Infliximab as rescue therapy in three cases of paediatric Wegener's granulomatosis

SIR, This is the first report of infliximab (IFX) use in childrenwith severe, refractory Wegener's granulomatosis (WG), a necrotizingvasculitis of the upper respiratory tract and kidneys. The rationalefor tumour necrosis factor (TNF) blockade includes a key roleof TNF in granuloma formation and maintenance of vasculitisin WG [1–6]. In addition, IFX has been shown to be effectivein the management of     

Polymyositis associated with infliximab treatment for rheumatoid arthritis

SIR, Treatment of rheumatoid arthritis (RA) with the chimericanti-tumour necrosis factor (TNF-) monoclonal antibody infliximabhas been proven efficacious and well tolerated [1, 2]. However,there are concerns about the safety of such treatment, withreports about induction of autoimmune phenomena [anti-double-strandedDNA (dsDNA) antibodies] and, rarely, development of systemiclupus erythematosus [3–5]. We describe a patient withRA who developed polymyositis following treatment with infliximab. A 52-yr-old woman presented in January 2001 with     

Activated CD4+ and CD8+ T-cell subsets in Wegener's granulomatosis

Several lines of evidence argue in favour of an involvement of T cells in the pathogenesis of Wegener's granulomatosis (WG). These include the presence of highly specific IgG autoantibodies to proteinase 3, perivascular T-cell infiltrates and elevated amounts of soluble interleukin-2 (IL-2) receptors in patient's serum. In order to further address this question we evaluated by double immunoflourescence and flow cytometry the expression of several cell surface molecules associated with T-cell activation. As compared to healthy controls (n=15), the CD4⁺ subset was significantly diminished, while the percentage of CD8⁺ T cells was elevated in WG patients (n=24). Within the CD4⁺ T-cell subset we found a highly significant increase in activation/memory markers (CD25, CD29, HLA-DR). Within the CD8⁺ T-cell subset the expression of CD11b, CD29 and CD57 was significantly elevated, while the expression of VD28 was reduced. The use of 10 V-, 1 V-and 1 V-specific monoclonal reagents failed to reveal any significant bias in the peripheral T-cell receptor V-gene repertoire of WG patients. There was also no correlation between T-cell activation markers and laboratory parameters [C-reactive protein (CRP), ESR], disease duration or therapy. A significant correlation was found only for the degree of organ involvement and the increase in CD4⁺ T cells coexpressing HLA-DR, as well as the increase in CD57 expression on CD8⁺ T cells. In conclusion, both CD4⁺ and CD8⁺ T-cell subsets were activated in WG. Cytotoxic CD8⁺ CD57⁺ CD11b⁺ CD28^– T cells may directly contribute to damage of vascular endothelium.     

Is TNFalpha really a good therapeutic target in motoneuronal degeneration? A case of amyotrophic lateral sclerosis in a patient with RA receiving infliximab

SIR, Tumour necrosis factor- (TNF-) has been implicated in thepathogenesis of various inflammatory conditions such as rheumatoidarthritis (RA), Crohn's disease and psoriasis. In these diseases,TNF- blockade is a successful and safe treatment option [1].TNF- can be neurotoxic and has also been implicated in the pathogenesisof some central nervous system diseases where inflammation hasrecently emerged as a significant contributor to motor neurondamage [2]. TNF- acts as the main driver for neuroinflammationin amyotrophic lateral sclerosis (ALS). Animal studies [3–5]as well as phase II     

Two Takayasu arteritis patients successfully treated with infliximab: a potential disease-modifying agent?

SIR, Takayasu arteritis (TA) is a chronic, idiopathic, inflammatorydisease that primarily affects large vessels [1]. The managementof this disorder is largely unresolved, since a large numberof patients fail to reach stable remission on conventional treatment[2]. Thus, the need for more efficacious medical therapies isparamount in order to spare steroids and to prevent long-termtoxicity and reduce disease-related morbidity and eventual mortality[3]. Recently, Hofmann et al. [4] have claimed the safety andefficacy of anti-tumour necrosis factor (TNF) therapy in anopen label study in 15 patients with TA. Here we present twomore cases of Takayasu arteritis treated with anti-TNF infliximab,in which clinical remission was observed. Two patients with TA were treated at the Immunology and RheumatologyUnits of the University of Pisa.     

Detection of tuberculosis by extensive screening in a patient with rheumatoid arthritis prior to anti-TNF-alpha therapy

SIR, TNF- blocking agents have seen increasing use in the treatmentof systemic inflammatory diseases such as rheumatoid arthritis(RA). An association of anti-TNF- agents with the occurrenceof mycobacterial infections (MTBI), with a high proportion ofextrapulmonary and disseminated cases, has been noted [1, 2].The article by Horsburgh [3] highlights the public health consequencesof MTBI in     

Acute myelogenous leukaemia following etanercept therapy

SIR, Tumour necrosis factor- (TNF-) blocking agents have becomeincreasingly popular in the treatment of chronic polyarthritis.While approved for patients with severe (juvenile) rheumatoidarthritis (RA) that is resistant to disease-modifying anti-rheumaticdrugs (DMARDs), they are under investigation in seronegativespondylarthritis and vasculitis [1–4]. They increase infectiouscomplications, especially extrapulmonary tuberculosis, but noincreases in the occurrence of malignancies have been describedso far [5–8]. We report the development of acute myelogenous     

The BSR Standards Guidelines and Audit Working Group (SGAWG)

Following the success of the report by the working party ofthe British Society for Rheumatology (BSR) on guidelines forprescribing TNF- blockers in adults with rheumatoid arthritis[1], the BSR decided to set up a committee to develop furtherstandards and guidelines. The NHS, through a variety of bodies,including NICE and the National Service Frameworks, use thevehicle of guidelines and standards to improve the quality ofcare for patients with a number of different diseases, mostnoticeably myocardial infarction [2], stroke [3] and diabetesmellitus [4]. Audit is the tool by which     

Increased morbidity from ischemic heart disease in patients with Wegener's granulomatosis

Objective

Experimental studies indicate that patients with Wegener's granulomatosis (WG) experience accelerated atherosclerosis. The purpose of this study was to investigate whether the occurrence of overt ischemic heart disease (IHD) is increased in WG.

Methods

A total of 293 WG patients were included in the study. Information on all hospitalizations for IHD in Denmark from 1977 to 2006 was obtained from the Danish National Hospital Register. The WG patients were compared with the Danish background population with respect to rates of hospitalization for clinical manifestations of IHD after the date of vasculitis diagnosis by calculating standardized ratios of observed to expected (O:E) events.

Results

Sixty‐three first IHD events were registered in the WG group during the 2,482 patient‐years of followup, corresponding to a significantly increased O:E ratio for IHD of 1.9 (95% confidence interval [95% CI] 1.4–2.4). A significantly increased risk was found for acute myocardial infarction (MI) (O:E ratio 2.5 [95% CI 1.6–3.7]), but not for angina pectoris (O:E ratio 1.3 [95% CI 0.7–2.1]). In analyses stratified according to the time between the diagnosis of vasculitis and the cardiovascular event, increased O:E ratios were found for IHD and acute MI occurring <5.0 years after WG diagnosis (2.1 [95% CI 1.4–3.0] for IHD and 3.6 [95% CI 2.0–5.9] for acute MI) and for IHD occurring ≥10.0 years after WG diagnosis (2.2 [95% CI 1.3–3.4]). Significantly increased O:E ratios for IHD and acute MI were found in patients who were ≥50.0 years of age at the time of diagnosis of WG, in male patients, and in patients who received high cumulative doses of cyclophosphamide.

Conclusion

Compared with the background population, WG patients seem to experience an increased number of both early and late cardiovascular events due to IHD.

     

The effect of pre-operative optimization on post-operative outcome in Crohn’s disease resections

Background

The timing of surgical intervention in Crohn’s disease (CD) may depend on pre-operative optimization (PO) which includes different interventions to decrease the risk for unfavourable post-operative outcome. The objective of this study was to investigate the effect of multi-model PO on the post-operative outcome in CD.

Method

This is a multicentre retrospective cohort study. The primary outcome was 30-day post-operative complications. Secondary outcomes were intra-abdominal septic complications, surgical site infection (SSI), re-operation, length of post-operative stay in a hospital and re-admission. PO included nutritional support, discontinuation of medications, pre-operative antibiotic course and thrombosis prophylaxis.

Results

Two hundred and thirty-seven CD elective bowel resections were included. Mean age was 39.9 years SD 14.25, 144 (60.8 %) were female and 129 (54.4 %) had one or more types of medical treatment pre-operatively. Seventy-seven patients (32.5 %) optimized by at least nutritional support or change in pre-operative medications. PO patients were more likely to have penetrating disease phenotype (p = 0.034), lower albumin (p = 0.015) and haemoglobin (p = 0.021) compared to the non-optimized. Multivariate analyses showed that treatment with anti-TNF alpha agents OR 2.058 CI [1.043–4.4.064] and low haemoglobin OR 0.741 CI [0.572–0.0.961] increased the risk of overall post-operative complications. Co-morbidity increased the risk of SSI OR 2.567 CI [1.182–5.576] while low haemoglobin was a risk factor for re-admission OR 0.613 CI [0.405–0.926]. Low pre-operative albumin correlated with longer stay in hospital.

Conclusions

PO did not change post-operative outcome most likely due to selection bias. Anti-TNF alpha agents, low haemoglobin, low albumin and co-morbidity were associated with unfavourable outcome.

     

Etanercept combined with conventional treatment in Wegener's granulomatosis: A six‐month open‐label trial to evaluate safety

Objective

To evaluate the safety of etanercept (Enbrel) in patients receiving conventional treatment for Wegener's granulomatosis (WG).

Methods

We performed a 6‐month open‐label trial of etanercept (25 mg subcutaneously twice weekly) which was added to standard therapies for WG (glucocorticoids, methotrexate, cyclophosphamide, azathioprine, cyclosporine) and prescribed according to disease severity. Evaluations of clinical response were determined by the Birmingham Vasculitis Activity Score for WG (BVAS/WG) in 20 patients with persistently active disease or with new flares of previously established WG. Fourteen of the 20 patients (70%) had etanercept added as the only new therapeutic variable.

Results

Injection site reactions (ISRs) were the most common adverse event related to etanercept (8 episodes in 5 patients [25%]; <1% of all injections). All ISRs were mild. Two patients had a combined total of 5 hospitalizations (1 patient had 4), but no hospitalizations were attributable solely to etanercept‐related adverse events. One patient with severe subglottic stenosis developed pneumococcal tracheobronchitis and subsequently had a localized Herpes zoster infection. Nineteen patients (95%) were still taking etanercept at 6 months, the single exception being a patient who developed progression of orbital (retro‐bulbar) disease at 4 months. There were no deaths. The mean BVAS/WG at entry was 3.6 (range 1–8), which decreased at 6 months to 0.6 (P < 0.001, 95% confidence interval [95% CI] −4.0 to −2.1). Among the 14 patients in whom etanercept was the only new treatment variable, the mean daily prednisone dose decreased from 12.9 mg at entry to 6.4 mg at 6 months. This comparison did not achieve statistical significance (difference −6.5; P = 0.19, 95% CI −16.6 to +3.6). Sixteen of the patients (80%) achieved BVAS/WG scores of 0 at some point. However, intermittently active disease was observed in 15 patients (75%).

Conclusion

In this open‐label trial, etanercept used in combination with standard treatments was well‐tolerated in patients with WG. Adverse events were few. BVAS/WG scores improved at 6 months, but intermittently active WG (occasionally severe) was common. A randomized, double‐masked trial to assess the efficacy of etanercept in WG has begun.

     

Soluble adhesion molecules in rheumatoid arthritis

SIR, The expression of cell adhesion molecules is up-regulated(or induced) by pro-inflammatory cytokines, and may have a centralrole in the mechanism of immune-mediated inflammation [1]. Inrheumatoid arthritis (RA), pro-inflammatory cytokines such astumour necrosis factor- (TNF-), interleukin-1 (IL-1), IL-6,and IL-8 are produced in excess [2], and they may induce theexpression of cell adhesion molecules on endothelial cells andleucocytes [3]. More recently, soluble isoforms of several typesof cellular adhesion molecules have been described [4], andprevious reports have shown increased     

Lack of Evidence for Small Intestinal Mucosal T-Cell Activation as a Pathogenic Mechanism in African HIV-Associated Enteropathy

The role of mucosal T-cell activation in HIV-associated enteropathy is uncertain. Twenty Zambian patients with AIDS and chronic diarrhea were studied, as were nine controls. Distal duodenal biopsies were taken at endoscopy. Morphometric analysis and dual color immunofluorescence staining were performed. Villous height was reduced [177 (118–228) vs 305 (244–358) m P = 0.002] and crypt depth increased [220 (164–202) vs 194 (164–202) m P = 0.008] in AIDS patients compared to controls. CD3⁺CD4⁺ T cells were reduced in AIDS patients compared to controls [12.9 (5.7–25.2) vs 47.6 (33.4–65.5)% P = 0.04]. There was no significant difference in expression of CD8, CD25, CD69, HML-1, or HLA-DR on T cells between the AIDS patients and controls, with the exception of CD3⁺HML-1⁺ cells, which were increased in AIDS patients (P = 0.05). Small intestinal T-cell activation was similar between AIDS patients and controls. We conclude, therefore, that this mechanism is not likely to be important in the pathogenesis of HIV-associated enteropathy.     

Treatment of active ankylosing spondylitis with pamidronate

SIR, Ankylosing spondylitis (AS) is a frequently appearing chronicinflammatory rheumatic disease and prototype of the spondyloarthritidess(SpA) [1]. Currently, treatment of AS patients consists mainlyof nonsteroidal antirheumatic drugs (NSAIDs) and physical therapy[2]. The burden of disease in AS is comparable to rheumatoidarthritis (RA). The prevalence of osteoporosis is increasedin both patient groups. Bisphosphonates are not only known to inhibit osteoclasts, improveosteoporotic bone density measurements and prevent fractures[3], they also suppress proinflammatory cytokines such as interleukin(IL-1), tumour necrosis factor (TNF)- and IL-6, and show anti-inflammatoryproperties in arthritic conditions [4]. Furthermore, in threesingle-centre Canadian studies Maksymowych et al. [5     

Comment on: Use of the QuantiFERON-TB(R) Gold test as part of a screening programme in patients with RA under consideration for treatment with anti-TNF-{alpha} agents: the Newcastle (UK) experience: reply

SIR, We are grateful to Dr Kaushik and co-authors [1] for theircautionary comments regarding the interpretation of data arisingfrom our audit [2]. We agree wholeheartedly that further andmore in-depth studies are needed in this area to properly establishthe precise role of IFN-based tests in screening for Latenttuberculosis infection (LTBI) amongst RA patients due to startanti-TNF- therapy, with a particular emphasis on cost-effectiveness(which, in our concluding remarks, we clearly stated was a matterof potential, not fact).     

Onset of systemic lupus erythematosus after conversion of infliximab to adalimumab treatment in rheumatoid arthritis with a pre-existing anti-dsDNA antibody level

SIR, Drug-induced systemic lupus erythematosus (SLE) has beendescribed for rheumatoid arthritis (RA) patients treated withthe tumour necrosis factor- (TNF-)-blocking agents, infliximaband etanercept [1, 2]. This complication of clinically manifestSLE seems to be induced considerably less often, if not at all,in patients treated with the fully human anti-TNF- antibody,termed adalimumab [3]. The present case report describes a patientwho develops SLE upon conversion of infliximab to adalimumaband provides data that indicate the involvement of a Th1-driveninflammatory response in this patient. A 56-yr-old Asiatic woman with     

Long-term treatment of rheumatoid arthritis with tumour necrosis factor alpha blockade: outcome of ceasing and restarting biologicals

SIR, Infliximab, a chimeric monoclonal antibody, has demonstratedeffective suppression of disease and prevention of the progressionof structural damage in rheumatoid arthritis (RA) in its phaseIII randomized study (ATTRACT study) [1, 2]. Two anti-tumour-necrosisfactor (TNF-) drugs, infliximab and etanercept, have recentlybeen approved by the National Institute of Clinical Excellence[3]. With a large number of patients at a single centre for the ATTRACTstudy [1], the follow-up     

Successful treatment of refractory polyarticular juvenile idiopathic arthritis with rituximab

SIR, Juvenile idiopathic arthritis (JIA), being the most commonchronic musculoskeletal disease of childhood, has a prevalenceestimated to be 1 in 1000 children [1]. Up to 10% of these remainseverely disabled in adulthood [2]. Numerous disease-modifyinganti-rheumatic drugs (DMARDs) have been trialled with varyingsuccess in JIA, and therefore additional therapeutic targetshave been investigated. Pro-inflammatory cytokines have beenimplicated in the pathogenesis of JIA especially tumour necrosisfactor- (TNF-), interleukin-1 (IL-1) and IL-6. Biological     

Are environmental factors important in primary systemic vasculitis?: A case–control study

Objective

To investigate the association between primary systemic vasculitis (PSV) and environmental risk factors.

Methods

Seventy‐five PSV cases and 273 controls (220 nonvasculitis, 19 secondary vasculitis, and 34 asthma controls) were interviewed using a structured questionnaire. Factors investigated were social class, occupational and residential history, smoking, pets, allergies, vaccinations, medications, hepatitis, tuberculosis, and farm exposure in the year before symptom onset (index year). The Standard Occupational Classification 2000 and job‐exposure matrices were used to assess occupational silica, solvent, and metal exposure. Stepwise multiple logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) adjusted for potential confounders. Total PSV, subgroups (47 Wegener's granulomatosis [WG], 12 microscopic polyangiitis, 16 Churg‐Strauss syndrome [CSS]), and antineutrophil cytoplasmic antibody (ANCA)–positive cases were compared with control groups.

Results

Farming in the index year was significantly associated with PSV (OR 2.3 [95% CI 1.2–4.6]), with WG (2.7 [1.2–5.8]), with MPA (6.3 [1.9–21.6]), and with perinuclear ANCA (pANCA) (4.3 [1.5–12.7]). Farming during working lifetime was associated with PSV (2.2 [1.2–3.8]) and with WG (2.7 [1.3–5.7]). Significant associations were found for high occupational silica exposure in the index year (with PSV 3.0 [1.0–8.4], with CSS 5.6 [1.3–23.5], and with ANCA 4.9 [1.3–18.6]), high occupational solvent exposure in the index year (with PSV 3.4 [0.9–12.5], with WG 4.8 [1.2–19.8], and with classic ANCA [cANCA] 3.9 [1.6–9.5]), high occupational solvent exposure during working lifetime (with PSV 2.7 [1.1–6.6], with WG 3.4 [1.3–8.9], and with cANCA 3.3 [1.0–10.8]), drug allergy (with PSV 3.6 [1.8–7.0], with WG 4.0 [1.8–8.7], and with cANCA 4.7 [1.9–11.7]), and allergy overall (with PSV 2.2 [1.2–3.9], with WG 2.7 [1.4–5.7]). No other significant associations were found.

Conclusion

A significant association between farming and PSV has been identified for the first time. Results also support previously reported associations with silica, solvents, and allergy.

     

Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study

Aim of the study

To determine the occurrence of intestinal and extraintestinal cancers in the 1993–2009 prospective European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort.

Patients–methods

A physician per patient form was completed for 681 inflammatory bowel disease patients (445UC/236CD) from 9 centers (7 countries) derived from the original EC-IBD cohort. For the 15-year follow up period, rates of detection of intestinal and extraintestinal cancers were computed.

Results

Patient follow-up time was fifteen years. In total 62/681 patients (9.1%) [41 with ulcerative colitis/21 with Crohn's disease, 36 males/26 females] were diagnosed with sixty-six cancers (four patients with double cancers). Colorectal cancer was diagnosed in 9/681 patients [1.3%] (1 Crohn's disease and 8 ulcerative colitis). The remaining 53 cancers were extraintestinal. There was a higher prevalence of intestinal cancer in the Northern centers compared to Southern centers [p = NS]. Southern centers had more cases of extraintestinal cancer compared to Northern centers [p = NS]. The frequency of all observed types of cancers in Northern and in Southern centers did not differ compared to the expected one in the background population.

Conclusions

In the fifteen-year follow up of the EC-IBD Study Group cohort the prevalence of cancer was 9.1% with most patients having a single neoplasm and an extraintestinal neoplasm. In Northern centers there were more intestinal cancers while in Southern centers there were more extraintestinal cancers compared to Northern centers. In this IBD cohort the frequency of observed cancers was not different from that expected in the background population.