Updating the British Society for Rheumatology guidelines for anti-tumour necrosis factor therapy in adult rheumatoid arthritis (again).
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Antirheumatic Agents↗
Biomedical subjects
R A Luqmani
Publications and source records attributed to R A Luqmani.
The role of biologic therapies in the management of systemic vasculitis.
The recent development of biologic therapies capable of selectively targeting components of the immune system has revolutionised the treatment of inflammatory arthritides. The steady increase in use of biologic agents coupled with the expansion in the knowledge of the pathogenesis of vascular inflammation has led to their application in the treatment of primary systemic vasculitis. These agents may have a role in addition to or in place of conventional immunosuppression and also be effective when the latter fails to induce remission. The use of biologics as targeted therapies has also, in reverse, improved our understanding of the pathophysiology of vascular inflammation. While the advent of biologics heralds a new era in the management of the systemic vasculitis, evidence for their efficacy is still in its infancy and has yet to match that of conventional immunosuppressants. In this review, we examine the up-to-date evidence for the use of biologics in systemic vasculitis, including TNF-alpha inhibitors, and highlight the challenges facing their use. We examine the rationale for using biologics based on the pathophysiology of vasculitis. Issues of toxicity and pharmacovigilance with the use of biologics are also discussed. Finally, future directions and predictions are presented.
Antibodies, Antineutrophil Cytoplasmic↗
Should rituximab be used to treat antineutrophil cytoplasmic antibody associated vasculitis?
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Antibodies, Antineutrophil Cytoplasmic↗
A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS).
OBJECTIVE: To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG). METHODS: Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS: We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION: The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.
Granulomatosis with Polyangiitis↗
Introduction to, and classification of, the systemic vasculitides.
This overview serves as an introduction to the systemic vasculitides, which are a group of heterogeneous disorders sharing a common pathophysiological mechanism leading to blood vessel inflammation and tissue necrosis. Our lack of understanding of the aetiology for most forms of vasculitis has resulted in the development of a classification system, which is primarily based on vessel size. Such a system assists in the grouping together of similar conditions for the purposes of multi-centre studies. Difficulties arise in classification of the vasculitides due to considerable overlap of clinico-pathological features; for example, microscopic polyangiitis (MPA), Wegener's granulomatosis (WG) and Churg-Strauss syndrome (CSS) may all cause the identical renal lesion of necrotizing glomerulonephritis. The rationale for treatment often depends on the type of vasculitis and on the extent of organ involvement. Treatment may be similar for different types of disease. The lack of validated diagnostic criteria has, however, resulted in the application of classification criteria in their place, and has highlighted the limited usefulness of classification criteria in clinical practice. Classification systems should assist in the determination of therapy and prediction of outcomes, but have many limitations, which are discussed further in this review.
Humans↗
The diagnostic value of anti-neutrophil cytoplasmic antibody testing in a routine clinical setting.
Anti-neutrophil cytoplasmic antibody (ANCA) tests are a routine clinical assay in most UK hospitals. We examined the role of routine ANCA testing in achieving a diagnosis of systemic vasculitis in a routine clinical setting. From April 1996 to March 2000, 2734 samples from five hospital departments were tested for ANCA by indirect immunofluorescence (IIF) at a single laboratory. After April 1999, enzyme-linked immunosorbent assays (ELISAs) were performed on all IIF-positive samples. Clinical diagnosis was determined for all patients with a positive IIF ANCA, and a sample of the ANCA-negative patients. Some 2-18% of patients with suspected ANCA-associated systemic vasculitis (AASV) had positive IIF ANCA. The AASV diagnosis was confirmed in 0-56% of these cases. Analysis by department suggested that 88-100% of patients with a positive IIF ANCA did not have AASV, except in the Rheumatology department. The positive predictive value (PPV) of IIF ANCA for AASV was 59% and the negative predictive value (NPV) was 84%. Of the patients with proven AASV, 41% did not have ANCA on IIF. Combined ANCA testing by IIF/ELISA had a higher sensitivity and PPV but lower specificity than IIF alone for AASV. For the combined IIF/ELISA test, only the Rheumatology department had a sensitivity or PPV >0% for AASV. The PPV of ANCA by IIF/ELISA for AASV was 79% and the NPV was 63%. The ANCA test is being widely applied with very poor return. Guidelines for more effective usage are proposed.
Antibodies, Antineutrophil Cytoplasmic↗
Is it possible to offer evidence-based treatment for systemic vasculitis?
The evidence base for treatment of systemic vasculitis is reviewed in this article. Accurate diagnosis and evaluation of disease status is crucial to the appropriate management of these cases and disease status should be employed as a means of staging so that appropriate therapy can be offered tailored to the individual requirements of each case. Large vessel vasculitides are almost exclusively managed with corticosteroids. Small vessel vasculitis with internal organ involvement usually requires more aggressive immuno-suppression; by contrast, small vessel vasculitis without internal organ involvement rarely requires intervention. Despite our current efforts, the long-term morbidity of patients with systemic vasculitis remains high. We need better therapeutic strategies in order to limit or control disease rapidly and thereby prevent the accumulation of subsequent damage. Large-scale randomised trials comparing different therapeutic strategies offer the only hope of establishing a firmer evidence base for the optimal management of these diseases.
Diagnosis, Differential↗
Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI).
Assessment of disease severity in systemic vasculitis encompasses mortality, which is now uncommon, and morbidity, which is increasing in significance. Morbidity includes permanent scars or damage, an evolving concept offering a novel perspective which may be particularly valuable in chronic disease. We have developed a method for assessing damage in systemic vasculitis, but the relationship between damage and disease severity was unknown. Therefore, we examined whether the number of items of damage or the pattern of damage varied with the severity of systemic vasculitis. We established the characteristics of severe disease by examining fatal vasculitis as an example of the most severe disease possible. We then showed that more damage occurred in fatal vasculitis, more systems were damaged, and critical damage akin to organ failure was more common in fatal than non-fatal vasculitis. These observations were reproduced in specific diagnostic groups, namely classical Wegener's granulomatosis and systemic rheumatoid vasculitis. Thus, severe disease was characterized by many items of damage, multisystem damage and critical damage. This pattern of damage was also seen in a subgroup of patients with non-fatal vasculitis, who also have severe disease.
Adult↗
Optimisation of cyclophosphamide therapy in systemic vasculitis.
There is no doubt that the prognosis for systemic vasculitides has been considerably improved by the use of immunosuppressive agents, chiefly cyclophosphamide. Increasingly, we are becoming aware of the enormous burden of chronic 'grumbling' disease, the high incidence of relapse and the longer term effects of toxic therapy in these patients. The general approach is more intense therapy (with intermittent high dose 'pulses' or lower dose continuous cyclophosphamide) in the initial phase of therapy to induce remission, followed by a less toxic therapy in the maintenance phase (either longer intervals between pulses or a switch to a less toxic drug, such as azathioprine). The pathogenetic mechanisms in vasculitis, which are becoming more precisely defined, are diverse, but cyclophosphamide remains the drug of choice. A number of different cyclophosphamide regimens are in use, which reflects the current dilemma of trying to balance effectiveness with toxicity in diseases where the quality of long term survival remains unsatisfactory. Evidence from controlled trials does not support major differences in immediate outcome between different regimens of cyclophosphamide. Future studies need to address the use of agents designed to interfere precisely with the underlying pathogenetic mechanisms. Alternative approaches should also be considered, for example the use of sublethal doses of cyclophosphamide, with autologous bone marrow rescue, which may achieve long lasting remission or even cure.
Controlled Clinical Trials as Topic↗
Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides.
OBJECTIVE: To develop and validate the Vasculitis Damage Index (VDI) for the standardized clinical assessment of damage in the systemic vasculitides. METHODS: Using a nominal group consensus approach, the Birmingham Vasculitis Group generated guiding principles for assessment of damage in all systemic vasculitides. Damage was defined as irreversible change resulting from scars. Consensus principles were developed into the VDI, including guidelines for use, a list of items of damage, and a glossary. RESULTS: For 100 surviving patients with systemic vasculitis, the median VDI score at last observation was 3 (range 0-8). Within the Wegener's granulomatosis subgroup, the median VDI score for 12 non-survivors was higher than for 47 survivors (non-survivors median score 7, interquartile range 5-8 versus survivors median score 4, interquartile range 2-5; P = 0.003). VDI scores for 100 patients with systemic vasculitis increased from initial presentation to last observation by a median score of 3 (range 1-4; P < 0.001). The VDI assesses more items and is more sensitive to change than other indices of damage (P < 0.001). Using the VDI, trained observers can produce moderately consistent damage scores. CONCLUSION: The VDI is a sensitive, reproducible, comprehensive, and credible clinical tool for quantifying damage. The data presented herein should enable further validation and testing of the VDI in specific vasculitic syndromes, and should facilitate the comparison of different therapies.
Humans↗
Disease assessment and management of the vasculitides.
The improvement in survival with chemotherapy has resulted in a change of the natural history of the systemic vasculitic syndromes. The vasculitides are now viewed as chronic disease rather than fatal conditions. Their course is frequently characterized by relapse as well as the scars of irreversible organ damage from disease and drug toxicity. Assessment tools are available which can serve as outcome measures in clinical trials as well as a guide to better management of individual patients. Improvements in therapy in future are dependent on a better understanding of the pathogenesis of these conditions and the ability to assess disease accurately.
Animals↗
Damage occurs early in systemic vasculitis and is an index of outcome.
Because death after acute systemic vasculitis is now uncommon, alternative measures of outcome are required. A significant component of patient morbidity is disease-related damage, which can be quantified by the Vasculitis Damage Index (64 items in 11 organ-based systems). We investigated serially the time-course of damage in 120 patients with systemic vasculitis, to determine the earliest indicators of outcome. High damage scores at 2 years after presentation were characteristic of fatal disease (OR 8.1-12.4). Significant damage occurred within 6 months of presentation, and was a feature of fatal disease. More damage occurred after presentation than after relapse. Lung and multi-system damage were early indicators of poor outcome in severe non-fatal disease. Damage occurs early in systemic vasculitis, and is an indicator of poor outcome. This novel observation, together with evidence of persistent subclinical disease activity and the high frequency of relapse, suggests a need for new treatment strategies. Analogy with the management of acute leukaemia suggests a strategy of early diagnosis and intensive induction of remission, with early escalation of treatment for resistant disease.
Acute Disease↗
Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis.
Although cyclophosphamide and prednisolone are effective in treating systemic vasculitis, the optimum treatment regimes and duration of treatment are unknown. We randomized 54 patients aged 15-70 years (median 57.5 years) with systemic vasculitis (classical polyarteritis n = 8, microscopic polyarteritis n = 17, Wegener's granulomatosis n = 29) to treatment with either pulse cyclophosphamide and prednisolone (PCYP) (n = 24) or continuous oral and prednisolone and cyclophosphamide, with the latter followed after a median of 3 months (range 1.5-10 months) by azathioprine (CCAZP) (n = 30). Patients on CCAZP were more likely to develop leucopenia (13/30) than patients on PCYP, (7/24) although the difference was not significant. The numbers of infective episodes during follow up were comparable in the two groups at 1.7/patient for PCYP and 1.66/patient for CCAZP. Overall, 26/30 patients (87%) treated with CCAZP developed treatment-related toxicity, as did 17/24 patients (71%) treated with PCYP. After a median follow-up of 40.4 months (range 0.7-64.8), there was no difference in the frequency of deaths (PCYP 5, CCAZP 4), relapses (PCCYP 7, CCAZP 8), treatment failures (PCYP 4, CCAZP 4), improvement in disease activity scores or renal function. Survival at three years was 77% in patients treated with PCYP, and 90% in patients on CCAZP (p = 0.38). There was a tendency towards increased toxicity in patients treated with the continuous regimen.
Adolescent↗
Rheumatoid constrictive pericarditis.
A 73-yr-old woman with a 4 yr history of rheumatoid arthritis presented with the clinical features of congestive cardiac failure. She had a good early response to standard therapy although she subsequently developed recurrent biventricular failure. The preservation of good ventricular function on echocardiography in the face of clinical evidence of myocardial insufficiency raised the possibility of constrictive pericarditis, which was confirmed on cardiac catheterization. Constrictive pericarditis should be considered in patients with rheumatoid arthritis who develop unexplained cardiac failure. Early diagnosis requires a high index of suspicion and cardiac catheterization may be necessary to confirm the diagnosis. Medical treatment is largely ineffective and pericardiectomy should be considered.
Aged↗
Correlation of blood levels of soluble vascular cell adhesion molecule-1 with disease activity in systemic lupus erythematosus and vasculitis.
Levels of soluble adhesion molecules have been shown to reflect their cell surface expression in vitro, and thus may provide a useful surrogate marker of surface expression at inflammatory sites. In patients with SLE and vasculitis, serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-Selection were determined by ELISA during different stages of disease activity. Levels of soluble(s) VCAM-1 correlated with disease activity in patients with SLE, being significantly higher during active compared with inactive disease (P = 0.003), and normalizing with clinical remission. By contrast, in patients with vasculitis, although sVCAM-1 levels were elevated in active disease, they fell but did not normalize in inactive disease, suggesting that treatment may be suppressing the clinical manifestations rather than targeting the underlying pathogenic mechanism. Soluble ICAM-1 and E-Selectin levels did not relfect disease activity in either SLE or vasculitis.
Adolescent↗
Posterior scleritis--an unusual manifestation of Cogan's syndrome.
Cogan's syndrome is characterized by a non-luetic interstitial keratitis associated with vertigo, tinnitus and profound deafness. Evidence of a systemic vasculitis is found in up to 50% of patients. Atypical forms of Cogan's syndrome have been described in which the ocular inflammatory disease may be more severe. We describe a case of atypical Cogan's syndrome in association with bilateral posterior scleritis. Serial B-scan ultrasound measurements of posterior scleral thickness were found to be useful in assessing disease activity, in combination with clinical findings. Combination therapy with prednisolone and cyclosporin controlled the ocular disease but the deafness was irreversible. The length of follow-up of this case highlights the frequent relapses and difficult management problems which may be faced. This multisystem disease requires the close co-operation of ophthalmologist, physician and otorhinolaryngologist. Aggressive therapeutic intervention with high-dose combined immunosuppressive agents may be necessary to control severe ocular inflammatory disease.
Adult↗
Treatment of vasculitis in rheumatoid arthritis.
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Arthritis, Rheumatoid↗
Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis.
The continuing morbidity of patients with vasculitis, despite the improved prognosis with aggressive therapy, underlines the need for accurate disease assessment. We have devised a clinical index of disease activity, and evaluated its use in several forms of necrotizing vasculitis. The weighted score is based on symptoms and signs in nine separate organ systems. Disease features are only scored if they are attributable to active vasculitis. The Birmingham Vasculitis Activity Score (BVAS) was compared with two other published vasculitis activity scores, with the physician's global assessment (PGA), with outcome, and with serological markers of disease activity. In a cross-sectional study of 213 consecutive patients with different forms of vasculitis, all 107 vasculitis patients who were judged completely well on clinical assessment had a BVAS score of 0. Twenty-two patients with active vasculitis prior to treatment had a median score of 7.5 (range 4-30) and 69 with active disease on treatment had a median score of 10 (1-29). Of the 12 who died, median score immediately prior to death was 20.5 (9-30). In a serial prospective study, 30 cases had documented episodes of active disease. During periods of disease activity, the median BVAS values were significantly higher than in remission (15 [range 3-32] vs. 0 [0-2], p < 0.001); the same was true for CRP values (80 [9-361] vs. 13.5 [5-68], p < 0.001). This was not true for erythrocyte sedimentation rate (ESR), haemoglobin (Hb) or von Willebrand factor (VWF).(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗