Antibodies against cyclic citrullinated peptide don��t decrease after 6?months of infliximab treatment in refractory rheumatoid arthritis

Anti-citrullinated peptide antibodies (ACPA) and the rheumatoid factor (RF) are well-established serological markers for rheumatoid arthritis (RA). ACPA are very useful in the diagnosis of RA, especially at the early stages of the disease when ACPA have a greater diagnostic value than RF. The aim of the study was to assess the influence of infliximab treatment on RF IgM and ACPA serum levels and RA activity during 6 months of treatment. Thirty-two patients with refractory RA were treated with infliximab during a 6-month period. At baseline, 3 and 6 months of treatment the patients were examined for the number swollen and tender joints out of 28 (SJC, TJC) and the visual analogue scale of arthritis activity according to the patient (VAS). Serum samples were tested for erythrocyte sedimentation rate (ESR), C-reactive protein level (CRP), ACPA and RF IgM. The disease activity score (DAS-28) parameter was also calculated at the same time. During the course of our study, we observed statistically significant improvement in ESR, CRP, TJC, SJC, VAS DAS-28, and RF IgM after 3 and 6 months of infliximab treatment when compared to the baseline, whereas the ACPA level remained unchanged after 3 and 6 months of treatment (P = 0.96 and P = 0.85). The changes in the ACPA level are not a factor for evaluation of successful infliximab treatment but the changes in RF IgM are. According to different behavior of these antibodies during infliximab treatment, we suggest that the roles of ACPA and RF in the pathogenesis of RA are different.     

Magnetic resonance imaging quantification of hand synovitis in patients with rheumatoid arthritis treated with adalimumab

OBJECTIVE: To investigate the clinical response and to evaluate by magnetic resonance imaging (MRI) the inflammatory tissue changes in patients with refractory rheumatoid arthritis (RA) treated with adalimumab. METHODS: Thirteen patients with refractory RA who were treated with adalimumab (40 mg every 2 weeks subcutaneously) were examined with MRI of the dominant affected wrist and hand before treatment and one year after therapy. The volume of the enhanced inflammatory tissue (VEIT) was evaluated in fat-suppressed contrast-enhanced T1-weighted MRI images using the Analyse 4.0 software. Disease activity was evaluated using the Disease Activity Score 28-joint (DAS-28). Clinical improvement was evaluated according to the American College of Rheumatology 20% response criteria (ACR20%). RESULTS: We studied 12 women and one man, with mean age 52.0 +/- 10.9 years and mean disease duration 13.0 +/- 8.5 years. Eight patients had positive IgM rheumatoid factor. One year after treatment, 11 (84.6%) patients showed a decrease of the VEIT. Moreover the values of C-reactive protein (CRP; 4.3 +/- 6.6 mg/l), the erythrocyte sedimentation rate (ESR; 26.3 +/- 19.5 mm/h), the DAS-28 (3.5 +/- 1.1), and the VEIT (21.6 +/- 10.7 cm3) after treatment were significantly lower compared to the corresponding values before treatment (CRP 41.6 +/- 39.2), (ESR 54.3 +/- 28.6) (DAS-28 5.8 +/- 0.8), and (VEIT 36.9 +/- 16.8) (p < 0.01). All but 3 (76.9%) patients with RA achieved the ACR20% response, while 7 (53.8%) and 5 (38.5%) patients achieved ACR50% and ACR70% response, respectively. A positive correlation between VEIT, swollen joint count, and ESR was found before treatment (r = 0.59, r = 0.64, respectively; p < 0.05). CONCLUSION: In patients with refractory RA, treatment with adalimumab resulted in improvement of clinical, laboratory, and MRI findings. MRI assessment of the VEIT may represent an additional tool for investigation of joint disease activity and responsiveness to treatment.     

Risk of cervical myelopathy in rheumatoid arthritis patients with neck pain

BackgroundCervical spine (CS) evaluation in rheumatoid arthritis (RA) is challenging since subtle neurological insult is usually masked by the severe peripheral joint affection or muscle atrophy. Neglected CS lesions could end up with cervical myelopathy. Magnetic resonance imaging (MRI) has been the modality of choice in assessing CS in RA.Aim of the workTo evaluate CS in RA using MRI and detect the risk factors for its involvement.Patients and methodsForty RA patients with neck pain were assessed using disease activity score (DAS28), Ranawat classification of rheumatoid myelopathy, simple erosion narrowing score (SENS), bilateral hand and wrist musculoskeletal ultrasound (MSKUS) for early erosion detection and CS MRI.ResultsThe mean age of patients was 44.3 ± 10.1 years, disease duration 7.9 ± 6.6 years and the DAS28 was 4.8 ± 1.6. 70% of patients were in Ranawat class I, 30% in class II, and none in class III. 70% of patients had CS lesions where synovitis occurred in 67.5% of patients, odontoid erosions in 15%, atlanto-axial marrow edema in 5%, atlanto-occipital marrow edema in 5% and none had atlanto-axial subluxation (AAS), subaxial subluxation (SAS), spinal cord/brain stem compression. CS involvement was significantly related to peripheral joint erosion, high SENS and positive RF (p = 0.01, p < 0.0001, p < 0.0001 respectively).ConclusionCS involvement is remarkable in RA especially in those with peripheral joint erosions, high SENS and positive RF. RA patients with persistent neck pain, even in absence of objective neurological deficit should be evaluated early for detection and management of CS lesions before irreversible neurological damage takes place.     

Effects of rheumatoid factor isotypes on disease activity and severity in patients with rheumatoid arthritis: a comparative study

The value of rheumatoid factor (RF) isotypes for assessing rheumatoid arthritis (RA) remains debatable. In this study, we have examined the relationships between RF isotypes and disease activity and severity in RA patients. Sixty-two patients with RA, 48 women and 14 men, were studied. RF was measured by nephelometry (RF–N) and IgG–, IgA–, and IgM–RF isotypes were measured using enzyme-linked immunosorbent assay. Serum C-reactive protein and erythrocyte sedimentation rate were also determined. The patients were classified according to disease activity, joint damage, functional status, and presence of pulmonary involvement, rheumatoid nodule, and secondary Sjögren’s syndrome. Although the patients with active disease had significantly higher IgA–RF and IgM–RF levels compared to inactive patients, IgA–RF and IgM–RF were not found to be independently associated with disease activity in multivariate analysis. In patients with severe joint damage, IgA–RF and RF–N were significantly higher than those of the other patients. Multiple regression analysis showed that IgA–RF was the unique variable independently associated to severe joint damage. The patients with class III and IV functional index had significantly higher IgM–RF, IgA–RF, and RF–N levels compared to the patients with class I and II functional index; however, RFs were not significantly associated with functional status in multivariate analysis. IgA–RF and IgM–RF were significantly associated with pulmonary involvement and rheumatoid nodule, respectively. No significant associations were found between RF isotypes and secondary Sjögren’s syndrome. Our results suggest that the clinical usefulness of IgA and IgM isotypes is better than RF–N. Elevated IgA–RF may be a marker of erosive disease. The usefulness of RF isotypes for monitoring disease activity or functional status appears to be limited.     

抗环瓜氨酸肽抗体与类风湿关节炎疾病活动及骨侵蚀关系的研究

目的 探讨类风湿关节炎(RA)患者抗环瓜氨酸肽(CCP)抗体、类风湿因子(RF)与疾病活动度、功能状态及骨侵蚀的关系.方法 入选RA患者218例.健康对照41名,ELISA法检测抗CCP抗体,乳胶凝集法检测RF,同时记录RA患者的临床资料.分析抗CCP抗体、RF阳性和阴性患者中疾病活动指数28(DAS28)、健康评估问卷(HAQ)的变化,并探讨其中124例病程>2年的患者抗CCP抗体、RF与骨侵蚀的关系.结果 RA患者中抗CCP抗体阳性率为76%,RF阳性率为71%.DAS28评分在抗CCP抗体、RF阳性患者明显高于阴性患者(P＜0.05);抗CCP抗体浓度与DAS28评分相关(r=0.385,P=0.032);RF滴度与DAS28评分相关(r=0.141,P=0.037);红细胞沉降率(ESR)、C反应蛋白(CRP)及HAQ评分在抗CCP抗体、RF阳性和阴性患者之间的差异无统计学意义(P＞0.05).抗CCP抗体阳性患者更易出现骨侵蚀,与阴性患者相比,差异有统计学意义(P＜0.05).RF阳性和阴性患者之间骨侵蚀的差异无统计学意义.结论 抗CCP抗体、RF与疾病活动度相关,抗CCP抗体阳性患者更易出现骨侵蚀,但RF与骨侵蚀未表现出相关性.     

The influence of mannose binding lectin polymorphisms on disease outcome in early polyarthritis. TIRA Group

OBJECTIVE: To determine whether variant alleles of the mannose binding lectin (MBL) gene causing low serum concentrations of MBL are associated with increased susceptibility to rheumatoid arthritis (RA) and erosive outcome in an inception cohort of patients with early polyarthritis. METHODS: MBL and HLA-DRB1 alleles were determined by polymerase chain reaction in 68 Danish patients with incident early polyarthritis observed for one year. The associations between MBL and specific HLA-DRB1 genotypes and disease outcomes were analyzed. RESULTS: Among the patients with early polyarthritis 7.4% (5/68) and 41.2% (28/68) were homozygous and heterozygous for MBL variant alleles, compared with 2.8% (7/250) and 34.4% (86/250) of healthy controls (p = 0.09), while the corresponding figures in the patients with RA were 10% (5/50) and 42% (21/50) (p = 0.03), and in the patients with erosive RA 18.8% (3/16) and 35.3% (6/16), respectively (p = 0.004). Patients with early polyarthritis homozygous for MBL variant alleles had an increased risk of having erosive RA at inclusion by a factor of 4.7 (p = 0.02) and after one year by a factor of 3.6 (p = 0.04). MBL deficiency was associated with increased levels of C-reactive protein (CRP) and IgM rheumatoid factor (RF) at inclusion (p < 0.05). HLA-DRB1 alleles were not found to be associated with disease outcome. CONCLUSION: MBL variant alleles appear to be weak susceptibility markers for RA, and patients with early polyarthritis and homozygous for MBL structural variant alleles have a higher risk of developing early erosive RA. These findings, together with the positive association between MBL variant alleles and the increased serum levels of IgM RF and CRP, point at the MBL gene as a relevant locus in the pathophysiology of RA.     

Prospective study of early rheumatoid arthritis. I. Prognostic value of IgA rheumatoid factor.

Thirty-three patients with early arthritis, 28 of whom developed classical/definite rheumatoid arthritis (RA), were followed up for two to four years. Rheumatoid factor (RF) levels of the IgM, IgA, and IgG isotypes were measured in serum and synovial fluid by an ELISA technique developed in our laboratory. All seven patients who presented with raised IgA RF developed erosions of their hands and wrists. This was significantly different from the remaining 26. By contrast none of the five patients who presented with isolated elevation of IgM RF developed erosive disease. The patients with raised IgA RF needed significantly more treatment with 'specific' drugs than the remaining 26. It is suggested that the detection of IgA RF in early RA indicates poor prognosis, justifying a more aggressive treatment at an early stage.     

Rheumatoid factors in psoriatic arthropathy and in Waaler-Rose negative rheumatoid arthritis

Summary Serum levels of IgG, IgA and IgM rheumatoid factor (IgG RF, IgA RF and IgM RF) were determined by means of the diffusion-in-gel enzyme-linked immunosorbent assay (DIG-ELISA) in 42 Waaler-Rose negative patients with psoriatic arthropathy (PsA) type 1 (arthritis with involvement of distal interphalangeal joints) and type 3 (polyarthritis of rheumatoid type) according to the criteria of Moll and Wright as well as in 53 patients with Waaler-Rose negative rheumatoid arthritis (RA). Elevated levels of RF were found in 22% of patients with PsA type 3 and 45% of patients with Waaler-Rose negative RA. In contrast, none of the patients with PsA type 1 had detectable amounts of RF. It is suggested that the presence of IgG, IgA or IgM RF in patients having psoriasis in conjunction with inflammatory polyarthritis indicates the RA nature of the joint disease and should be considered as exclusion criterion for the diagnosis of PsA.     

Ethnic differences in the prognostic utility of rheumatoid factor isotypes and anticyclic citrullinated peptides in rheumatoid arthritis patients: a cross-sectional study

Abstract

Objectives The prognostic significance of rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) in rheumatoid arthritis (RA) remains contentious due to the conflicting lines of evidence. This study aims to determine the association between RF isotypes and anti-CCP with disease severity in RA patients from three ethnic groups.

Methods A total of 147 RA patients from three different ethnic groups (Malays, Chinese, and Indians) who fulfilled the 1987 American College of Rheumatology (ACR) revised criteria for RA were recruited into this study. The seroprevalence of RF isotypes immunoglobulin (Ig)A, IgG, and IgM, as well as anti-CCP was determined using commercial enzyme-linked immunosorbent assay (ELISA) kits. Multinomial regression analysis was performed to assess the independent effects of autoantibody status on the development of deforming and erosive RA and the presence of extra-articular manifestations (EAM).

Results In Chinese patients, we found a significant association (p < 0.05) between IgG RF and anti-CCP and the presence of erosive disease, as well as IgM RF and IgG RF with the presence of joint deformities. In Indian patients, IgM RF was associated with deforming disease, whereas none of the antibodies were associated with disease severity in Malay patients. Multinomial regression analysis revealed that IgG RF was the most important predictor variable for erosive disease in Chinese patients, and IgM RF the only predictor variable associated with deforming disease in both Chinese and Indian RA patients.

Conclusions There is variability in the phenotypic association of RF isotypes and anti-CCP in relation to disease severity of RA in the three ethnic groups. RF, in particular, IgG and IgM, may be better prognosticators of severe disease in Chinese and Indian patients.     

Cervical spine involvement early in the course of rheumatoid arthritis

Objectives

Cervical spine involvement in rheumatoid arthritis (RA) is considered a feature of long-standing disease. We describe two patients who presented with cervical symptoms as early features of RA.

Methods

We report two RA cases with cervical spine involvement as early features and use MEDLINE to review the literature concerning the frequency and disease duration of this manifestation and its imaging with plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI).

Results

An 80-year-old man with cervical myelopathy from a C1–C2 rheumatoid pannus underwent decompression surgery before development of peripheral synovitis from RA. A 63-year-old woman presented with neck pain and polyarthritis at RA diagnosis, with imaging that confirmed a C1–C2 rheumatoid pannus. Onset of cervical spine involvement in RA is generally after 10 years of disease duration, ranging from 3 months to 45 years after peripheral synovitis among patients with seropositive erosive RA. Occurring in 9–88% of RA patients, cervical spine involvement may result in cervical instability due to either mechanical compression or vascular impairment of the spinal cord. Bone erosions and atlanto-axial subluxation on standard radiographs are two major signs of cervical spine involvement in RA. MRI identifies earlier signs of RA and has a higher sensitivity in detecting bone erosions compared to conventional radiography.

Conclusions

Cervical spine involvement in RA is not an uncommon condition but is rare at early disease onset. Symptoms of cervical pain and myelopathy should prompt a thorough neurological examination accompanied by imaging.     

Radiological cervical spine involvement in patients with rheumatoid arthritis: a cross sectional study

OBJECTIVE: To investigate the frequency and the severity of radiological cervical spine involvement in patients with rheumatoid arthritis (RA). METHODS: We investigated 165 consecutive unselected patients with RA who fulfilled the revised American College of Rheumatology criteria for RA. All patients had a complete physical and laboratory evaluation. Patients had a radiological evaluation that included hand and wrist radiographs, as well as cervical spine radiographs in anteroposterior, lateral, and lateral in full flexion views. Hand radiographs were evaluated according to the Larsen criteria, while cervical radiographs were evaluated according to Winfield classification. RESULTS: There were 143 women and 22 men, with a mean age of 59.6 +/- 12.5 and disease duration 12.3 +/- 13.9 years. Positive rheumatoid factor was found in 63.6% of patients. One hundred forty-six patients presented radiological findings related to cervical spine involvement: atlantoaxial subluxations were found in 20.6% and erosions of the odontoid process in 2.4%; none presented vertical subluxation. Subaxial subluxations were found in 43.6%, disc space narrowing at C2-C3, C3-C4, C4-C5 levels in 66.1%, and vertebral plate sclerosis and erosions in 43.6%. CONCLUSION: Cervical spine radiological involvement is a frequent finding in our patients with RA, but the severity of the disease is rather mild, possibly related to the ethnic background.     

Association of anti-CCP positivity with serum ferritin and DAS-28

Antibodies to cyclic citrullinated peptides (anti-CCP) are highly specific for the diagnosis of rheumatoid arthritis (RA) with a marginal increased prediction of the disease. In this study, we aimed to investigate the relation of the presence of anti-CCP with clinical manifestations and disease activity in a cohort of RA patients. A total of 61 RA patients were included in this study. Data of disease-related parameters such as duration of disease, medications, degree of pain (visual analog scale, VAS), disease activity score 28 (DAS-28) and health assessment questionnaire (HAQ) were recorded. Laboratory workup included erythrocyte sedimentation rate (ESR), plasma C-reactive protein (CRP), rheumatoid factor (RF), anti-CCP, complete blood count and anemia parameters. Anti-CCP positivity was associated with higher scores of DAS-28, longer duration of morning stiffness, serum RF positivity and low levels of serum ferritin, while it was not associated with disease duration, VAS, HAQ, ESR, CRP and hemoglobin.     

Synovial membrane enhancement and bone erosion by magnetic resonance imaging for prediction of radiologic progression in patients with early rheumatoid arthritis

Objective The aim of this study was to determine the prognostic factors related to radiographic progression in patients with early rheumatoid arthritis (RA) (less than 1 year after onset) undergoing enhanced MRI at entry.Methods Demographic characteristics, disease duration, and enhanced MRI of the dominant wrists were recorded at entry. Duration of morning stiffness, number of swollen joints, serum rheumatoid factor (RF), erythrocyte sedimentation rate, C-reactive protein (CRP) level, and radiographs of hands and feet (Sharp/van der Heijde score) were assessed at each follow-up. Outcome was defined as damage seen on radiography.Results One hundred fourteen patients were followed up for 10 years. Logistic regression analysis showed that high MRI score, CRP, and RF positivity were associated with radiologic progression. The MRI score at baseline was a better predictor than CRP level and RF positivity at entry.Conclusion The assessment of synovial membrane enhancement and bone erosion by MRI of the wrist in early RA is very helpful to predict erosive outcome.     

Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis

OBJECTIVE: To evaluate a contribution of selected laboratory parameters for a prediction of progressive and erosive development in patients with early rheumatoid arthritis (RA). METHODS: In a prospective study baseline levels of antibodies to cyclic citrullinated peptide (anti-CCP), IgM, IgA, and IgG rheumatoid factors (RFs) were measured by enzyme linked immunosorbent assay (ELISA) in 104 patients with RA with disease duration <2 years. Antikeratin antibodies (AKA) and antiperinuclear factor (APF) were detected by indirect immunofluorescence. Patients were divided into two groups based either on the presence or absence of erosions or according to progression of Larsen score at the end of the 24 months' follow up. RESULTS: Sixty seven (64%) patients developed radiographic erosions, 49 (47%) had progression in Larsen score, and 36 (35%) progressed by more than 10 Larsen units. Significant differences in erosions and progression between the two groups were detected for anti-CCP, AKA, APF, IgM RF, IgA RF, and IgG RF. Baseline Larsen score correlated significantly with anti-CCP, IgM RF, and IgA RF levels, and all measured antibodies correlated with the progression >10 units. The combination of anti-CCP and IgM RF increased the ability to predict erosive and progressive disease. CONCLUSION: The data confirmed that measurement of anti-CCP, AKA, APF, and individual isotypes of RFs was useful for prediction of structural damage early in the disease course. Combined analysis of anti-CCP and IgM RF provides the most accurate prediction.     

Anti-CCP antibodies in rheumatoid arthritis and psoriatic arthritis

Our aim is to assess the prevalence and associated clinical features of anti-CCP (cyclic citrullinated peptide) antibodies for RF (rheumatoid factor)-positive and RF-negative rheumatoid arthritis (RA) and psoriatic arthritis (PsA). In a prospective, cross-sectional, multi-centre study, we determined the titres of anti-CCP antibodies in 208 RA patients (129 RF-positive, 79 RF-negative), 56 PsA patients and 39 healthy controls (HC). Clinical parameters including disease activity (disease activity score 28-DAS28), physical disability (health assessment questionnaire-HAQ), functional capacity (functional class) and radiological erosions were investigated in patients with RA. In PsA patients, clinical and radiological features were determined. Anti-CCP2 antibodies were measured using a second-generation anti-CCP enzyme-linked immunosorbent assay (Euro-Diagnostica, Netherlands). One-hundred four of 129 RF-positive RA (81%), 16 of 79 RF-negative RA (20%), seven of 56 PsA patients (12.5%) and none of the HC had anti-CCP antibodies. RA patients with anti-CCP antibodies had significantly higher disease activity, greater loss of function and more frequent erosive disease than anti-CCP antibody-negative group. In subgroup analysis, anti-CCP antibodies in RF-negative patients were also associated with erosive disease. All PsA patients with anti-CCP antibodies had symmetric arthritis with higher number of swollen joints. The prevalence of anti-CCP antibodies in RF-positive RA patients was significantly higher than in RF-negative RA and PsA patients. Anti-CCP antibodies were also associated with erosive disease in RF-negative RA patients. Both anti-CCP and RF tests were negative in 30% of the patients. Anti-CCP positivity was a frequent finding in PsA and associated with symmetrical polyarthritis.     

Unilateral destructive wrist synovitis in juvenile idiopathic arthritis

OBJECTIVE: To describe the clinical and radiographic features of a group of juvenile idiopathic arthritis (JIA) patients who developed unilateral destructive wrist synovitis. METHODS: All wrist radiographs performed yearly between 1986 and 2002 in JIA patients who had wrist involvement were retrospectively reviewed to identify patients who had unilateral erosive wrist synovitis, defined as a difference of at least -3 units in the Poznanski score between the affected wrist and the unaffected wrist, with the Poznanski score in the unaffected wrist being > -2 units throughout the follow-up period. Clinical and radiographic data obtained during follow-up were recorded for all patients. RESULTS: Of a total of 250 patients for whom we had approximately 900 wrist radiographs, 6 patients were found to have unilateral erosive wrist synovitis. The JIA onset subtype was oligoarticular in 5 patients and polyarticular in 1 patient and the disease duration from presentation to the last follow-up visit ranged from 2 to 16 years. The arthritis course was polyarticular in all patients. Five patients had positive antinuclear antibodies (ANA) and 1 had positive rheumatoid factor (RF). At the last follow-up visit, all patients had some impairment of wrist function and 2 patients had wrist subluxation. There was a marked radiographic damage in all affected wrist, with the Poznanski ranging from -8.0 to -8.50 units in 3 patients and being -5.5, -3.1 and -2.4 units, respectively, in 3 patients. The severity of radiographic damage in the ANA-positive patients with the longest disease duration was comparable to that observed in the RF-positive patient. CONCLUSION: Unilateral erosive wrist synovitis seems to be uncommon in JIA. Patients with unilateral wrist synovitis may be at risk of a destructive course irrespective of the JIA onset subtype.     

Clinical significance of rheumatoid factor isotypes in seropositive arthritis

Summary In this cross-sectional study a comparison was made of rheumatoid factor (RF) isotypes in 203 RF positive patients with arthritis. Of these, 129 had rheumatoid arthritis (RA) and 74 a milder disease that would formerly have been classified as probable RA. The majority (74%) of the RA patients had elevations of two or three RF isotypes compared with only 34% of the patients with the milder form of arthritis. A striking feature was that combined elevation of IgM RF and IgA RF was found in 67% of the RA patients compared to only 20% of the patients with milder arthritis who most frequently had an isolated elevation of IgM RF (41%). RA patients with an isolated elevation of IgA RF were younger and had a shorter disease history than RA patients with an isolated elevation in IgM RF or a combined elevation of IgA RF and IgM RF. The prevalence of raised IgM RF was, furthermore, found to increase with age and disease duration. We concluded that a raised level of IgA RF is an adverse phenomenon in patients with seropositive arthritis while patients with an isolated increase in IgM RF may be expected to experience a relatively mild disease course.     

Prognostic markers of radiographic progression in early rheumatoid arthritis

OBJECTIVE: To identify prognostic markers that are predictive of progressive erosive disease in patients with early rheumatoid arthritis (RA). METHODS: The study involved an inception cohort of 111 consecutive patients with RA and a disease duration of <1 year. Patients were treated according to an algorithm designed to avoid overtreatment of mild disease and to accelerate treatment in patients who had continuous disease activity. Patients were evaluated for the presence of clinical and laboratory disease activity markers. We determined the frequency of CD4+,CD28(null) T cells by flow cytometry, HLA-DRB1 gene polymorphisms by polymerase chain reaction (PCR)/sequencing, and 26 single-nucleotide polymorphisms in 19 candidate genes by multiplex PCR and hybridization to an immobilized probe array. Data were analyzed using proportional odds models to identify prognostic markers predictive of erosive progression over 2 years on serial hand/wrist radiographs. RESULTS: After 2 years, disease activity in 52% of the cohort was controlled by treatment with hydroxychloroquine and nonsteroidal agents. Forty-eight percent of the patients did not develop erosions. Older age, presence of erosions at baseline, presence of rheumatoid factor, rheumatoid factor titer, and HLA-DRB1*04 alleles, particularly homozygosity for HLA-DRB1*04, were univariate predictors of radiographic progression. Promising novel markers were the frequency of CD4+,CD28(null) T cells as an immunosenescence indicator, and a polymorphism in the uteroglobin gene. CONCLUSION: Clinical disease activity in patients with early RA can frequently be controlled with nonaggressive treatment, but this is not always sufficient to prevent new erosions. Rheumatoid factor titer, HLA-DRB1 polymorphisms, age, and immunosenescence markers are predictors of poor radiographic outcome. A polymorphism in the uteroglobin gene may identify patients who have a low risk of erosive disease.     

Prospective study of early rheumatoid arthritis. II. Association of rheumatoid factor isotypes with fluctuations in disease activity.

Thirty-three patients with early peripheral synovitis were followed up for two to four years in order to study the relationship between fluctuations in rheumatoid factor (RF) levels and indices of clinical activity. Twenty-eight of these patients developed classical/definite rheumatoid arthritis (RA). Seventeen patients developed erosive disease of their hands and wrists and thirteen had a positive RF agglutination test. Nineteen patients had raised levels of IgM, RF, IgA, RF, or IgG RF as measured by isotype-specific ELISA techniques. The within-patient fluctuations in IgA RF levels correlated significantly with the corresponding fluctuations in grip strength (p less than 0.05), erythrocyte sedimentation rate (ESR) (p less than 0.01), and a composite index of disease activity (p less than 0.02). IgG RF levels were also associated with changes in ESR and grip strength, but IgM RF showed only a weak association with fluctuations in ESR and not with any other clinical parameters. It is suggested that serum IgA RF may be a useful marker of disease activity in rheumatoid arthritis.     

Autoantibodies in rheumatoid arthritis: association with severity of disease in established RA

Introduction: Autoantibodies in rheumatoid arthritis (RA) are useful both for diagnosis and prognosis. Antibodies directed against citrullinated antigens have recently been shown to predict development of RA as well as poor outcome in early arthritis. Data on their role in established RA is limited. We studied the association of various autoantibodies in RA with its severity. Materials and methods: A total of one hundred and twenty nine-patients with established RA was enrolled and sera were collected and stored at −70°C. Data regarding erosions, deformities, and extra-articular features were collected. IgM rheumatoid factor (RF) was measured using nephelometry and value above 20 U was considered positive. IgA RF was measured by enzyme-linked immunosorbent assay (ELISA) and value above the mean±2 SD of normal healthy control was taken as positive. Anti-keratin antibody (AKA) was detected by indirect immunofluorescence assay using rat esophagus as substrate. Anti-cyclic citrullinated peptide (CCP) antibodies were measured by commercial ELISA and a value above 5 U was considered as positive. Results: The prevalence of various autoantibodies was: IgM RF 82.2%, anti-CCP antibodies 82.2%, AKA 51.9%, and anti IgA RF 45%. The concordance rate of anti-CCP antibodies with IgM RF was 83%, with AKA 68%, and with IgA RF 60.5%. All but one patient positive for AKA were positive for anti-CCP antibodies. The presence of IgM RF, AKA, and anti-CCP antibody was associated with joint erosions and deformities. None of the antibodies had any association with presence of extra-articular features. No association of IgA RF was seen with erosions, deformities, or extra-articular features. Among 23 seronegative RA patients, 11 were positive for anti-CCP antibodies and 6 were AKA positive. The presence of anti-CCP antibodies was associated with presence of deformities (p<0.05). Conclusion: Anti-CCP antibodies are present in majority of patients with established RA including seronegative patients. Both anti-CCP and AKA, in addition to conventional marker like IgM RF, are associated with severe erosive disease.