Failure of first anti-TNF agent in Takayasu's arteritis: to switch or to swap?

OBJECTIVES: Biologic drugs (bDMARD), especially TNF-α-inhibitors (TNFi), are used in refractory Takayasu's arteritis (TAK) patients. Up to 23% of patients are switched to a different bDMARD because of inefficacy. No data are available on which strategy is more efficient after TNFi failure. The aim of our study is to evaluate whether a switch or swap strategy should be preferred in TAK patients failing TNFis. METHODS: TAK patients treated with a second bDMARD after the failure of the first TNFi were identified from 3 referral centres. Patients were classified as switch if treated with a different TNFi, and swap if treated with a non-TNFi bDMARD. Baseline features were evaluated. Efficacy and safety of the second bDMARD at 6 and 12 months were assessed and a comparison between switch and swap patients was made. RESULTS: Twenty-four TAK patients were identified. Eleven patients (46%) were switched and 13 patients (54%) were swapped (12 to tocilizumab, 1 to ustekinumab). Baseline features of patients in the 2 groups were comparable. At 12 months, the second bDMARD was suspended in 4 switch (36%) and in 5 swap (42%) patients. Second biologic drug survival and relapse-free survival were equivalent between the two groups at 6 and 12 months. A vascular worsening was observed in 4 switch (40%) and 2 swap (25%) patients. Severe infections, myocardial infarction, ischemic stroke or cancer were recorded in no patient. CONCLUSIONS: Our retrospective study suggests that in first-line TNFi failure TAK patients both switch and swap strategies can be considered suitable approaches.

Observational study on the QUality of life of Italian Axial SpondyloARthritis patients (QUASAR): baseline data.

OBJECTIVES: To describe the baseline characteristics of the patients enrolled in the QUality of life in patients with Axial SpondyloARthritis (QUASAR) study in terms of quality of life (QoL), disease activity, therapy adherence, and work ability in a real-world setting. METHODS: QUASAR is an Italian multicentre, prospective 12-month observational study, including consecutive adult patients classified as axial spondyloarthritis (axSpA) according to the Assessment of SpondyloArthritis international Society criteria for axSpA. RESULTS: Of 512 patients enrolled in 23 rheumatology centres, 80.7% had ankylosing spondylitis (AS) and 19.3% had non-radiographic axSpA (nr-axSpA). Mean ages were 34.1±13.3 years at axSpA symptoms onset and 39.5±13.0 years at diagnosis. Of the patients, 51.4% presented with ≥1 extra articular manifestation (EAM); the most common were psoriasis (17.8%) and uveitis (16.4%). Patients with nr-axSpA and AS had similar EAM rates, disease activity, and QoL. Biologic disease-modifying anti-rheumatic drugs (bDMARDs; 83.2%) were the most commonly received medication, followed by conventional synthetic DMARDs (22.9%) and non-steroidal anti-inflammatory drugs (NSAIDs; 16.6%). At baseline, higher treatment satisfaction was reported with bDMARDs which, together with NSAIDs, were associated with the best overall scores for disease activity, function, and QoL in the overall population and AS subgroup. CONCLUSIONS: QUASAR is the first Italian prospective study that comprehensively evaluated a large axSpA patient sample in a real-world setting. This interim analysis at baseline confirmed that i) patients with AS and nr-axSpA have similar QoL and disease burden, ii) nearly all axSpA patients receive treatment, and iii) bDMARDs and NSAIDs, overall, yield better disease activity and QoL.

Physician's Global Assessment in Psoriatic Arthritis: A Multicenter GRAPPA Study.

OBJECTIVE: Physician's global assessment (PGA) of disease activity is a major determinant of therapeutic decision making. This study assesses the reliability of the PGA, measured by means of 0-100 mm visual analog scale (VAS), and the additional use of separate VAS scales for musculoskeletal (PhysMSK) and dermatologic (PhysSk) manifestations in patients with psoriatic arthritis (PsA). METHODS: Sixteen centers from 8 countries enrolled 319 consecutive patients with PsA. PGA, PhysMSK, and PhysSk evaluation forms were administered at enrollment (W0) and after 1 week (W1). Detailed clinical data regarding musculoskeletal (MSK) manifestations, as well as dermatological assessment, were recorded. RESULTS: Comparison of W0 and W1 scores showed no significant variation (intraclass correlation coefficients were PGA 0.87, PhysMSK 0.86, PhysSk 0.78), demonstrating the reliability of the instrument. PGA scores were dependent on PhysMSK and PhysSk (p < 0.0001) with a major effect of the MSK component (B = 0.69) compared to skin (B = 0.32). PhysMSK was correlated with the number of swollen joints, tender joints, and presence of dactylitis (p < 0.0001). PhysSk scores were correlated with the extent of skin psoriasis and by face, buttocks or intergluteal, and feet involvement (p < 0.0001). Finally, physician and patient assessments were compared showing frequent mismatch and a scattered dot plot: PGA versus patient's global assessment (r = 0.36), PhysMSK versus patient MSK (r = 0.39), and PhysSk versus patient skin (r = 0.49). CONCLUSION: PGA assessed by means of VAS is a reliable tool to assess MSK and dermatological disease activity. PGA may diverge from patient self-evaluation. Because MSK and skin/nail disease activity may diverge, it is suggested that both PhysMSK and PhysSk are assessed.

IL-23A, IL-23R, IL-17A and IL-17R polymorphisms in different psoriatic arthritis clinical manifestations in the northern Italian population.

To investigate the genetic variability of IL-17A, IL17-RA, IL-23A and IL-23R genes on an in-depth phenotypically characterized northern Italian Psoriatic arthritis (PsA) case-control cohort, in search for associations specific to different PsA clinical sub-phenotypes. We examined 118 patients with PsA according to CASPAR criteria (mean age 57 ± 13, female 38.4 %, mean disease duration 13.9 ± 8.6 years, peripheral disease 83.8 %, axial manifestations 34.5 %, radiological erosive disease 49 %) compared with 248 controls of the same ethnic origin matched for age and sex. The presence of axial disease was defined by the clinical axial involvement and/or the presence of radiological alteration consistent with spondyloarthropathy according to New York criteria. The presence of peripheral disease (arthritis and/or enthesitis) was defined only on clinical basis. A total of 40 SNPs, mapping within the genes mentioned above, were genotyped in both groups and used to perform association analyses by subdividing the PsA sample into subgroups according to different clinical manifestations on the basis of axial and peripheral involvements. No differences between patients and controls were found in the distribution of the IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants. Comparing patients with axial disease versus those without, we found that axial manifestations were significantly associated with the presence of IL-23R rs12401432 GG homozygosity (26.8 % vs. 5.3 %, p corr = 0.019, OR 2.63 [95 % CI 1.13-6.16]). No differences in distribution of the allelic variants were found comparing patients with versus those without peripheral disease or patients with versus without radiological peripheral erosions. In PA patients of northern Italian origin, IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants are not associated with disease susceptibility. However, a strong association with the IL-23RA rs12401432 GG genotype is associated with axial involvement of the disease.

Efficacy of infliximab in a patient with refractory idiopathic retroperitoneal fibrosis.

Glucocorticoids are the mainstay of treatment of idiopathic retroperitoneal fibrosis (IRF). However, relapses are frequent upon tapering of the glucocorticoid dose. A variety of traditional immunosuppressants have been proposed as steroid-sparing agents, but some patients fail to adequately respond to combined glucocorticoid and immunosuppressive therapy. We report a patient with IRF refractory to combined glucocorticoid and methotrexate therapy treated with the anti-TNF-α monoclonal antibody infliximab. Infliximab was administered at 5 mg/kg/bodyweight at week 0, 2, 6 and 8-weekly thereafter for 3 consecutive years. Drug efficacy and safety were assessed clinically and by laboratory tests at treatment onset and subsequently before each infusion. In addition, 18FFluorodeoxyglucose (FDG) positron emission computerised tomography (PET/CT) and abdominal CT scans were used to monitor disease activity and response to treatment. Infliximab therapy resulted in a satisfactory clinical and laboratory response paralleled by an improvement in imaging findings. No serious adverse events were noted. Infliximab may be an effective and safe treatment for refractory IRF. A controlled study is required to confirm our findings.

Rescue treatment with tocilizumab for Takayasu arteritis resistant to TNF-α blockers.

Anti-TNF-α therapy has successfully been used to treat Takayasu arteritis (TA) refractory to conventional immunosuppressive treatment. However, some patients fail to respond even to TNF-α blockers. Interleukin-6 (IL-6) is a key player in the pathogenesis of TA. Preliminary data also suggest efficacy of the IL-6 receptor inhibitor tocilizumab in patients with large-vessel vasculitis. We report a patient with TA refractory to multiple conventional immunosuppressive agents and two TNF-α blockers successfully treated with monthly tocilizumab infusions (8 mg/kg body weight) for 6 consecutive months. Clinical indices of disease activity, inflammatory markers, and 18Ffluorodeoxyglucose positron emission/computerised tomography findings normalised, while the prednisone dosage could be tapered. Serum IL-6 and soluble IL-6 receptor (sIL-6R) levels raised during tocilizumab treatment consistent with the mode of action of tocilizumab. Tocilizumab holds promise for patients with refractory TA. Larger studies are required to confirm our findings.

Small-vessel vasculitis surrounding an uninflamed temporal artery and isolated vasa vasorum vasculitis of the temporal artery: two subsets of giant cell arteritis.

OBJECTIVE: To evaluate the frequency and clinical characteristics of periadventitial small-vessel vasculitis (SVV) and isolated vasa vasorum vasculitis (VVV). METHODS: We identified 455 temporal artery biopsies performed in residents of Reggio Emilia, Italy between 1986 and 2003. Slides of temporal artery biopsy specimens were reviewed by a pathologist who was blinded with regard to clinical data. SVV was defined as inflammation of the small vessels external to the temporal artery adventitia, and VVV was defined as isolated inflammation of temporal artery vasa vasorum. Medical records of patients with SVV and/or VVV were reviewed, and demographic, clinical, laboratory, and followup data were collected. For comparison purposes, we collected the same data from an equal number of randomly selected patients with evidence of classic giant cell arteritis (GCA). RESULTS: Sixteen patients had SVV, 18 had isolated VVV, and 5 had both SVV and VVV. Compared with patients with classic GCA, the frequencies of headache, scalp tenderness, abnormalities of temporal arteries, jaw claudication, anorexia, and weight loss, the levels of acute-phase reactant at diagnosis, and the initial and cumulative doses prednisone were significantly lower and the frequency of peripheral synovitis was higher in the patients with SVV, and the frequency of cranial ischemic events was similar in the 2 groups. In contrast, the clinical characteristics and erythrocyte sedimentation rate at diagnosis of patients with isolated VVV were similar to those of patients with classic GCA. CONCLUSION: Our findings indicate that isolated VVV and SVV should be considered part of the histopathologic spectrum of GCA.

Patient global assessment in psoriatic arthritis: a multicenter GRAPPA and OMERACT study.

OBJECTIVE: During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0-100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA). METHODS: In total, 319 consecutive patients with PsA (186 men, 133 women, mean age 51 ± 13 yrs) were enrolled. PGA, PJA, and PSA were administered at enrolment (W0) and after 1 week (W1). Detailed clinical data, including ACR joint count, Psoriasis Area and Severity Index (PASI), and Hospital Anxiety and Depression Scale, were recorded. RESULTS: Comparison of W0 and W1 scores showed no significant variations (intraclass correlation coefficients for PGA 0.87, PJA 0.86, PSA 0.78), demonstrating the reliability of the instrument. PGA scores were not influenced by patient anxiety or depression, but were dependent on PJA and PSA (p = 0.00001). PJA was dependent on the number of swollen and tender joints (p < 0.00001). PSA scores were influenced by the extent of skin psoriasis and by hand skin involvement (p = 0.00001). Joint and skin disease were found not to correlate in terms of disease activity as evidenced by the swollen joint count compared to PASI (r = 0.11) and by the PJA compared to PSA (r = 0.38). CONCLUSION: PGA assessed by means of VAS is a reliable tool related to joint and skin disease activity. Because joint and skin disease often diverge it is suggested that in some circumstances both PJA and PSA are also assessed.

Longitudinal examination with shoulder ultrasound of patients with polymyalgia rheumatica.

OBJECTIVE: To determine if ultrasonography (US) and power Doppler (PD) may be useful in identifying polymyalgia rheumatica (PMR) patients with relapsing disease. METHODS: For a mean of 41 months, 57 consecutive untreated patients with PMR were prospectively assessed for relapses/recurrences. This cohort represented all the patients diagnosed over a 18-month period in one Italian secondary referral centre. Clinical signs and symptoms as well as ESR and CRP were evaluated. US examination of the shoulders was performed in all 57 patients at diagnosis and after the onset of prednisone treatment (mean 24 +/- 3 weeks). Power Doppler ultrasonography (PDUS) was performed in 24 patients. Shoulder sonograms were obtained according to standardized techniques. RESULTS: Prednisone therapy significantly reduced the frequency and the degree of subacromial/subdeltoid bursitis, long head biceps tenosynovitis and glenohumeral synovitis. At diagnosis, a positive PD signal was observed more frequently in the subacromial/subdeltoid bursae (33%). Prednisone therapy significantly reduced the frequency of patients with positive PD signal. Of the 44 patients in remission or with low disease activity at the time of the second US, 26 (59%) still had evidence of persistent inflammatory lesions. There was no association between the persistence of inflammation at US and relapses/recurrences; in contrast, a positive PD signal at diagnosis was significantly associated with the occurrence of relapses/recurrences at follow-up. CONCLUSION: Subclinical inflammation detected by US persists in most PMR patients despite glucocorticoid treatment. PDUS may be useful to detect at diagnosis the patients with most active inflammation who have a higher risk of relapses/recurrences.

Treatment of refractory polymyalgia rheumatica with etanercept: an open pilot study.

OBJECTIVE: To investigate whether etanercept has a steroid-sparing effect in the treatment of patients with relapsing polymyalgia rheumatica (PMR). METHODS: The study group comprised patients with relapsing PMR who were not able to reduce their prednisone dosage below 7.5-10 mg/day and who had experienced corticosteroid-related side effects. Patients received injections of etanercept 25 mg twice weekly for 24 weeks, and were followed up for 3 additional months after treatment withdrawal. Patients regularly underwent clinical assessment, measurement of erythrocyte sedimentation rate and C-reactive protein level, and ultrasound (US) examination of the shoulders during the 9 months of the followup period. RESULTS: All 6 enrolled patients responded to etanercept with sustained remission (improvement of at least 70% according to European League Against Rheumatism response criteria for PMR in 4 patients and at least 50% in 2 patients) and were able to significantly reduce their median prednisone daily dosage without experiencing a disease relapse (8.75 mg versus 2.5 mg; P = 0.026) at the end of the 9-month study period. US shoulder examination performed at the end of followup demonstrated a parallel reduction of glenohumeral and periarticular inflammation. A significant reduction in the cumulative prednisone dose 9 months before versus the 9-month study period was observed (mean +/- SD 1,767 +/- 524 mg versus 730 +/- 182 mg; P = 0.028). Three patients developed nonsevere side effects: bacterial cystitis in 2 and influenza in 1. CONCLUSION: These results, which should be confirmed in a controlled study, suggest that etanercept may be a safe and useful corticosteroid-sparing agent in relapsing PMR.

Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial.

BACKGROUND: A reliable alternative to steroids for treating polymyalgia rheumatica has not yet been identified. Although infliximab has been used occasionally in steroid-resistant cases, its efficacy has not been demonstrated in a controlled study. OBJECTIVE: To compare the efficacy of prednisone plus infliximab with that of prednisone plus placebo in patients with newly diagnosed polymyalgia rheumatica. DESIGN: Randomized, placebo-controlled trial. SETTING: 7 rheumatology clinics in Italy. PATIENTS: 51 patients with newly diagnosed polymyalgia rheumatica. Patients with associated giant cell arteritis and those who had been previously treated with steroids or biological or immunosuppressive agents were excluded. INTERVENTION: Initial therapy with oral prednisone tapered from 15 mg/d to 0 mg/d over 16 weeks according to a standard protocol, plus infusions of placebo or infliximab, 3 mg/kg of body weight, at weeks 0, 2, 6, 14, and 22. MEASUREMENTS: The primary efficacy end point was the proportion of patients without relapse or recurrence through week 52. Secondary outcomes were the proportion of patients no longer taking prednisone, the number of relapses and recurrences, the duration of prednisone therapy, and the cumulative prednisone dose. RESULTS: Four patients (3 in the infliximab group and 1 in the placebo group) did not complete the trial. The proportion of patients who were free of relapse and recurrence at 52 weeks did not differ between groups (6 of 20 patients [30%] in the infliximab group vs. 10 of 27 patients [37%] in the placebo group; adjusted risk difference, -3 percentage points [95% CI, -31 to 24 percentage points]; P = 0.80). In a sensitivity analysis that included dropouts, the best-case scenario yielded a difference of 5 percentage points (CI, -21 to 31 percentage points) between the groups. The secondary outcomes at weeks 22 and 52 did not differ between the groups. LIMITATIONS: The study had a small sample and a short follow-up. A low dosage of infliximab was used, and the prednisone dosage was rapidly tapered. CONCLUSIONS: Although too small to be definitive, the trial provides evidence that adding infliximab to prednisone for treating newly diagnosed polymyalgia rheumatica is of no benefit and may be harmful. If there is benefit, it is unlikely to be large. Australian Clinical Trials Registry number: ACTRN012606000205538.

Epidemiology and clinical course of Behçet's disease in the Reggio Emilia area of Northern Italy: a seventeen-year population-based study.

OBJECTIVE: To investigate the epidemiology and clinical course of Behçet's disease (BD) over a 17-year period in a defined area of northern Italy. METHODS: All patients with incident BD diagnosed over a 17-year period (from January 1, 1988 to December 31, 2004) living in the Reggio Emilia area were identified through the following sources: physicians at Reggio Emilia Hospital, medical practitioners, and community-based specialists. We identified all patients registered in a centralized index and in the Reggio Emilia district database for rare diseases. Patients were followed up from the time of diagnosis until either their death or April 1, 2005. RESULTS: Eighteen patients (9 men and 9 women) had complete BD. Mean +/- SD age at diagnosis was 33 +/- 7 years. The incidence rate of BD was 0.24 per 100,000. The prevalence of BD on January 1, 2005 was 3.8 per 100,000. No patients died during the followup period. Although all patients developed oral ulceration during the disease course, 22.2% had no oral lesions at disease onset. Eye disease occurred in 55.6%. Ocular disease was more common in men and appeared at disease onset or within the first few years of disease onset (median 3 years). Only 1 patient had loss of useful vision in at least 1 eye at the end of followup. In all affected patients, visual acuity improved once treatment was started. CONCLUSION: This population-based study is the first to report the prevalence and incidence of BD in Italy. In Italian patients, BD is nonfatal and the prognosis of eye disease is good.

Interleukin-10 promoter polymorphisms in giant cell arteritis.

OBJECTIVE: To investigate potential associations between interleukin-10 (IL-10) promoter polymorphisms and susceptibility to, and clinical features of, giant cell arteritis (GCA). METHODS: A total of 140 patients with biopsy-proven GCA who were residents of Reggio Emilia, Italy, and 200 population-based controls from the same geographic area were genotyped for promoter polymorphisms of the IL-10 gene, by molecular methods. The patients were subgrouped according to the presence or absence of polymyalgia rheumatica (PMR) and ischemic complications (any or all of the following: vision loss, jaw claudication, cerebrovascular accidents, or aortic arch syndrome). RESULTS: The distribution of the C/A 592 genotype differed significantly between the GCA patients and the controls (P(corr) = 0.003). Carriers of the A592 allele (A/A or C/A) were significantly more frequent among the GCA patients than among the controls (P(corr) = 0.004, odds ratio [OR] 2.0 [95% confidence interval (95% CI) 1.3-3.1]). Homozygosity for the A592 allele was significantly more frequent among the GCA patients than among the controls (P(corr) = 0.002, OR 3.4 [95% CI 1.6-7.2]). The distribution of the A/G 1082 genotype was similar in GCA patients and controls. In the haplotype analysis, the frequency of the ATA haplotype was significantly higher in GCA patients than in the controls (P = 0.0001), whereas the frequencies of the ACC and GTA haplotypes were significantly lower (P = 0.0001 for both comparisons). No significant associations were found for comparisons of GCA patients with and those without PMR or GCA patients with and those without ischemic complications. CONCLUSION: Our findings show that the -592 C/A promoter polymorphism of the IL-10 gene is associated with susceptibility to GCA.

Relationship between interleukin 6 promoter polymorphism at position -174, IL-6 serum levels, and the risk of relapse/recurrence in polymyalgia rheumatica.

OBJECTIVE: To assess the role of -174 G/C promoter polymorphism of interleukin 6 (IL-6) in the susceptibility to polymyalgia rheumatica (PMR). We also investigated whether this polymorphism modulates the circulating level of IL-6 and the risk of relapse/recurrence in a series of patients with PMR followed up prospectively. METHODS: A prospective study of 112 consecutive, untreated patients with isolated PMR (i.e., without evidence of giant cell arteritis) who were followed up for at least 24 months. This cohort represented all patients diagnosed over a 5-year period in one Italian rheumatological secondary referral center. Patients were monitored for clinical signs/symptoms and acute-phase reactants. All PMR patients and 112 population-based controls from the same geographic area were genotyped for IL-6 polymorphism at position -174 by molecular methods. IL-6 serum levels were measured in 67 PMR patients and 43 population-based controls. RESULTS: The distribution of the G/C 174 genotype was similar in PMR patients and controls. No significant associations with IL-6 promoter polymorphism at position -174 were found when PMR patients with and without relapse/recurrence were compared. Controls homozygous for the C allele had higher serum IL-6 levels than the carriers of the G allele (4.5 +/- 3.7 pg/ml vs 1.8 +/- 2.1 pg/ml, p = 0.01). Patients homozygous for the allele C had significantly higher values of IL-6 during followup than patients carrying GC or GG genotypes. CC homozygosity was significantly more frequent in patients with persistently elevated levels of IL-6 than in those without. The presence of persistently elevated IL-6 levels, but not the CC genotype, was associated with an increased frequency of relapse/recurrence. CONCLUSION: Our findings show that the 174 G/C promoter IL-6 polymorphism is not implicated in susceptibility to PMR. However, CC genotype characterized PMR patients with persistently elevated levels of IL-6 who are at higher risk of developing relapse/recurrence. A genetically modulated pattern of IL-6 production could affect the longterm outcome of patients with PMR.

Interleukin-6 promoter polymorphism at position -174 in giant cell arteritis.

OBJECTIVE: To investigate potential associations between the -174 G/C interleukin-6 (IL-6) promoter polymorphism and susceptibility to and clinical features of giant cell arteritis (GCA), particularly in patients with or without polymyalgia rheumatica (PMR) and with or without ischemic complications. METHODS: One hundred and twenty-six patients with biopsy-proven GCA who were residents in Reggio Emilia, Italy, and 112 population-based controls from the same geographic area were genotyped for IL-6 polymorphism at position -174 by molecular methods. Patients were divided in subgroups according to presence or absence of PMR and ischemic complications (visual loss, jaw claudication, cerebrovascular accidents, aortic arch syndrome). RESULTS: Distribution of the G/C 174 genotype was similar in patients with GCA and controls. No significant associations with the IL-6 promoter polymorphism at position -174 were found when GCA patients with or without PMR or with or without ischemic complications were compared. Further, IL-6 genotypes did not significantly affect levels of C-reactive protein or other inflammatory markers at diagnosis. CONCLUSION: Our findings show that the 174 G/C promoter IL-6 polymorphism does not seem to be implicated in susceptibility to and clinical expression of GCA.

Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis.

OBJECTIVE: To evaluate the frequency of visual manifestations at presentation in an Italian population-based cohort of patients with biopsy-proven giant cell arteritis (GCA), and to investigate predictors for the development of permanent visual loss. METHODS: We identified 136 Reggio Emilia (Italy) residents with biopsy-proven GCA diagnosed between 1986 and 2002. Medical records of these 136 patients were reviewed, and demographic, clinical, and laboratory data were collected.Multivariate analysis with multiple logistic regression models was performed to identify the best predictors of visual loss. RESULTS: Visual manifestations developed in 41 patients (30.1%). Partial or total visual loss was observed in 26 patients (19.1%). Anterior ischemic optic neuropathy was seen in 24 patients, and 2 patients had central retinal artery occlusion. Unilateral vision loss occurred in 19 patients, and bilateral visual loss in 7. In 25 patients, visual loss developed before glucocorticoid therapy for GCA was started. The age at disease onset was significantly higher in patients with permanent visual loss compared with those without it. The frequency of systemic signs/symptoms and erythrocyte sedimentation rate (ESR) and C-reactive protein values at diagnosis were significantly lower in patients with permanent visual loss. By multivariate logistic regression, the only statistically significant predictor for the development of permanent visual loss was the absence of high levels of ESR at diagnosis (tertile 2: Odds ratio [OR] 0.08; tertile 3: OR 0.11). Other predictors included in the model were the absence of systemic manifestations (OR 0.24), an older age at disease diagnosis (quintile 5: OR 5.60), and the presence of an elevated platelet count at diagnosis (OR 4.99), however they were only of borderline statistical significance. CONCLUSION: The proportion of Italian patients with GCA that developed visual loss was similar to that reported from other countries. The patients with low inflammatory response had a higher risk of visual loss.

Acute-phase reactants and the risk of relapse/recurrence in polymyalgia rheumatica: a prospective followup study.

OBJECTIVE: To determine laboratory parameters that may be useful in identifying polymyalgia rheumatica (PMR) patients who require long-term corticosteroid therapy. METHODS: A prospective followup study of 94 consecutive untreated patients with PMR were assessed for relapse/recurrence for a mean of 39 months. This cohort represented all the patients diagnosed over a 4-year period in 2 Italian secondary referral centers. Patients were monitored for clinical signs and symptoms, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum interleukin-6 (IL-6). IL-6 levels were also measured in 43 controls matched to the patients for age and sex. RESULTS: The ESR was elevated in 91.5% of the patients prior to therapy initiation, as were CRP in 98.9% and serum IL-6 in 92.6%. Forty-seven (50.0%) patients had at least 1 relapse/recurrence during the followup period and 24 (25.5%) had at least 2. After 4 weeks of prednisone therapy, ESR was elevated in 13.2% patients, CRP in 41.9%, and serum IL-6 in 37.2%. IL-6 levels remained persistently elevated in 9.9% and CRP in 8.7% of patients during the first year of followup, whereas no patient had persistently elevated ESR. Persistently elevated CRP and IL-6 levels were significantly associated with an increased risk of relapse/recurrence. In particular, patients with persistently elevated levels of IL-6 during the first year of therapy had the highest relative risk. CONCLUSION: Despite the control of clinical symptoms, corticosteroids do not adequately control the inflammatory process in a subset of patients with PMR who have persistently elevated levels of CRP and IL-6 and who have a higher risk of relapsing.

Endothelial nitric oxide synthase gene polymorphisms in giant cell arteritis.

OBJECTIVE: To examine potential associations of the Glu/Asp(298) polymorphism in exon 7 and the 4a/b polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene with susceptibility to and clinical expression of giant cell arteritis (GCA), particularly in patients with versus those without ischemic complications. METHODS: Ninety-one consecutive patients with biopsy-proven GCA, who were residents of Reggio Emilia, Italy, and 133 population-based controls from the same geographic area were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for eNOS polymorphisms in exon 7 and intron 4. The patients were separated into 2 subgroups according to the presence or absence of ischemic complications (visual loss and/or jaw claudication and/or aortic arch syndrome). RESULTS: The distribution of the Glu/Asp(298) genotype differed significantly between GCA patients and controls (corrected P [P(corr)] = 0.003). Carriers of the Asp(298) allele (Asp/Asp or Glu/Asp) were significantly more frequent among the GCA patients than among the controls (P(corr) = 0.0002, odds ratio 3.3, 95% confidence interval 1.7-6.3). The distribution of the 4a/b genotype was similar in GCA patients and controls. No significant associations were found when GCA patients with and without ischemic complications were compared. CONCLUSION: Our findings show that the Glu/Asp(298) polymorphism of the eNOS gene is associated with GCA susceptibility.

Vascular endothelial growth factor gene polymorphisms in giant cell arteritis.

OBJECTIVE: To examine potential associations of vascular endothelial growth factor (VEGF) gene polymorphisms with giant cell arteritis (GCA) and disease expression, in particular in patients with and without ischemic complications. METHODS: We enrolled 92 consecutive patients with biopsy-proven GCA residing in Reggio Emilia, Italy. Two hundred healthy blood donors from the same geographic area were selected as controls. All the GCA patients and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for 936 C/T and 634 C/G mutations and for an 18 bp insertion/deletion (I/D) polymorphism in the VEGF promoter region. In vitro release of VEGF by peripheral blood mononuclear cells (PBMC) was investigated by ELISA in controls homozygous for the polymorphisms studied. RESULTS: The carriage rates of the alleles I and C634 were significantly more frequent in GCA patients than in controls (p = 0.025, OR 1.9, 95% CI 1.1-3.1 and p = 0.015, OR 2.1, 95% CI 1.1-3.6, respectively). The distribution of allele T936 was similar in GCA patients and controls. No significant differences in the distribution of the polymorphisms studied were observed in patients with ischemic manifestations compared to those without ischemic manifestations. Lipopolysaccharide (LPS)-stimulated VEGF production by PBMC from controls was higher in II homozygous compared to DD homozygous patients. CONCLUSION: Our data indicate that carriers of C634 and I alleles are associated with susceptibility to developing GCA.