinant erythropoietin (r-HuEPO, n = 36, 300 U/kg body weight) or placebo (n = 10) for 12 weeks in a multicenter study. An adequate response was defined as elevation of Hb > or = 120 g/l. Relevant clinical and laboratory assessments were made to evaluate efficacy and secure safety. A significant elevation in Hb from week 10 onwards was noted in twenty-six patients (five drop-outs) out of nine patients receiving placebo (one drop-out) (12 +/- 1.2 g/l vs 4 +/- 0.5 g/l; Hb elevation from 95 g/l to 107 g/l vs 93 g/l to 97 g/l, P < 0.05). Only 14.6%, however, were considered responders according to preset criteria. In the responders a lower initial CRP, a significant reduction in ESR but not in CRP was seen compared to the remaining r-HuEPO group. A significant elevation of energy level was noted in the r-HuEPO group; otherwise, no differences in clinical variables were seen. No serious adverse effects were noted. When analyzing patients receiving oral iron in combination with r-HuEPO and adding five additional, openly selected patients receiving both adequate iron supplementation and r-HuEPO, there was a significant weekly elevation of Hb from week 8 onwards in favor of combination therapy over the ones only receiving r-HuEPO (18 +/- 1.1 g/l vs 7 +/- 1.1 g/l, P < 0.05). The initial six responders had now reached ten of whom seven belonged to the combination therapy group. Response to r-HuEPO in RA patients appears to be dependent on availability of iron and on the degree of inflammation. If r-HuEPO treatment is considered, iron deficiency should always be corrected and strenuous efforts should have been made to control the disease itself.
11036822 A DNA polymorphism at the alpha2-macroglobulin gene is associated with the severity of rhe 2000 Oct OBJECTIVE: To determine if DNA polymorphisms at the alpha2-macroglobulin (alpha2m) and angiotensin converting enzyme (ACE) genes were associated with rheumatoid arthritis (RA). METHODS: A total of 160 patients (71 with early active severe RA, 89 with non-severe RA) were genotyped (polymerase chain reaction) for the alpha2m (5 bp deletion/insertion) and ACE (I/D) polymorphisms. We also genotyped 500 healthy controls from the same Caucasian population (Asturias, Northern Spain). RESULTS: Carriers of the alpha2m deletion allele were at a significantly higher frequency among patients with an early active severe form of the disease, compared to patients with non-severe RA (p = 0.037). The frequency of the alpha2m deletion allele was significantly higher in patients with severe compared to nonsevere RA (p = 0.017). In addition, the frequency of the deletion allele was significantly higher among patients with 5 or more episodes of acute exacerbation of disease activity per year (n = 39) compared to those with none (n = 46) (p = 0.002). Gene and genotype frequencies for the ACE-I/D polymorphism did not differ between those with early active severe and non-severe RA. CONCLUSION: The genetic variation at alpha2m is associated with the severity of RA. Carriers of the alpha2m deletion allele would have increased risk of developing an early active severe form of the disease. Our data suggest that alpha2m could be a valuable target in the treatment of RA.