Fibromyalgia in patients with ankylosing spondylitis: prevalence and utility of the measures of activity, function and radiological damage.

OBJECTIVES: To determine the prevalence of fibromyalgia (FM) in ankylosing spondylitis (AS). To evaluate the effect of FM on the measures of activity in AS. To analyse predictive factors in order to identify this group of patients. PATIENTS AND METHODS: A cross-sectional study based on 462 patients with definite ankylosing spondylitis included in the REGISPONSER. Sociodemographic data, clinical features, Bath AS disease activity index (BASDAI), Bath AS functional index (BASFI), Bath AS radiology index (BASRI), Stoke modified index (Sasss-m), laboratory data, Short-Format 12 (SF-12), AS specific quality of life (ASQoL), Fibromyalgia Impact Questionnaire (FIQ) and treatments used were all documented. To diagnose FM, the ACR 1990 criteria had to be fulfilled. All statistical tests were performed using STATA. RESULTS: The prevalence of fibromyalgia in all AS was 4.11%. Among the women with AS, the prevalence of FM increased to 10.83%. The BASDAI, BASFI and total BASRI were strongly influenced by the presence of FM. The inverse relationship between BASDAI or BASFI and total BASRI was taken to generate a ratio. Accordingly, if the patient presented BASDAI/BASRI ≥1.5 or BASFI/BASRI ≥1.08, the probability of having FM was very high. CONCLUSIONS: There is an increased risk of FM in females with AS. The fact of having FM distorts the measures of activity and functional damage of AS. As a result, it is possible that some patients with AS and FM are being overtreated. The BASDAI/BASRI and BASFI/BASRI ratios are very useful to identify these patients.

Disease pattern of spondyloarthropathies in Spain: description of the first national registry (REGISPONSER) extended report.

OBJECTIVE: The national registry of spondyloarthropathies (REGISPONSER) is launched to classify patients with this group of diseases treated in Spanish rheumatology clinics. This manuscript describes the methodological and organizational background as well as characteristics of patients finally included, and provides a comparative analysis between characteristics of both ankylosing spondylitis and undifferentiated spondyloarthropathy groups of patients. PATIENTS AND METHODS: Twelve members of the GRESSER group have participated in the registry, for a one-year recruitment period. All consecutively registered adult patients treated in their clinics met the classification criteria of the European Spondyloarthropathies Study Group (ESSG). Data collected reflect the socio-demographic characteristics, as well as disease activity and functional status, clinical form at onset, treatment used and quality of life; all measured by standard instruments. RESULTS: Throughout 1 yr, 1385 patients have been included in the registry: 939 males (68%) and 440 females (32%), with an average age of 47 +/- 13 years (mean +/- s.d.), and an average disease duration of 12 +/- 9 years. Diagnoses of the included patients were: AS (n = 842, 61%), PsA (n = 290, 21%), u-SpA (n = 205, 15%), reactive arthritis (n = 16, 1.2%), inflammatory bowel disease arthritis (n = 13, 0.9%) and JCA-spondyloathropathy (n = 13, 0.9%). Regarding clinical form, 54% had axial disease, 20% peripheral disease, 24% mixed disease and 0.6% isolated enthesitic form. Low-back pain was the first symptom reported in 53% of the patients, and most common extra-articular disease manifestations were psoriasis (25%), anterior uveitis (16%) and intestinal inflammatory disease (4%). Some kind of work disability was reported by 353 patients (25.5%). CONCLUSIONS: Such databases are very useful to obtain information about characteristics of SpA patients treated in a certain location or following a specific treatment practice, and provide a tool for assessing the impact of the disease. Data collected in this registry provide an appropriate clinical and demographic profile of patients suffering from SpA in Spain.

Prediction of major clinical response (ACR50) to infliximab in psoriatic arthritis refractory to methotrexate.

OBJECTIVES: To determine the predictive factors of clinical response to infliximab in patients with refractory psoriatic polyarthritis. METHODS: A multicentre open study which included 69 patients with psoriatic polyarthritis refractory to methotrexate (15 mg/week at least for 8 weeks). Patients were treated with infliximab 5 mg/kg every 8 weeks in addition to their stable doses of methotrexate. A major clinical response was defined by the ACR50 at week 38. Logistic regression analysis was performed to analyse which of the following measures at the start of treatment were associated with an ACR50 response: demographic and clinical characteristics, duration of disease, tender and swollen joint counts, involvement of large joints (knee or hip, or both), erythrocyte sedimentation rate, C reactive protein (CRP), Health Assessment Questionnaire disability index, axial involvement, and the presence of erosions at baseline. RESULTS: In an intention to treat analysis 30/69 (44%) patients achieved an ACR50 response. In the univariate analysis both the presence of large joint involvement and severe disability were associated with a poor clinical response. In a multivariate logistic regression analysis high CRP values were independently associated with a good therapeutic response (odds ratio (OR)=18.7; 95% confidence interval (CI) 1.8 to 181.6; p=0.011). In contrast, large joint involvement and severe disability were associated with a poor response, which reached significance for large joint involvement (OR=29.3; 95% CI 3.2 to 266.3; p=0.003). CONCLUSION: A lower disability and, in particular, the absence of large joint involvement and higher CRP serum levels at the start of infliximab treatment are factors that seem to influence the probability of achieving a good therapeutic response in patients with psoriatic arthritis.

Effectiveness of reducing infliximab dose interval in non-responder patients with refractory spondyloarthropathies. An open extension of a multicentre study.

OBJECTIVE: To evaluate the therapeutic effectiveness of reducing the infliximab dose interval to 6 weeks in spondyloarthropathy patients not responding to 5 mg/kg every 8 weeks. METHODS: After 30 weeks of infliximab therapy, 25 patients were classified as responders [Bath Ankylosing Spondylitis Activity Index (BASDAI) <4 cm or ESR <30 mm/h and CRP <5 mg/l, n = 15; group A] or non-responders (patients who did not achieve the response established for group A; n = 10; group B). Responders continued on 5 mg/kg every 8 weeks and non-responders decreased the dose interval to 6 weeks. BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), ESR, CRP and ankylosing spondylitis assessment (ASAS) criteria were used to assess response. RESULTS: At 62 weeks, 11 of 15 patients (73.3%, 95% confidence interval = 44.9-92.2%) from group A and three of 10 patients (30%, 95% confidence interval = 6.7-65.2) from group B were responders (P = 0.049). Eighty per cent (eight of 10 patients from group A) and 22.2% (two of 9 patients from group B) achieved 50% BASDAI improvement (P = 0.023), and nine of 11 patients (81.8%) and four of 10 (40%) from groups A and B, respectively, reached ASAS20 at 62 weeks (P = 0.08). CONCLUSION: Patients on infliximab 5 mg/kg every 8 weeks with persistent disease activity may benefit from reducing the dose interval to 6 weeks.

The effect of HLA-DR antigens on the susceptibility to, and clinical expression of psoriatic arthritis.

OBJECTIVE: To analyse the relative role of HLA-DR antigens in the susceptibility to, and clinical expression of psoriatic arthritis (PsA). PATIENTS AND METHODS: A retrospective cohort study of 120 patients with PsA who were assessed according to a standard protocol. Patients were classified in accordance with the predominant pattern observed in the last 5 years of disease evolution: polyarthritis (n = 33), oligoarthritis (n = 45), and spondylitis (n = 42). HLA-Cw gene typing was done by the polymerase chain reaction (PCR) sequence-specific oligonucleotide probes (PCR-SSOP) method, while HLA-DR and B27 typing were performed by serological methods. The distribution of HLA-DR and Cw antigens was also analysed in 50 patients with psoriasis alone. One hundred and seventy subjects from our general population served as controls. RESULTS: No definite association was found between HLA-DR alleles and the risk of psoriasis or PsA. HLA-DR4 was found to be under-represented in arthritic patients [probability (p) = 0.03]. HLA-DR7 showed association with oligoarthritis [odds ratio (OR) 6, 95% confidence interval (CI): 2-16, corrected probability (Pc) = 0.01], whereas HLA-DR8 appeared to be related to the risk of polyarthritis (OR 9.5, 95% CI: 2-42, Pc = 0.02). HLA-Cw*0602 conferred risk for psoriasis (Pc < 0.00001), but not for PsA. As expected, HLA-B27 appeared to be over-represented in patients with spondylitis (p = 0.03). CONCLUSIONS: This is the first report that associates HLA-DR8 with psoriatic polyarthritis. Although HLA-DR antigens have a marginal role in PsA or psoriasis susceptibility, they may be relevant to the modulation of the clinical expression of PsA. These HLA data add support to the classification of PsA into three disease subsets.

Psoriasis vulgaris and psoriatic arthritis share a 100 kb susceptibility region telomeric to HLA-C.

OBJECTIVE: To map the locus for susceptibility to psoriasis in patients with psoriatic arthritis. METHODS: Seventy-four patients with psoriatic arthritis and 95 patients with psoriasis vulgaris were included in this study. Polymorphic genes and microsatellite markers centromeric (C1_2_5) and telomeric (C1_4_4, OTF3, HCR and the corneodesmosin gene) to HLA-C were studied in an association analysis. Typing was also performed on a control population of 104 matched donors. RESULTS: The allele Cw*0602 was associated both with psoriasis [49 vs 21%, Pc<0.0003; odds ratio (OR)=3.6, aetiological factor (AF)=0.72] and with psoriatic arthritis (62 vs 21%, Pc<0.000001; OR=6.1, AF=0.83). In psoriatic patients a susceptibility region telomeric to HLA-C that includes C1_4_4 (56 vs 22%, Pc<0.0002; OR=4.39, AF=0.77), OTF3 (85 vs 60%, Pc<0.0002; OR=3.7, AF=0.73) and HCR (63 vs 26%, Pc<0.00001; OR=3.8, AF=0.74) was observed. In psoriatic arthritis patients the susceptibility region was delimited by HLA-C and C1_4_4 (384 allele, 56 vs 22%, Pc<0.0002; OR=4.37, AF=0.77). CONCLUSIONS: Comparing the susceptibility regions associated with the two diseases, an overlapping interval of 100 kb between HLA-C and OTF3, which might contain the psoriasis gene, can be defined.

A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis.

OBJECTIVES: To analyse the factors predicting erosive-deforming arthropathy in patients with psoriatic arthritis (PsA). METHODS: A prospective cohort study was undertaken with 71 patients diagnosed as having PsA (44 men and 27 women, mean age 47 (SD 12) years). At the recruitment period patients had disease without evidence of radiological damage. Patients were studied and followed up according to a standard protocol from January 1991 to June 2001. Erosive and deforming disease was defined by the presence of erosions, joint space narrowing, subluxation, and/or ankylosis of peripheral joints. Univariate and multivariate analyses were performed to evaluate factors predicting erosive and deforming disease. RESULTS: At the end of the study 32 of 71 (45%) patients had developed erosive and deforming disease. Among them, 18 of 32 (56%) had a polyarticular onset, two of 32 (6%) showed a distal interphalangeal joint disease onset, six of 32 (19%) presented with oligoarthritis, and six of 32 (19%) presented with axial disease as the form of disease onset (p=0.001). Mean time to detect erosions or joint space narrowing was 20 (SD 4) months. Men showed fewer erosions than women (p=0.05). Patients who carried the HLA-B27 antigen showed less erosive disease than patients who lacked it (p=0.05). Patients with erosive and deforming disease had poorer functional performance than those without it as measured with the Health Assessment Questionnaire (HAQ) and the American College of Rheumatology (ACR) criteria (p<0.05 with both measurements). In multivariate analysis, only a polyarticular onset remained as an indicator of erosive and deforming disease (odds ratio (OR) 37, 95% confidence interval (95% CI) 3.6 to 88, p=0.025). CONCLUSIONS: A polyarticular onset (five or more swollen joints) of PsA was the unique independent risk factor which predicted the appearance of erosive and deforming disease over time. These data may be useful for clinicians treating patients with PsA, as it may guide treatment towards a more aggressive and earlier intervention.

TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients.

OBJECTIVE: To investigate the relative contribution of MHC loci in their susceptibility to primary ankylosing spondylitis (AS) in HLA-B27 negative patients and to compare the clinical features and genetic factors with those of HLA-B27 positive AS. METHODS: DNA from patients with B27 negative primary AS (n = 28), B27 positive primary AS (n = 77), and matched healthy controls (B27-, n = 100; B27+, n = 70) were analyzed to investigate whether HLA genes determine the disease susceptibility, or whether other closely linked loci might play a role in disease development. HLA typing was carried out by serology and PCR/SSP (HLA-B, -DR), MICA-TM polymorphism in the transmembrane region by radioactive PCR, and tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism at positions -238 and -308 by PCR-RFLP. RESULTS: Subtle clinical differences were found for primary AS, the B27 negative patients being less frequently complicated by acute anterior uveitis and more associated with peripheral arthritis than B27 positive. Differences were found in the distribution of TNF-alpha -238 genotypes among patients with primary AS (B27- vs B27+). The TNF-alpha -238(A) polymorphism was present in 50% of the B27 negative patients carrying the -238 G/A and A/A genotypes and was significantly increased compared with B27 positive AS (odds ratio 4.3) and with the B27 negative control group (OR 5.9). The TNF-alpha genotypes were equally prevalent in B27 positive AS and healthy matched B27 positive controls. No significant HLA and MICA typing differences were found between the populations under study. CONCLUSION: Our results indicate that the polymorphism variation in the TNF-alpha promoter -238.2(A) influences disease susceptibility in B27 negative primary AS but had no effect in our B27 positive AS population.

The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is independent of the association of Cw*0602 in psoriasis.

OBJECTIVE: To investigate the relative contribution of HLA antigens in the susceptibility to psoriasis and to localize additional genetic factors involved in psoriatic arthritis (PsA). METHODS: DNA from 45 patients with psoriasis, 65 with PsA, and 177 healthy control subjects was examined by polymerase chain reaction (PCR) using sequence-specific oligonucleotide probes to determine HLA-C. To examine whether MICA (class I major histocompatibility complex chain-related gene A) confers additional susceptibility, trinucleotide repeat polymorphism in the transmembrane region of the MICA gene was investigated by radioactive PCR. Further analysis of MICA was made by PCR-single-strand conformational polymorphism to determine the allelic variant corresponding to MICA transmembrane polymorphism. RESULTS: Our results reveal new findings: 1) the frequency of the Cw*0602 allele was significantly increased in both patient groups: psoriasis (corrected P [Pcorr] < 10(-5), relative risk [RR] 6.2), PsA (Pcorr < 10(-6), RR 6.3), 2) the trinucleotide repeat polymorphism MICA-A9 was present at a significantly higher frequency in PsA patients (Pcorr < 0.00035, RR 3.2), whereas a similar distribution was found in both the control and psoriasis population, 3) this polymorphism corresponds to the MICA-002 allele and was found to be overrepresented in patients with the polyarticular form (Pcorr < 0.0008, RR 9.35), 4) the increase in MICA-A9 in PsA patients is independent of linkage disequilibrium with Cw*0602, 5) this allele confers additional relative risk (RR 3.27, etiologic fraction 0.44; etiologic fraction is the proportion of disease cases among the total population that are attributable to 1 allele when the relative risk is > 1) in PsA patients who carry Cw*0602. CONCLUSION: The data obtained in this study are consistent with the polygenic inheritance of psoriasis. Cw*0602 appears to be the stronger genetic susceptibility factor for psoriasis. Independent of the HLA-C association, MICA-A9 polymorphism corresponding to the MICA-002 allele is a possible candidate gene for the development of PsA.

Annexin V autoantibodies in rheumatoid arthritis.

OBJECTIVE: To investigate the occurrence of anti-annexin V autoantibodies in sera of patients with rheumatoid arthritis to assess involvement with the disease and any relation to glucocorticoid treatment. METHODS: Anti-annexin V antibodies were measured by an enzyme linked immunosorbent assay (ELISA) which used the purified human recombinant protein as antigen. RESULTS: Concentrations of anti-annexin V autoantibodies, predominantly of the IgG class, were significantly raised in sera from patients with rheumatoid arthritis compared to normal controls. This was not correlated with other indices of disease activity such as erythrocyte sedimentation rate or C reactive protein and was unrelated to glucocorticoid treatment. CONCLUSIONS: Extracellular annexin V provides an antigenic stimulus for autoantibody production and its in vivo expression is independent of glucocorticoid control. Such autoantibodies may have a detrimental role in the arthritic condition by interfering with putative functions of annexin V, including collagen type II binding, inhibition of phospholipase A2 activity, and Fc receptor activity.

Upregulated expression of IL-4 receptors and increased levels of IL-4 in rheumatoid arthritis patients.

The level of IL-4R expression on peripheral lymphocyte subsets from rheumatoid arthritis (RA) patients and controls was studied by flow cytometric analysis of the binding of phycoerythrin-labelled IL-4 (PE-IL-4). In normal lymphocytes, IL-4R is mainly expressed on CD19+ cells, although it was also seen, at lower levels, on CD3+, CD4+ and CD8+ cells. In RA patients, a significantly increased spontaneous expression of IL-4R was observed, compared with controls, in the CD3+, CD4+ and CD19+ cell subsets. No significant differences in IL-4R expression were found between patients receiving steroids and those who were not, suggesting that steroids are not involved in upregulating IL-4R levels in vivo. Because IL-4 is a potent upregulator of IL-4R, we considered the possibility that incremented levels of circulating IL-4 in RA accounted for the high surface expression of IL-4R. By ELISA, we found abnormally high levels of immunoreactive IL-4 in 35.13% of patient serum samples, while it was undetectable in control sera. In addition, we examined IL-4 mRNA expression by polymerase chain reaction (PCR) in the PBMC of patients and controls. IL-4 PCR products were observed in four out of 10 patients studied but in none of the controls. No correlation was observed between the seric concentrations of IL-4 and IL-4R, indicating that activator factors other than IL-4 contribute to the upregulation of IL-4R expression in RA. Since the patients' sedimentation rate and CRP values did not correlate with the concentration of circulating IL-4, we conclude that this lymphokine does not contribute to the deleterious effect of the disease. Rather, due to its antiinflammatory properties, the overproduction of IL-4 in RA may be a compensatory mechanism neutralizing the harmful effect of activated macrophages.

Decrease in detectable complement receptor type 1 levels on erythrocytes from patients with psoriatic polyarthritis.

The complement receptor type 1 (CR1) levels on erythrocyte membranes from 23 patients with PsA was determined by using ELISA. Six patients had an axial form, the rest had peripheral arthritis (10 polyarthritis and seven oligoarthritis). A significant decrease in levels of this receptor was found in patients with polyarthritis compared with healthy controls. Non-significant differences were found when comparing the other two groups of patients with the controls, although the mean values of CR1 were lower in the patients' group. We also found an inverse correlation between CR1 levels and articular index, but not with ESR, CRP or disease duration. No differences in the CR1 density were obtained for HLA-B27 positive and HLA-B27 negative patients.

Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients.

We carried out a prospective study of the clinical, laboratory and radiological features of 180 patients with psoriatic arthritis. We initially classified our patients into five groups as described in the publications of Moll and Wright. Thirty-seven per cent had oligoarthritis, 36% polyarthritis, 23% spondarthritis (sacroiliitis and/or spondylitis) and 4% had the mutilans form. The distal joint arthritis type did not exist as an entity and the distal interphalangeal (DIP) joints were affected in all groups. The spondarthritis form includes patients with exclusively axial manifestations and also those who in addition have peripheral arthritis (oligoarthritis, polyarthritis, DIP arthritis). Only 53% of our patients had nail involvement. We found an increase of IgA levels in patients with axial disease. This suggests a relationship between ankylosing spondylitis and psoriatic spondylitis. The HLA-B17/Cw6 association increased in the oligoarticular form. The increase of antigen B17 correlated with the spondarthritic and oligoarthritis forms whereas Cw6 was more important in the oligoarthritis form. An increase of the HLA-B27/Cw1 association and the spondarthritic form was also found. Moreover, we detected a greater incidence of the HLA-B27 antigen in patients with bilateral sacroiliitis (85%) than in patients with unilateral sacroiliitis (22%). Our work revealed that PA is not a harmless disease; 57% of our patients had erosive arthritis while 19% had ARA class III or IV functional impairment.

HLA antigens in psoriatic arthritis subtypes of a Spanish population.

HLA-A, B, and C antigens were studied in 104 Spanish patients with psoriatic arthritis. Different clinical features were evaluated and the patients divided into disease subsets. HLA-B17, B27, B16, and Cw6 were the most common haplotypes in the total group. The HLA-B17/Cw6 haplotype was increased in patients with oligoarthritis. The increase of antigen B17 correlated with oligoarthritis and spondarthritis, whereas Cw6 was more significant in oligoarthritis. The prevalence of the B27/Cw1 haplotype was greater in association with spondarthritis and was probably related to the B27.5 subtype linked to Cw1. A significant negative association between the B44/Cw5 haplotype and psoriatic arthritis was found. The existence of several haplotypic factors in the different subsets is discussed. Lack of one or more HLA factors is thought to be responsible for the different clinical forms of psoriatic arthritis.