Can granulomatosis with polyangiitis be diagnosed earlier in primary care? A case-control study.

BACKGROUND: People with granulomatosis with polyangiitis (GPA) commonly described long delays before diagnosis. AIM: To study the natural history of GPA prior to diagnosis using primary care data, and determine whether clinical features could be identified to help earlier diagnosis. DESIGN: Case-control study using the Clinical Practice Research Datalink. METHODS: We compared primary care activity and clinical features between cases and 10 matched controls. RESULTS: We identified 757 cases and matched 7546 controls. Compared to controls, cases had more GP consultations and overall healthcare activity in the 5 years prior to their diagnosis, with a marked increase in the year before diagnosis, and particularly in the last 3 months. However, consultations were mostly for symptoms that were not specifically related to GPA. In the year prior to diagnosis, the most frequent and strongly predictive clinical features of GPA were Ear Nose and Throat (ENT) symptoms [34.5% of cases, odds ratio (OR) 10.5, 95% confidence intervals (CI) 8.6-12.7], and general (constitutional) symptoms (21.5% of cases, OR 9.0, 95% CI 7.1-11.3). In the year before diagnosis a larger number of cases attended secondary care (382, 50.5%) than had records of clinical features of GPA. CONCLUSIONS: After discussing our findings, we conclude that it would be difficult to identify cases of GPA earlier in primary care. Our results support a need for heightened awareness of this condition among secondary care clinicians, especially those assessing emergency admissions, and in the clinics which were most frequently attended by cases 3-12 months prior to diagnosis.

Lupus nephritis: a 15-year multi-centre experience in the UK.

OBJECTIVES: Our aim was to audit the outcome of lupus nephritis (LN) at three East Midlands centres. METHODS: We undertook a retrospective review of all biopsy-proven LN types III-V 1995-2010. RESULTS: In total, 61 patients with LN were identified, with a median follow-up of 68 months. LN was present at the time of systemic lupus erythematosus (SLE) diagnosis in 20 patients. The median time from SLE diagnosis to the first LN episode was 5.3 years. Some 35 patients received IV cyclophosphamide and 17 received mycophenolate mofetil (MMF) as induction therapy; 81.8% of those treated with cyclophosphamide and 81.3% with MMF had at least 'improved' according to the ACR-response criteria 6 months from induction; 33.3% and 37.5%, respectively, had a 'complete' response. MMF and azathioprine were the most frequently used maintenance therapy. We found that 32.8% experienced a flare after a mean post-induction time of 3.5 years, irrespective of the maintenance therapy used, and 43.8% of partial responders flared compared with 4.8% of complete responders. End-stage renal failure developed in 8.2%. CONCLUSIONS: Overall, outcomes (response, flare-rate, end-stage renal failure) were comparable with European clinical studies. Partial responders are more likely to flare compared with complete responders. The results highlight that LN can occur, and flare, after many years of SLE, emphasizing the importance of continued vigilance for LN in all patients.

Modification and validation of the Birmingham Vasculitis Activity Score (version 3).

BACKGROUND: Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee. OBJECTIVE: To modify and validate version 3 of the BVAS in patients with systemic vasculitis. METHODS: The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis. RESULTS: The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman's r(s) = 0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (r(s) = 0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (r(s) = 0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (r(s) = 0.43, 95% CI 0.31 to 0.54), physician's global assessment (r(s) = 0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (r(s) = 0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test). CONCLUSION: BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.

Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril.

OBJECTIVE: To evaluate the efficacy and tolerability of prolonged administration of quinapril, a long-acting angiotensin-converting enzyme inhibitor, in the management of the peripheral vascular manifestations of limited cutaneous systemic sclerosis (lcSSc) and in the prevention of the progression of visceral organ involvement in the disease. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study evaluating quinapril 80 mg/day, or the maximum tolerated dosage, in 210 patients with lcSSc or with Raynaud's phenomenon (RP) and the presence of SSc-specific antinuclear antibodies. Treatment was for 2-3 years. The primary outcome measure was the number of new ischemic ulcers appearing on the hands; secondary measures were the frequency and severity of RP attacks, skin score, treatments for ischemia, health status (measured by the Short Form 36 instrument), measures of kidney and lung function, and echocardiographic estimates of pulmonary artery pressure. An intent-to-treat analysis was used. RESULTS: Quinapril did not affect the occurrence of digital ulcers or the frequency or severity of RP episodes. It did not alter the treatments that were prescribed for either infected ulcers or severe RP symptoms. There was no apparent effect on the estimated tricuspid gradient. Health status was not affected by quinapril, and one-half of the patients who believed they had benefited from the trial treatment were in the placebo arm. Quinapril was not tolerated by one-fifth of the patients, with dry cough being the most frequent side effect. CONCLUSION: Administration of quinapril for up to 3 years had no demonstrable effects on the occurrence of upper limb digital ulcers or on other vascular manifestations of lcSSc in this patient population.

Lessons learnt in the management of Wegener's Granulomatosis: long-term follow-up of 60 patients.

OBJECTIVE: To assess all patients with Wegener's Granulomatosis treated in Nottingham, with particular focus on relapse rate and the useful predictors of relapse. We evaluated how well the findings of nasal examination correlated with disease relapse compared to other parameters such as c-ANCA, ESR and CRP. Presenting features, diagnosis, adverse effects of treatment and mortality rate, were also studied. DESIGN: Retrospective examination of 60 patient notes, diagnosed and treated for Wegener's granulomatosis at Queen's Medical Centre, Nottingham. The mean follow up period was 8.7 years. Relapse was defined as per the European Vasculitis Study criteria. RESULTS: cANCA is a useful test at presentation for diagnosis but a negative result does not rule out the disease. Those presenting with ENT symptoms alone may have less raised inflammatory markers but similar cANCA titres as patients with multi-system disease. However, at relapse, patients with ENT disease alone have similar levels of inflammatory markers as those with multi-system relapse. Nasal examination was useful at monitoring the presence of disease activity where the nasal lining is affected. CONCLUSIONS: Signs of intranasal disease in the form of granular tissue, erythema and bleeding to light touch and crusting over granulation tissue are good predictors of disease activity. A raised cANCA, ESR or CRP provide supporting information about disease activity but if they are negative this does not exclude active disease. cANCA levels were as elevated at relapse in patients who had isolated nasal symptoms and signs as in those with evidence of systemic disease. Low relapse rates were found possibly due to prompt and rigorous initial immunosuppression even in limited disease. This seemed to lead to less progression of patients to multi-system disease and hence a low mortality rate of 5%.

Influence of radiographic phenotype on risk of hip osteoarthritis within families.

OBJECTIVE: To determine whether the magnitude of the genetic influence on the development of hip osteoarthritis (OA) varies according to the radiographic phenotype within families. PARTICIPANTS AND METHODS: 331 families in which at least one sibling (index participant) had undergone total hip replacement for OA and whose preoperative x ray findings were available; 505 siblings of these index participants, who have high exposure to genetic risk of hip OA; and 1718 participants who had previously undergone intravenous urography, representative of the average general population exposure to genetic risk. Prevalence of hip OA was determined by individual radiographic features and minimum hip joint space. OA phenotype was partitioned according to pattern of femoral head migration and osteophyte bone response. Age adjusted odds ratios for hip OA in siblings, stratified according to phenotypic pattern in their index sibling, were assessed by unconditional logistic regression. RESULTS: The superior pattern of femoral head migration was more common in men, and the axial pattern more common in women. A poor bone response (absent osteophytosis) was associated with an indeterminate pattern of migration. The age adjusted odds ratios for definite hip OA were twofold higher in siblings of index participants who had no osteophyte response than in siblings whose index case had any degree of osteophyte (OR 2.05, 95% CI 1.12 to 3.76). The risk of the siblings from these families having undergone hip replacement themselves was threefold higher. Patterns of migration and bone response were not concordant within families, even among same sex siblings. CONCLUSION: Careful phenotypic characterisation is essential for genetic studies of hip OA. The results of these studies are likely to be influenced by the phenotypic pattern of hip disease, particularly osteophyte bone response.

Assessment of Be1 and Be2 cells in systemic lupus erythematosus indicates elevated interleukin-10 producing CD5+ B cells.

Recent studies indicate that normal B cells can be primed to differentiate into two distinct cytokine-secreting effector subsets, Be1 and Be2. The aim of this study was to analyse, for the first time, Be1 and Be2 cells at the single cell level in SLE patients using the recently developed technique of flow cytometry for intracellular cytokines. Peripheral blood mononuclear cells (PBMC) from SLE patients and age- and sex-matched normal controls were cultured for 24 h in the presence or absence of phorbal myristate acetate and ionomycin (PMA/I) or lipopolysaccharide (LPS). The production of type I (IFN-gamma, IL-2) and type 2 (IL-4, IL-5, IL-6, IL-10, IL-13) cytokines by B cells (and IL-10 production by fractionated CD5+ and CD5- B cells) was investigated using an intracellular cytokine staining technique and flow cytometry. In the absence of PMA/I stimulation, the percentage of B cells from SLE patients was significantly lower than those of normal subjects and significantly more SLE B cells spontaneously produced IL-10 than controls. Moreover, CD5+ B cells from SLE patients were enriched for cells with signs of previous in vivo activation and for high levels of IL-10 production. A significant positive correlation was observed between the percentage of IL-10- and IL-6-producing PMA/I-stimulated B cells in SLE patients, but not in controls. There were no significant differences in the production of other cytokines by B cells of SLE patients and normal subjects. In conclusion, a general alteration of type 1 and type 2 cytokine production by B cells is not observed in SLE patients. The role of B cell cytokines in the pathogenesis of SLE appears to be exerted by elevated secretion of in vivo IL-10, which may play an important role in the immune dysregulation observed in SLE patients. Moreover, the cross regulation of IL-10 and IL-6 is disrupted in SLE patients.

Characterisation of size and direction of osteophyte in knee osteoarthritis: a radiographic study.

OBJECTIVES: To examine the size and direction of osteophyte in knee osteoarthritis (OA) and to determine associations between osteophyte size and other radiographic features. METHODS: Knee radiographs (standing extended anteroposterior and 30 degrees flexion skyline views) were examined from 204 patients referred to hospital with symptomatic knee OA (155 women, 49 men; mean age 70, range 34-91 years). A single observer assessed films for osteophyte size and direction at eight sites; narrowing in each compartment; varus/valgus angulation; patellofemoral subluxation; attrition; and chondrocalcinosis using a standard atlas, direct measurement, or visual assessment. For analysis, one OA knee was selected at random from each subject. RESULTS: Osteophyte direction at the eight sites was divisible into five categories. At all sites, except for the lateral tibial plateau and the medial patella, osteophyte direction varied according to (a) the size of osteophyte and (b) the degree of local narrowing. At the medial femur, medial tibia, and lateral femur osteophyte direction changed from being predominantly horizontal to predominantly vertical with increasing size. The size of osteophyte correlated positively with the severity of local narrowing, except for the medial patellofemoral compartment where osteophyte size correlated positively with the severity of narrowing in the medial tibiofemoral compartment. Logistic regression analysis showed that osteophyte size was associated not only with local narrowing but also with local malalignment and bone attrition, and that chondrocalcinosis was positively associated with osteophyte size at multiple sites. CONCLUSION: In patients referred to hospital with knee OA different patterns of osteophyte direction are discernible. Osteophyte size is associated with local compartmental narrowing but also local alignment and attrition. Chondrocalcinosis is associated with osteophytosis throughout the joint. These data suggest that both local biomechanical and constitutional factors influence the size and direction of osteophyte formation in knee OA.

Quantitative and qualitative analysis of the balance between type 1 and type 2 cytokine-producing CD8(-) and CD8(+) T cells in systemic lupus erythematosus.

The production of type 1 (IFN-gamma, IL-2) and type 2 (IL-4, IL-5, IL-10, IL-13) cytokines by CD8(-) and CD8(+) T cells from systemic lupus erythematosus (SLE) patients and normal subjects was investigated using an intracellular cytokine-staining technique. This flow cytometric method facilitates analysis of both surface markers and cytoplasmic cytokines, after a short term (6 h) culture with or without phorbol myristate acetate and ionomycin (PMA/I) stimulation. In SLE patients, more unstimulated T cells produced IL-10 in comparison with controls; other cytokines were not detected in unstimulated cells. The percentage of IL-10-secreting T cells did not significantly increase after PMA/I stimulation of cells from SLE patients. The mean intensity of fluorescence (MIF) of intracellular IL-4 staining was significantly higher in CD8(-) T cells of SLE patients than controls. Significantly fewer CD8(-) and CD8(+) T cells from SLE patients secreted IFN-gamma after PMA/I stimulation compared with controls. The MIF and percentage of IL-2, IL-5, and IL-13-secreting cell subsets were not significantly different between SLE patients and controls. These findings indicate that T cells of SLE patients are already stimulated to produce IL-10 in vivo, which may result in downregulation of IFN-gamma secreting CD8(-) and CD8(+) T cells observed following PMA/I stimulation. Thus, the population size of Th1 and Tc1 cells are reduced in SLE patients whereas the effector function of Th2 cells, with respect to IL-4 production, is enhanced in SLE patients. Furthermore, although the balance between Th1/Th2 and between Tc1/Tc2 is disrupted in SLE patients, it is significantly biased in favour of the Th2 subset only.

Assessment of a genetic contribution to osteoarthritis of the hip: sibling study.

OBJECTIVES: To study the influence of genetics on the development of hip osteoarthritis as determined by structural change on plain radiographs. DESIGN: Sibling study. SETTING: Nottinghamshire, England. PARTICIPANTS: 392 index participants with hip osteoarthritis of sufficient severity to warrant total hip replacement, 604 siblings of the index participants, and 1718 participants who had undergone intravenous urography. MAIN OUTCOME MEASURE: Odds ratios for hip osteoarthritis in siblings. RESULTS: The age adjusted odds ratios in siblings were 4.9 (95% confidence interval, 3.9 to 6.4) for probable hip osteoarthritis and 6.4 (4.5 to 9.1) for definite hip osteoarthritis. These values were not significantly altered by adjusting for other risk factors. CONCLUSION: Siblings have a high risk of hip osteoarthritis as shown by structural changes on plain radiographs. One explanation is that hip osteoarthritis is under strong genetic influence.

Development of a logically devised line drawing atlas for grading of knee osteoarthritis.

OBJECTIVES: To (a) develop an atlas of line drawings for the assessment and grading of narrowing and osteophyte (that is, changes of osteoarthritis) on knee radiographs, and (b) compare the performance of this atlas with that of the standard Osteoarthritis Research Society (OARS) photographic atlas of radiographs. METHODS: Normal joint space widths (grade 0) for the medial and lateral tibiofemoral and medial and lateral patellofemoral compartments were obtained from a previous community study. Grades 1-3 narrowing in each compartment was calculated separately for men and women, grade 3 being bone on bone, grades 1 and 2 being two thirds and one third the value of grade 0. Maximum osteophyte size (grade 3) for each of eight sites was determined from 715 bilateral knee x ray films obtained in a knee osteoarthritis (OA) hospital clinic; grades 1-2 were calculated as two thirds and one third reductions in the area of grade 3. Drawings for narrowing and osteophyte were presented separately. 50 sets of bilateral knee x ray radiographs (standing, extended anteroposterior; flexed skyline) showing a spectrum of OA grades were scored by three observers, twice using the OARS atlas and twice using the drawn atlas. RESULTS: Intraobserver and interobserver reproducibility was similar and generally good with both atlases, though varied according to site. All three observers preferred the line drawing atlas for ease and convenience of use. Higher scores for patellofemoral narrowing and lower scores for osteophyte, especially medial femoral osteophyte, were seen using the line drawing atlas, showing that the two atlases are not equivalent instruments. CONCLUSION: A logically derived line drawing atlas for grading of narrowing and osteophyte at the knee has been produced. The atlas showed comparable reproducibility with the OARS atlas, but was discordant in several aspects of grading. Such a system has several theoretical and practical advantages and should be considered for use in knee OA studies.

Radiographic assessment of symptomatic knee osteoarthritis in the community: definitions and normal joint space.

OBJECTIVE: To evaluate radiographic features of osteoarthritis (OA) to determine which is more closely associated with knee pain and hence might be used as a radiographic definition of OA in the community. To evaluate joint space width in normal subjects. METHODS: 452 subjects from a case-control community study of knee pain (294 women, 158 men, mean age 62 years, range 40-80) underwent AP standing and midflexion skyline radiographs. Joint space width, measured by metered calliper to 0.1 mm, and graded individual features of OA (osteophyte 0-3, narrowing 0-3, sclerosis 0-1, cysts 0-1) were assessed in all three compartments independently by two observers who were blind to clinical status. Subjects were categorised as having knee pain by a positive response to both parts of the question "Have you ever had pain in or around the knee on most days for at least a month? If so, have you experienced any pain during the last year?" RESULTS: Intraobserver reproducibility for joint space width measurements was to within +/- 0.4 mm (95% CI for limits of agreement); kappa values for grading were > 0.7. One hundred and twenty five subjects were without knee pain or osteophyte. In these radiographically normal knees, mean joint space width varied according to sex but did not decrease with age. A definition based on the presence of osteophyte > or = grade 1 in any compartment was more efficient at predicting pain than definitions based on either measurement or grading of joint space; there was no clear threshold of joint space loss at which the likelihood of pain substantially increased. The presence of osteophyte at the patellofemoral joint (PFJ) was more sensitive but less specific than at the tibiofemoral joint (TFJ); the addition of PFJ assessment improved sensitivity from 38.1% to 62.3% with a reduction in specificity from 82.7% to 58.7% for the presence of knee pain. CONCLUSION: Among men and women in the community, osteophyte is the radiographic feature that associates best with knee pain. Radiographic assessment of both TFJ and PFJ should be included in all community studies. Joint space loss is not a feature of asymptomatic aging, and there is not a biological cut off for joint space width below which the likelihood of knee pain markedly increases.