Methods. Minor salivary gland biopsies from a cohort of 141 patients fulfilling the American–European consensus classification criteria for pSS were re-examined and grouped according to focus score (FS) and germinal centre (GC) status; serum samples were analysed for autoantibodies, chemokines and cytokines.
Results. Of the 115 available biopsies, 18 (16%) lacked characteristic focal mononuclear cell infiltrates [FS < 1 (FS–)] but patients were positive for Ro/SSA and/or La/SSB. IL-17, IL-1RA, IL-15, macrophage inflammatory protein (MIP)-1, MIP-1β, eotaxin, IFN- and IL-4 levels were significantly increased in the 27 (23%) patients with ectopic GC formation (GC+) in the salivary glands compared with the GC– patients (n = 70). In addition, minor differences in cytokine levels were found when comparing age groups.
Conclusion. Degenerative changes observed in the minor salivary glands of patients with pSS may represent ‘burned out’ inflammation. The elevated levels of IL-4 found in these patients may influence the reduced salivary flow observed in GC+ patients. Increased titres of Th17-associated cytokines, IL-17, IL-1β and the IL-23 subunit IL-12p40, may indicate a higher activity of these cells in GC+ patients. Differences in cytokine levels may be utilized when sub-grouping the SS patients into disease phases and may consequently have implications for treatment.
]]>Methods. HR-QOL, employment and disability were assessed in SS patients regularly attending the University Medical Center Groningen (n = 235). HR-QOL, employment and disability were evaluated with the Short Form-36 questionnaire (SF-36) and an employment and disability questionnaire. Results were compared with Dutch population data (matched for sex and age). Demographical and clinical data associated with HR-QOL, employment and disability were assessed.
Results. Response rate was 83%. SS patients scored lower on HR-QOL than the general Dutch population. sSS patients scored lower on physical functioning, bodily pain and general health than pSS patients. Predictors for reduced HR-QOL were fatigue, tendomyalgia, articular involvement, use of artificial saliva, use of anti-depressants, comorbidity, male sex and eligibility for disability compensation (DC). Employment was lower and DC rates were higher in SS patients compared with the Dutch population.
Conclusion. SS has a large impact on HR-QOL, employment and disability.
]]>Methods. We examined prospectively 38 patients (50 elbows) with UNE. Patients were classified into mild, moderate and severe groups according to electrodiagnostic studies. Cross-sectional areas (CSAs) of the ulnar nerve were measured 4 cm proximal to the medial epicondyle (CSA-prox), 4 cm distal to the epicondyle (CSA-dist) and at the maximum CSA (CSA-max) of the ulnar nerve found between these points. We used a control group of 50 normal elbows.
Results. The CSA-max in the patient group was highly correlated with the severity score obtained by electrodiagnostic studies: mild: 11.1 ± 3.4 mm2, moderate: 15.8 ± 3.8 mm2, severe: 18.3 ± 5.1 mm2 (P < 0.001). Patients with UNE had larger ulnar nerve CSAs than controls at all three levels (P = 0.012 for CSA-prox, P < 0.001 for CSA-max, P = 0.003 for CSA-dist). A cut-off point of >=10 mm2 for CSA-max yields both sensitivity and specificity of 88%.
Conclusions. Ultrasonography can have a role not only in the diagnosis, but also in the severity stratification of patients with UNE.
]]>Methods. We prospectively studied 106 early RA patients receiving conventional DMARDs according to a disease activity score (DAS)-steered therapeutic protocol over a 24-month period. Standard evaluation included clinical, laboratory, functional and systematic (44 joints) US assessment. US indexes of grey scale (GS) and power Doppler (PD) synovitis were correlated with clinical evaluation, laboratory indexes and clinical outcome. Clinical remission was defined when DAS was <1.6 at two consecutive visits 3 months apart.
Results. US examination was significantly more sensitive than clinical examination, both in active disease and in remission. In patients with an active disease, both clinical and US indexes correlated with CRP, whereas in remission only PD still remained significantly correlated. In clinical remission, 95% of the patients showed residual GS synovitis, and 41% of them showed a positive PD signal. Positive PD signal, even in a single joint, resulted the main predictor of relapse within 6 months, both in univariable and multivariable logistic regression analysis.
Conclusions. In a cohort of early RA patients treated with conventional DMARDs, US-GS can detect residual disease activity more sensitively than clinical examination both in active disease and in remission. Moreover, PD-positive synovial hypertrophy identifies an ongoing inflammation even during remission and predicts short-term relapse.
]]>Methods. A total of 152 SLE patients and 427 healthy individuals in a female Japanese population were enrolled in the study. Case–control studies were performed for the polymorphisms of these three genes.
Results. The carriers of TNF-RII 196R were at a significantly increased risk for SLE with odds ratio (OR) of 1.59 (95% CI = 1.01, 2.52). CYP1A1 3801C homozygotes had a significantly increased risk of SLE (OR = 2.47, 95% CI = 1.28, 4.78). On the other hand, GSTM1 null genotype was not associated with SLE risk. As for combination action of two loci, CYP1A1 3801C/GSTM1 null combination was more strongly associated with an increased risk of SLE (OR = 4.35; 95% CI = 1.76, 10.73). Moreover, TNF-RII 196M/CYP1A1 3801C/GSTM1 null genotype combination was most significantly associated with SLE (OR = 5.83; 95% CI = 2, 17.04).
Conclusions. The individuals carrying two or more ‘at-risk’ genotypes of TNF-RII, CYP1A1 and GSTM1 had a significantly more increased risk for SLE compared with those having each ‘at-risk’ genotype. Combination of the risk genotypes will be important to more clearly identify the population at risk for SLE.
]]>Methods. In 1978, 152 consecutive patients (78% women, mean disease duration: 14.2 years) were enrolled. X-rays of the hands at inclusion were available in 108 patients. Reasons for not evaluating DXR in 24 patients were placement of joint prostheses or severe malalignment. BMD was evaluated by DXR on the same digitized hand X-rays used for scoring radiographic joint damage. Measures of disease activity and damage were used to predict mortality by Cox regression models.
Results. From February 1978 through March 2008, 62 of the 82 patients died, corresponding to a standardized mortality ratio of 2.92 (95% CI 2.19, 3.65) for both sexes combined. In age- and sex-adjusted proportional hazards models, BMD [hazard ratio (HR) = 0.58/1
Conclusion. Low DXR-BMD predicted overall mortality in age- and sex-adjusted analyses, which further supports it as a valid measurement of disease activity or damage and as having prognostic value.
]]>Methods. We conducted a cross-sectional investigation of three groups of patients: (i) 63 patients with SLE; (ii) 43 patients with other diseases; and (iii) 26 healthy controls. Erythrocytes were analysed by flow cytometry to determine the levels of E-C4d.
Results. We found a significant elevation in the mean levels of E-C4d in SLE patients compared with patients with other diseases or healthy controls. In SLE patients, the levels of E-C4d were correlated with the SLEDAI and inversely correlated with serum C3/C4 levels. In the subgroup of SLE patients with haemolytic anaemia (HA), a significantly higher level of E-C4d was observed than that in SLE patients without HA. However, in SLE patients with HA, there was no correlation between the levels of E-C4d and other markers of disease activity, including SLEDAI and levels of anti-dsDNA, C3 and C4.
Conclusion. E-C4d levels are useful diagnostic markers for SLE and can serve as biomarkers of disease activity in patients with SLE. However, E-C4d is of limited value in monitoring disease activity in SLE patients with HA.
]]>Methods. A cohort of 40 patients with SSc was included. Age- and sex-matched healthy subjects and subjects presenting a primary RP were included as controls. Platelets were isolated, activated with thrombin and the secretion of VEGF, platelet derived growth factor, homodimeric form BB (PDGF-BB), TGF-β1 and angiopoietins-1 and -2 measured. Plasma concentrations of these mediators and the functionality of platelet-derived VEGF were also studied. Platelet activation was assayed by measuring plasma β-thromboglobulin and expression of P-selectin on platelets. The effect of iloprost on VEGF secretion by platelets was studied.
Results. Platelets from SSc patients, in contrast to controls, secreted large amounts of VEGF when activated, but not PDGF-BB, TGF-β1 or angiopoietins. Increased expression of membrane P-selectin confirmed platelet activation in the patients. Iloprost inhibited VEGF secretion by platelets both in vivo and in vitro, through inhibition of platelet activation.
Conclusions. Platelets transport high levels of VEGF in SSc. They may contribute to circulating VEGF because of ongoing activation in the course of the disease. If activated at the contact of injured endothelium, platelets may be important in the altered angiogenesis associated with the disease through the secretion of high levels of VEGF.
]]>Methods. We identified all patients in the UKGPRD with a first diagnosis of TAK during 2000–05, using the Read code (G757); and in the NORVASC population. The annual incidence was calculated as the number of incident cases divided by total person-years.
Results. A total of 14 (13 females) subjects were identified with a first diagnosis of TAK during 2000–05 in the UKGPRD. The median age was 51.0 years (interquartile range 28–66). The overall annual incidence of TAK was 0.8/million (95% CI 0.4, 1.3). The incidence was stable throughout the study period. The mean prevalence of TAK was 4.7/million. There were six patients (five females) aged <40 years presenting in 2000–05 with TAK. The annual incidence in those aged <40 years was 0.3/million. In the NORVASC population, one case was identified (0.4/million/year) with three prevalent cases (7.1/million).
Conclusion. This is the first population-based study of the epidemiology of TAK. The annual incidence and prevalence are consistent with previous studies.
]]>Methods. Kidney biopsy specimens from 65 patients with SLE, including 36 with positive aPLs, were studied by IHC using antibodies against platelet glycoproteins CD41 and CD61. Clinical data at the time of kidney biopsy and during a mean follow-up of 7.5 years after biopsy were recorded and analysed with regard to histological or IHC data.
Results. Histological lesions previously defined as APS nephropathy were found in 33% of the SLE kidney biopsies and were not associated with positive aPLs. Microthrombi detected as intravascular CD61+ platelet deposits were present in 43% of the tissues and were significantly associated with positive aPLs, but not with histological APS nephropathy, nephritis manifestations nor with renal outcome. Histological APS lesions but not CD61+ microthrombi correlated with an older age at nephritis presentation, previous cardiovascular risk factors and worse renal outcome.
Conclusions. Immunodetection of intravascular CD61+ platelet aggregates is more sensitive than histological evaluation to detect acute microthrombosis and provides a better correlation with aPLs in SLE patients. In contrast, histological lesions consistent with APS nephropathy were not associated with aPLs but with cardiovascular risk factors and worse renal outcome.
]]>Methods. Skin punch biopsies were taken from the forearms of 61 SSc patients with lcSSc; 32 with calcinosis (lcSScCal) and 29 without lcSSc, 36 with the dcSSc subtype and 22 healthy control subjects. Immunohistochemical localization of AGE-CML [N-(carboxymethyl) lysine] and RAGE was assessed semi-quantitatively on the microvascular endothelium, dermal fibroblasts and the cutaneous extracellular matrix (ECM). The Kruskal–Wallis one-way ANOVA was used to compare data between groups.
Results. AGE-CML expression on the papillary dermis ECM of lcSScCal was greater than in the control group (P = 0.016). The reticular dermis of lcSScCal showed increased AGE-N-(carboxymethyl) lysine (CML) expression compared with controls (P = 0.002), dcSSc (P = 0.024) and lcSSc (P = 0.025). Increased immunostaining for RAGE was seen on the reticular dermis ECM of the lcSScCal group compared with controls (P = 0.007). The lcSScCal subgroup showed statistically significant correlations for AGE-CML, and to a lesser extent for RAGE, with increased RP duration. There was no consistent evidence that the expression of AGE-CML or RAGE related to autoantibody status, clinical or histological skin score or patient age.
Conclusions. Our results indicate the possible contribution of AGE-CML deposition on the ECM in the dermis of the lcSScCal subgroup to the pathogenesis of formation of calcinotic deposits.
]]>Methods. An international Delphi study through e-mail was performed among different health professions. Answers to open questions on areas relevant for functioning in the first round were linked to ICF categories and analysed in the two following two rounds for the degree of consensus.
Results. Of the 267 experts invited, 126 agreed to participate and 74 participated in all rounds; 28 were rheumatologists, 6 rheumatology nurses, 24 physiotherapists, 2 occupational therapists, 4 psychologists, 8 rehabilitation physicians and 2 social workers. More than 80% agreement was reached on 141 ICF categories, of which 30 (21%) were part of Body functions; 27 (19%) of Body structures; 56 (40%) of Activities and Participation; and 28 (20%) of Environmental factors. In addition, two Personal factors—illness knowledge and coping—were agreed upon.
Conclusion. 141 ICF categories and two personal factors represent the reference of functioning in AS from the perspective of health professional. The largest number of categories concerned restrictions in activities. Also, the impact of AS on participation in life situations and the role of environmental factors were underscored. This broadens the view on functioning in AS and has implications for future research into functioning.
]]>Methods. Adults aged >=50 years registered with three general practices were mailed a two-stage cross-sectional survey. A total of 1342 respondents who reported foot pain in the previous 12 months and completed the FPDI and 58 participants in a test–retest repeatability study were included.
Results. Confirmatory factor analysis verified the three-construct FPDI structure (pain intensity, functional limitation and appearance). Internal consistency for the three constructs was good (Cronbach's 0.74, 0.92 and 0.77, respectively). A total of 1320 (98.4%) of those persons with foot pain reported disability (at least one of the 17 FPDI items experienced on at least some days—Definition A). After restricting this definition to problems experienced on most/every day(s) (Definition B), 996 (74.2%) of those with foot pain reported disability (percentage difference 24.2%; 95% CI 21.9, 26.5%). For each of the three constructs, the prevalence of disability among persons with foot pain was significantly higher under Definition A than under Definition B. Test–retest repeatability for the individual constructs ranged from fair to substantial. Physical function, measured by the SF-36 physical function sub-scale, was poorer in those who reported problems within the function construct compared with those with problems in pain and/or appearance constructs only.
Conclusion. A practical definition of disabling foot pain [at least one of the 10 FPDI function items experienced on most/every day(s)] is proposed, which appears valid, repeatable and suitable for use in older adults.
]]>Methods. A prospective surveillance of children with TRAPS was conducted in Germany during a time period of 3 years (2003–06). Monthly inquiries were sent to 370 children's hospitals by the German Pediatric Surveillance Unit (Clinic-ESPED, n1) and to 23 laboratories (Laboratory-ESPED, n2). Inclusion criteria were TNFRSF1A mutation-positive patients <=16 years of age, more than three self-limiting episodes of fever >38.5°C, and increased inflammation markers. Clinical, epidemiological and genetic data were evaluated via questionnaires.
Results. Of the 23 cases included, 19 were identical in 20 clinical and 22 laboratory reports. The incidence of TRAPS in German children was estimated to be ~5.6 per 107 person-years. In 20 TRAPS patients of the Clinic-ESPED, median age of onset and duration of fever periods were 6 (range 1–16) years and 6.3 (range 2–24) days, respectively. Main symptoms were arthralgia, abdominal pain, lymphadenopathy, headache and skin involvement. The R92Q substitution was found in 19 (83%) of 23 cases.
Conclusion. The incidence of TRAPS is low and corresponds to 6–10 newly diagnosed patients <=16 years per year in Germany.
]]>Methods. This was a retrospective descriptive case series of children with PSV treated with biologic therapy between February 2002 and November 2007. Primary retrospective outcome assessment measures were: daily corticosteroid dose; Birmingham Vasculitis Activity Score (BVAS); and adverse events (including infection rate).
Results. Twenty-five patients median age 8.8 (range 2.4–16) years; 11 male with active PSV (n = 6 with anti-neutrophil cytoplasmic antibody associated vasculitides, n = 11 with polyarteritis nodosa, n = 7 with unclassified vasculitis and n = 1 with Behçet's disease) were treated with biologic agents including infliximab (n = 7), rituximab (n = 6), etanercept (n = 4), adalimumab (n = 1) or multiple biologics sequentially (n = 7). Overall, there was a significant reduction in BVAS from a median of 8.5 (range 5–32) at start of therapy to 4 (range 0–19) at median 32 months follow-up (P = 0.003) accompanied by significant reduction in median daily prednisolone requirement from 1 (range 0.2–2) to 0.25 (range 0–1) mg/kg/day, P = 0.000. For those receiving multiple biologic agents sequentially, a similar clinical improvement was observed with corticosteroid sparing. Infections occurred in 24%, the most severe in those receiving infliximab.
Conclusion. Our data provide retrospective evidence of efficacy of these agents, and highlight the associated infectious complications. Further multicentre standardization of treatment protocols and data collection to inform clinical trials of biologic therapy in systemic vasculitis of the young is required.
]]>Methods. We performed a retrospective cohort study of children with polyarticular JIA diagnosed and treated at Seattle Children's Hospital between 1 January 2000 and 31 December 2006. Each patient's disease status (active disease vs ID) was determined for every clinic visit. Adjusted relative risk estimates were obtained using Mantel–Haenszel methods.
Results. One hundred and four children were included. Patients were followed up for an average of 30 months. Patients achieved 138 episodes of ID. Fifty-one patients achieved 69 episodes of clinical remission on medication. When duration of active disease was summed over each patient's follow-up, patients spent a mean of 66.3% of their follow-up with active disease. Patients with evidence of joint damage on imaging studies obtained within 6 months of their first clinic visit spent a mean of 79% of their follow-up with active disease. Patients without these findings spent a mean of 58.5% of their follow-up with active disease (P < 0.001). Children who were RF+ and children with early evidence of joint damage tended to have a higher prevalence of active disease during the follow-up period.
Conclusions. In this cohort, children with polyarticular JIA spent the majority of their follow-up with active disease. Because children with early radiographic evidence of joint damage and children who were RF+ tended to have the most active disease, improving outcomes for these subgroups may be an important goal for prospective study.
]]>Methods. A total of 1000 patients with a confirmed diagnosis of AS under the clinical care of 10 specialist rheumatology centres across the UK were invited to participate in a study evaluating a new quality of life measure. Patients completed a questionnaire, which also included questions relating to the impact of AS on their sexual relationships, sociodemographic and clinical characteristics.
Results. Six hundred and twelve (64%) patients took part in the study. The majority were male (71.6%), mean age 50.8 ± 12.2 years, mean diagnosed disease duration 17.3 ± 11.7 years and mean symptom duration 23 ± 18.6 years. Of those who responded to the question on sexual relationships (n = 552), 210 (38.0%) reported that their sexual relationships were affected ‘moderately’, ‘quite a bit’ or ‘extremely’ by their AS. Males reported greater sexual problems with increasing age. Poor function [odds ratio (OR) 3.64; 95% CI 1.92, 6.87], depression (OR 2.03; 95% CI 1.21, 3.41), greater disease activity (OR 2.10; 95% CI 1.01, 4.40), unemployment (OR 1.99; 95% CI 1.16, 3.40) and poor self-efficacy (OR 1.25; 95% CI 1.09, 1.43) were independently associated with a greater impact on patients’ sexual relationships.
Conclusion. AS has a substantial impact on patients’ sexual relationships. Management of AS and its impact on sexual relationships should be directed not only towards physical outcomes such as disease activity and physical function, but also take into consideration the psychological state of the patient.
]]>Methods. Data on clinical and laboratory parameters, lung imaging by high-resolution CT thorax and pulmonary function tests were collected from patient examinations done up to 6 months before rituximab was initiated, and at 3 and 6 months post-treatment.
Results. All the 11 ASS patients had severe and progressive ILD and most of them had previously failed on cyclophosphamide and/or other immuno-modulating agents. Rituximab appeared to stabilize and/or improve the ILD in 7 of 11 ASS patients during the first 6 months after treatment. The rituximab treatment appeared to decrease the serum level of anti-Jo-1 antibodies, but the decrease was most often modest. One patient developed a fatal infection 3 months after the last infusion with rituximab. In the other ASS patients, the treatment was well tolerated.
Conclusions. This retrospective case series indicates a short-term beneficial effect of rituximab in ASS. Prospective, controlled studies are needed to validate this finding and further assess safety issues.
]]>Methods. The 2005–08 retrospective monocentric study: all patients positive for aSSA60 and/or aSSA52 antibodies were investigated.
Results. Among 297 patients, 82 were aSSA52 positive and aSSA60 negative. There were 21 males and 61 females. Forty-eight (58.5%) patients met our criteria for an AD. Two groups were distinguished according to the association (Group 1) or not (Group 2) of the aSSA52 with other autoantibodies. In Group 1, 33 out of 34 patients suffered from an AD. The two most common being SLE and SSc. The prevalence of AD was lower in Group 2 (15 out of 48, 31.3%, P = 0.001). aSSA52 levels were similar in patients with or without AD.
Conclusions. The existence of aSSA52 in association with other antibodies did not predict the presence of AD. There was no evidence to suggest that aSSA52 antibodies were associated with a specific clinical form of SLE or SSc. In the absence of other autoantibodies, aSSA52 was less associated with the presence of an AD. A positive aSSA52 test is of low diagnostic value for AD. Nevertheless, a longitudinal prospective follow-up study would determine whether or not persistence of these autoantibodies was of use in diagnosing AD.
]]>Methods. The digital CHAQ was tested with patients who visited the outpatient paediatric rheumatology clinic of the Erasmus MC Sophia Children's Hospital. These patients completed in a randomized order the paper form and digital CHAQ while being observed. Validity was tested by comparing outcomes with the paper form CHAQ. User-friendliness was evaluated through a short questionnaire.
Results. A digital CHAQ was developed and revised several times according to our observations. Outcome is automatically calculated and can be printed. Fifty-one patients completed both the digital and paper form CHAQ. Correlation coefficient between both outcomes of the CHAQ Disability Index was 0.974. No statistically significantly differences in median outcome were found in visual analogue scale (VAS) pain (25.6 vs 25.9 mm) and VAS well-being (20.1 vs 19.5 mm). Although the mean time (5.06 min) to complete the digital CHAQ was significantly longer than the mean time (3.75 min) to complete the paper form, the majority of patients (75%) preferred the digital version. User-friendliness received maximum positive score.
Conclusion. We developed a reliable and user-friendly digital CHAQ, which can be easily and systematically completed during routine clinic visits. Such digitalization of questionnaires can be applied in any field to make systematic monitoring of disease activity in daily practice possible.
]]>Methods. The number of circulating EPCs was determined by a colony-forming assay in a cohort of 41 patients with AAV. The patients were stratified into three subgroups according to the initial EPC count (low, medium and high) and prospectively followed. The primary goal was to determine the association between baseline EPC level and the time to the first relapse of the disease.
Results. A total of 19 (46%) patients relapsed during the study period. The cumulative relapse-free survival increased stepwise across three increasing baseline levels of EPCs (P = 0.013). EPC levels were not predictive of progression of renal disease, number of organs involved or death from any cause.
Conclusion. Low numbers of EPCs are associated with increased propensity for early relapse of AAV.
]]>Methods. The anti-P autoantibodies were evaluated in the serum of 200 Tunisian SLE patients at disease onset and 130 various control subjects by a sensitive immunodot assay. A complete laboratory evaluation and clinical examination were performed in each SLE patient. During the follow-up, the patients were regularly monitored for clinical parameters. Global SLE activity was measured by the ECLAM.
Results. The sensitivity and specificity of anti-P testing for SLE were 23.5 and 98.4%, respectively. The anti-P-positive samples 14/47 (29.8%), 27/47 (57.4%) and 5/47 (10.6%) were negative for anti-dsDNA, anti-Sm or both antibodies, respectively. The anti-P-positive patients showed more active disease activity and a much higher prevalence of arthritis. An association between IgG aCLs and anti-P antibodies was also found. However, anti-P antibodies were not associated with neuropsychiatric manifestations or lupus nephritis.
Conclusion. This study does not seem to confirm the described association of anti-P antibodies with neuropsychiatric manifestations of SLE. However, it supports the anti-P antibody association with arthritis and disease activity as well as the presence of aCL. Based on our study and other related studies, we propose that, akin to anti-Sm and anti-dsDNA, anti-P antibodies detected by one agreed method may be considered for inclusion as a criterion for the classification of SLE.
]]>Methods. Publications in the English literature were searched with the keywords ‘mycophenoate’, ‘mycophenolic’, ‘lupus nephritis’, ‘nephritis’ and ‘glomerulonephritis’ for RCTs in electronic databases. Primary outcome was relative risk (RR) of renal remission at 6 months. Secondary outcome included RRs of mortality, development of end-stage renal failure (ESRF) and side effects. Meta-regression was performed to identify factors explaining the heterogeneity of the effect sizes.
Results. Ten eligible RCTs involving 847 patients were included. MMF offers similar efficacy in inducing renal remission as CYC (RR 1.052; 95% CI 0.950, 1.166) and the risks of death (RR 0.709; 95% CI 0.373, 1.347) and ESRF (RR 0.453; 95% CI 0.183, 1.121) were comparable. Significantly fewer patients receiving MMF developed amenorrhoea (RR 0.212; 95% CI 0.094, 0.479) and leucopenia (RR 0.473; 95% CI 0.269, 0.832) while the risks of herpes infection and pneumonia tended to be lower and that of diarrhoea appeared higher in the MMF groups. Meta-regression revealed that the non-white and non-Asian ethnicities contributed significantly to the heterogeneity of the effect sizes of renal remission.
Conclusion. MMF offers similar efficacy in renal remission and survival as CYC. MMF appears safer than CYC in the treatment of proliferative lupus nephritis.
]]>Methods. Twenty-three RA patients were treated with two 1000-mg infusions of the B-cell depleting antibody, RTX, in an observational protocol. Clinical response was assessed by the European League Against Rheumatism (EULAR) response criteria. High-resolution grey-scale and colour-coded power Doppler (PD) ultrasonography was performed at baseline and 6 months after RTX. The second to fifth MCP and PIP joints were bilaterally examined with joints in a neutral 0 position from a palmar view and scored from 0 to 3.
Results. Median disease activity score (DAS28) improved from 5.03 to 3.56 (P = 0.001), which corresponded to a EULAR moderate response in 11 of 23 patients and a EULAR good response in another 6 patients. Improved control of disease activity by RTX was also indicated by tapering of median daily corticosteroid doses from 10 to 5 mg, without flare ups. Mean grey-scale scores correlated with the swollen joint count at baseline (r = 0.484, P = 0.022) and month 6 (r = 0.519, P = 0.011). Mean grey-scale scores improved upon RTX from a 0.90 median (range 0.13–1.87) to 0.75 (range 0.19–1.50, P = 0.023). Frequency of PD positive joints was low (6.1%) at baseline and did not significantly change following RTX treatment.
Conclusions. High-resolution grey-scale ultrasonography (US) examination confirmed reduced synovial hyperplasia, but the applied PD method displayed no significant changes. Therefore, only grey-scale US is recommended in follow-up examinations after RTX treatment.
]]>Methods. Articular cartilages were obtained from knee OA patients and were cultured in monolayers and explants. Induction of a phase II enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), in chondrocytes was assayed after incubation with various concentrations of SPN. Chondrocytes were stimulated with IL-1 or TNF- with or without pre-incubation with SPN. The expression and activation of MMP-1, -3 and -13 was evaluated by an ELISA, gel zymography and RT–PCR. MAP kinases [p38, extracellular signal-regulated protein kinase (ERK) and C-Jun N terminal kinase (JNK)] and NF-B activation were evaluated by western blotting and by an electrophoretic mobility shift assay, respectively.
Results. SPN significantly induced NQO1 activity in chondrocytes and the induction was maximal at 24 h. SPN inhibited the production of MMP-1, -3 and -13 protein and mRNA induced by either IL-1 or TNF- in a dose-dependent manner. This inhibition of MMP by SPN was accompanied by the inhibition of NF-B and JNK activation.
Conclusions. SPN was found to inhibit MMP production in pro-inflammatory cytokine-stimulated chondrocytes. Delineation of the biochemical mechanism regulating cartilage catabolism by SPN may identify safe and effective therapeutic targets for the inhibition of cartilage degradation.
]]>Methods. Human synovium was transplanted into SCID mice. Two to three weeks post-transplantation tissue vasculature was stimulated with TNF- by intra-graft injection 5 h prior to intravenous injection of 111In-labelled anti-E-selectin or isotype control antibody. At 1, 4, 24 and 48 h animals were imaged and transplant activity quantified.
Results. Activity was detectable in the grafts at all time points, with clear delineation of the transplants in the reconstructed images. A significant difference in graft radioactivity was observed at 4 and 24 h with a significantly higher uptake (P < 0.05) of 111In-anti-E-selectin compared with isotype control antibody.
Conclusions. This article highlights NanoSPECT/CT imaging in the SCID mouse chimeric model as a powerful tool for the pre-clinical development of radiopharmaceutical and delivery agents targeting human synovial tissue in vivo.
]]>Methods. Sera from 55 SSc patients were investigated. Joint involvement was determined by clinical, radiological and ultrasonographical evaluation. Anti-hnRNP proteins A1 and A2 (anti-hnRNP-A1/A2) antibodies were determined by immunoblotting. Anti-CCP, ACA, anti-topo I (ATA), Sm, U1-RNP, ribosomal RNP, Ro/SSA, La/SSB autoantibody and RF were determined.
Results. Six patients were positive for anti-hnRNP-A2 autoantibody and two were anti-A1 positive. Eight patients had joint erosions: seven of the eight patients positive for anti-hnRNP-A2 or A1 presented articular involvement (P < 0.04) and five of the eight erosive patients were positive for either of the two autoantibodies (P < 0.02). Of the four patients positive for anti-CCP, none had anti-hnRNP but three had erosive aspects. ATAs were found in 10 patients, six of which were also positive for anti-hnRNP (P < 0.05). RF was positive in 16 patients and in seven among those with articular involvement (P < 0.04). RF was significantly associated with anti-hnRNP in patients with erosive arthritis (P < 0.02), but not with the presence of anti-hnRNP alone. Epitope mapping of the three strongest anti-hnRNP-A2-positive sera recognized the same major epitope as patients with RA. SSc patients have higher incidence of erosions and anti-hnRNP-A2/A1 positivity. RF test and anti-hnRNP had a statistically significant diagnostic value for articular involvement.
Conclusions. These parameters might suggest that autoantibody to both hnRNP antigens might become a non-specific but useful marker for joint involvement in SSc patients and identify SSc patients prone to develop joint damage.
]]>Methods. Twenty patients 4 to 17 years old received 0.8 mg of etanercept per kilogram of body weight subcutaneously once weekly for 3 months in an open multicentre trial. Active polyarticular disease was defined by the presence of five or more active joints with swelling, alternatively with pain or tenderness combined with limitation of motion. Safety assessments were based on adverse events (AEs) reports. Efficacy was assessed using the PedACR30/50/70 criteria.
Results. At the start of treatment the patients showed high disease activity. A rapid reduction of all disease activity parameters was observed. A PedACR30/50/70 response was reached by 75%/35%/10% of patients after 4 weeks, 90%/75%/35% after 8 weeks and 95%/75%/75% after 12 weeks of treatment. There were 37 AEs, none of them serious, with injection site reactions and minor infections being the most frequent. There was no drop out. Long-term follow-up of the patients will be carried out in the German JIA Registry.
Conclusion. Treatment with etanercept once weekly using a double dosage leads to a significant improvement of disease activity in patients with active polyarticular course juvenile idiopathic arthritis and is well tolerated.
]]>Methods. We studied 100 (46 males, 54 females; mean age: 40 ± 6 years) patients with FMF. Also 94 (15 males, 79 females; mean age: 41 ± 7 years) patients with SLE and 103 (44 males, 59 females; mean age: 40 ± 5 years) apparently healthy volunteers were included as the control groups. Subclinical atherosclerosis was assessed by investigating atherosclerotic plaques and measuring IMT from carotid and common femoral arteries using B-mode ultrasonography (USG). Traditional atherosclerotic risk factors were also assessed.
Results. Both FMF and SLE patients had significantly higher carotid (C-IMT) and femoral artery IMT (F-IMT) compared with healthy controls. This was also true after adjustment for atherosclerotic risk factors. Only patients with SLE were found to have higher frequency of atherosclerotic plaques in the carotid and in the carotid and/or femoral artery. When all atherosclerotic risk factors were adjusted, again only patients with SLE were found to have risk for atherosclerotic plaques. In FMF, whereas the presence of atherosclerotic plaques was only associated significantly with diabetes mellitus; C-IMT was correlated with age, BMI and fasting glucose; and F-IMT with age and BMI.
Conclusions. Increased atherosclerosis defined as the presence of plaques was not observed in patients with FMF. The significance of increased C- and F-IMT among patients with FMF must be further assessed.
]]>Methods. The study was carried out in the Nijmegen inception cohort of early RA. All patients meeting indications for anti-TNF- therapy according to the Dutch reimbursement criteria were included in the analysis. Time from indication to start of anti-TNF- therapy or censoring was calculated in all patients. Multivariable Cox regression analysis was used to investigate the influence of age at indication on the time to commencement of anti-TNF- treatment. Hazard ratios were calculated for groups in age quartiles. The model was corrected for 28-joint disease activity score (DAS28), disease duration, gender, the Charlson comorbidity index and episodes of serious illnesses between indication and anti-TNF- therapy or censoring.
Results. From the 487 eligible patients, 215 patients started anti-TNF- treatment during their follow-up (44%). Age significantly influenced the time to receiving anti-TNF- after first indication, adjusting for confounders (HR = 0.975/year, P < 0.001). The same analysis using age quartiles showed that the younger age groups had a higher chance of receiving anti-TNF- treatment within an equal period of time than older patients [HR 2.67 (95% CI 1.64, 4.35); 2.30 (1.43, 3.71); 1.79 (1.14, 2.81) with increasing age; the eldest group as reference]. The eldest patients had significantly higher DAS28 values prior to anti-TNF- treatment than younger patients.
Conclusion. Elderly RA patients were less likely to receive anti-TNF- treatment within an equal period of time compared with younger patients, taking disease activity, disease duration and comorbidities into account.
]]>Methods. Cytokine measurements were performed using multiplex immunoassays. Using heuristic clustering methods, we set out to compare the pattern of 30 cytokines in plasma and SF of JIA, RA, OA, or diabetes type II patients and healthy controls.
Results. Analysis shows that oligo- and polyarticular JIA have similar biomarker profiles, both in plasma and SF. Systemic onset JIA (SoJIA) has a profile distinct from other JIA subtypes, suggesting that they involve different inflammatory processes. SoJIA samples do, however, cluster together with RA in SF, suggesting that these two conditions have similar cytokine profiles. Furthermore, we identify several clusters of ILs and chemokines that are co-expressed, suggesting that they are co-regulated.
Conclusions. We show that previously undetected clusters of cytokines and patients can be identified by applying cluster analysis to multiplex data. Cytokine clusters identified in plasma and SF samples were quite different, which underscore the differential cytokine signalling in these two compartments, and suggest that plasma samples may not be suitable for estimating joint biomarker profiles and inflammation.
]]>Methods. A randomized open-label pilot study in which 9 patients received rituximab alone and 10 patients received two doses rituximab + intravenous cyclophosphamide. The clinical, laboratory and renal histological changes were assessed after 48 weeks of treatment.
Results. At week 48, four patients had a complete response, 11 patients achieved partial response, 2 patients remained the same or stable and 2 worsened. There were no statistical differences in the proportion of patients with complete or partial response between the two groups. None of the variables was an independent predictor of response at week 48. Nine patients had significant improvement in activity indices in renal biopsies, but there were no significant differences between the two groups. Overall, 18 out of 19 patients were found to have effective B-cell depletion. The median duration of complete B-cell depletion in all patients was 22 weeks. There were no statistically significant differences in the proportion of patients with complete depletion at weeks 4, 8, 24 and 48 between the two groups except at week 2.
Conclusions. Rituximab monotherapy appears to be effective as induction therapy in lupus nephritis. The addition of cyclophosphamide offers no additional improvement in clinical, laboratory and renal histological assessment or the duration of B-cell depletion at 48 weeks. Large-scale studies with longer duration are needed to confirm these findings.
]]>Methods. Ninety-nine patients (31 men, 68 women; median age 46 years) with unspecified arthritis or suspected RA and negative X-ray findings were included. MR images of the hand and wrist of these patients were retrospectively evaluated for the presence of synovitis, erosions and tenosynovitis. The clinical diagnosis (early RA or non-RA) was made by a rheumatologist after clinical follow-up for 6–41 months. Clinical and laboratory data were collected from all patients.
Results. Fifty-eight patients had a clinical diagnosis of RA and 41 were diagnosed as non-RA. Step-wise logistic regression of all MR parameters evaluated identified tenosynovitis of the flexor tendons to be the most powerful predictor of early RA (sensitivity = 60%, specificity = 73%). Including ACR criteria in the analysis, positive serum RF and tenosynovitis were the strongest predictors of early RA (sensitivity = 83%, specificity = 63%). When serum anti-cyclic citrullinated peptides (CCP), ANA and CRP were included as additional parameters, anti-CCP and flexor tenosynovitis were the strongest predictors of early RA (sensitivity = 79%, specificity = 73%).
Conclusions. Flexor tenosynovitis diagnosed by MRI of the hand is a strong predictor of early RA. Combining flexor tenosynovitis on MRI with positive serum anti-CCP or positive RF is an even stronger predictor of early RA.
]]>Methods. Fourteen patients with SSc were evaluated. Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks [each cycle consisted of four weekly RTX infusions (375 mg/m2)] in addition to standard treatment, whereas six patients (control group) received standard treatment alone. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high-resolution CT (HRCT). Skin involvement was assessed both clinically and histologically.
Results. There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline (mean ±
Conclusion. Our results indicate that RTX may improve lung function in patients with SSc. To confirm our encouraging results we propose that larger scale, multicentre studies with longer evaluation periods are needed.
]]>Methods. Between September 2007 and June 2008, 10 rheumatologists attended a course in basic MSUS that was delivered by 7 rheumatologists with experience in MSUS. The course consisted of five separate modules that included tutorials on MSUS, self-directed learning of scanning techniques and personal mentoring. Progress was monitored throughout the course by the use of personal logbooks. Competency was formally assessed using the Royal College of Physicians’ Direct Operational Procedural Skills (DOPS) assessment and an exit examination.
Results. Five trainees completed the entire course and passed both the practical and written elements of the exit examination. All were deemed to have attained a basic level of competency in MSUS. The main obstacle to completion of the course was a lack of scanning practice and an inability to complete the required number of scans and DOPS assessments. Participants were more likely to fulfil the requirements of the course if they were employed full time in the regional rheumatology unit where the course was based. All participants reported high levels of confidence in their basic scanning skills at the conclusion of the course. They also felt that the training enhanced their clinical examination skills and their understanding of musculoskeletal anatomy.
Conclusions. A basic MSUS training course can be successfully delivered using a modular design that takes account of the trainee's level of experience and their work schedule. Important elements of such a course should include personal mentoring and the recording of scanning activity using a logbook. Periodic assessment of the trainee's performance is a useful means to motivate learning. Basic training in MSUS should become an accepted part of the routine training of rheumatologists in the UK.
]]>Methods. A call for observations of sarcoid-like granulomatosis following TNF blocker treatment was sent to the members of the French ‘Club Rhumatismes et Inflammation’. Histological evidence of granulomatosis was required.
Results. Observations of 10 patients [seven females; median age 50.5 (range 27–72) years] with sarcoid-like granulomatosis while on anti-TNF treatment were collected: five were treated with etanercept and five with monoclonal antibodies; four patients received TNF blockers for RA and six for SpA. The median delay between anti-TNF agent introduction and granulomatosis diagnosis was 18 (range 1–51) months. Clinical symptoms were mainly pulmonary and cutaneous. Angiotensin-converting enzyme activity was increased in six cases. Lymph-node and/or lung involvement were observed by CT scan of the chest for eight patients. The median delay between drug discontinuation and remission was 6 (range 1–11) months for clinical signs and 6 (range 2–12) months for biological and radiographic findings. Improvement was observed in all patients after drug discontinuation with or without steroids.
Conclusions. Sarcoid-like granulomatosis is rare but not exceptional in patients treated with TNF blockers (~1/2800) and does not seem to be related to gender, rheumatic disease or in our series the type of anti-TNF drug used (monoclonal antibodies or soluble receptor). Discontinuation of anti-TNF usually leads to recovery.
]]>Methods. We analysed data from a cohort of 5054 RA patients who were prescribed LEF since its launch in September 2003 in Japan. Multivariable logistic analysis was performed to identify the risk factors for newly developed and/or exacerbation of ILD.
Results. Sixty-one (1.2%) of 5054 RA patients who received LEF were reported to have development and/or exacerbation of ILD as an adverse drug reaction to LEF, judged by the attending physicians. Multivariable logistic regression analysis identified pre-existing ILD [odds ratio (OR) 8.17; 95% CI 4.63, 14.4], cigarette smoking (3.12; 95% CI 1.73, 5.60), a low body weight (<40 kg vs >50 kg) (2.91; 95% CI 1.15, 7.37) and the use of a loading dose (3.97; 95% CI 1.22, 12.9) as independent risk factors for LEF-induced ILD.
Conclusions. Pre-existing ILD was the most important risk factor for LEF-induced ILD. We suggest that LEF should not be prescribed for RA patients complicated with ILD.
]]>Methods. Thirty-two reported cases of LEIP (13 males and 19 females) were identified from a literature search and classified using Searles and McKendry's classification criteria. Their clinical characteristics were reviewed.
Results. All patients had a history of either exposure to MTX or interstitial lung disease (ILD) or both and all patients had RA. Most patients (82%) had LEIP within the first 20 weeks of initiation of LEF. All patients who had a loading dose LEF and most patients with ILD developed LEIP early (within 12 weeks of exposure). Case mortality was 19%. Two patients had previous MTX-induced pneumonitis (MTX-P) prior to initiation of LEF; both died from LEIP. There was a high mortality in the following groups of patients: diffuse alveolar damage (DAD) on histological examination, pre-existing ILD and ground glass shadowing on high resolution computerised tomography (HRCT). Treatment with cholestyramine did not appear to alter clinical outcome.
Conclusions. LEIP usually occurs within the first 20 weeks of initiation of LEF. Clinical features of patients who died were pre-existing ILD, ground glass shadowing on HRCT and DAD on histological examination, and these could be poor prognostic indicators. Patients need to be made aware of this rare complication. LEF should not be used in patients with previous MTX-P and should be used with caution in patients with ILD.
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