Travel-associated Legionnaires disease in residents from England and Wales travelling to Corfu, Greece, August to October 2011.

Fourteen cases of Legionnaires' disease were confirmed in residents from England and Wales with history of travel to Corfu, Greece, in the 14 days before symptom onset. These cases were reported to the Health Protection Agency national surveillance scheme for Legionnaires' disease in residents of England and Wales between August and October 2011. In addition, one case in a Greek national and a case of non-pneumonic legionellosis in a resident from Scotland were also reported. Few cases shared the same accommodation site in Corfu during their incubation period. Epidemiological investigations and microbiological analysis of clinical and environmental samples excluded a single source but rather implicated several accommodation sites as sources of sporadic infection. Control measures have since been implemented at these accommodation sites and no further cases have been reported. This incident highlights the value of epidemiological typing and the importance of effective international response to control and prevent legionella infection.

Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade.

OBJECTIVE: To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab. METHODS: Patients (n = 1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission (< or =3.3), low (>3.3 to < or =11), moderate (>11 to < or =26), high (>26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score. RESULTS: At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy. CONCLUSION: With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.

Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate.

OBJECTIVE: To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti-interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA). METHODS: The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo. RESULTS: A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX. CONCLUSION: These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

Ultrasonographic and radiographic results from a two-year controlled trial of immediate or one-year-delayed addition of infliximab to ongoing methotrexate therapy in patients with erosive early rheumatoid arthritis.

OBJECTIVE: To compare the impact of immediate and delayed introduction of anti-tumor necrosis factor therapy on inflammation and structural damage in methotrexate (MTX)-treated patients with early rheumatoid arthritis (RA). METHODS: Twenty-four patients with erosive early RA (duration < 3 years) who were receiving MTX were randomized to receive infliximab 5 mg/kg or placebo infusions at weeks 0, 2, and 6, and then every 8 weeks through week 46. Beginning at week 54 and thereafter, all patients received infliximab 5 mg/kg. Metacarpophalangeal joints were scanned using high-frequency ultrasonography and power Doppler imaging. Radiographs were evaluated using the modified Sharp/van der Heijde scoring system. RESULTS: From baseline to week 54, total synovial thickness was significantly improved in the infliximab + MTX group compared with the placebo + MTX group (median reduction 95.8% versus 37.5%; P = 0.005), as was the total color Doppler area (CDA; vascularity assessment) (median reduction 100% and 47.1%, respectively; P = 0.025). From week 0 to week 110, no significant between-group difference was observed in the change from baseline for total synovial thickening or the total CDA. At week 54, greater progression in the Sharp/van der Heijde score was apparent in patients receiving placebo + MTX compared with those receiving infliximab + MTX. Although radiographic progression in the placebo + MTX group was greatly reduced in the second year (after initiation of infliximab therapy), marked differences were observed between the infliximab + MTX group (median change in the Sharp/van der Heijde score 4.0) and the placebo + MTX group (median change 14.5) from baseline to week 110 (P = 0.076). CONCLUSION: The results indicate that the efficacy of 2 years of combination therapy with infliximab + MTX for inhibiting cumulative structural damage was superior to that of 1 year of treatment with MTX alone followed by the addition of infliximab.

Anti-TNF therapy: where have we got to in 2005?

The blockade of TNF has had significant impact on the therapy of a number of chronic autoimmune diseases. In this chapter we review the concepts leading up to this therapy in rheumatoid arthritis (RA), how it spreads into other autoimmune diseases, and how greater understanding of its use has led to augmented therapeutic benefit. There are still many limitations, but the prospects for the future are intriguing.

The 2005 International Symposium on Advances in Targeted Therapies: what have we learned in the 2000s and where are we going?

This essay summarises a personal perspective on where we have got to in the five years since the turn of the last century. The focus is on advances in knowledge of antitumour necrosis factor (anti-TNF) therapy of rheumatoid arthritis and other chronic immune-inflammatory rheumatic diseases. The accumulating knowledge is clarifying the scope and limitations of efficacy, safety, and durability of these agents. It is defining the unmet needs of patients and communities worldwide for the future. The call is for progress in providing more cost-effective advances in therapeutics that not only interrupt the disease process long term but also reverse the anatomical and functional consequences of disease and the impairment in quality of life.

Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study.

OBJECTIVE: To assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment. METHODS: Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial. RESULTS: At week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28-joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C-reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo-treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX-treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001). CONCLUSION: Even in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.

Association between baseline radiographic damage and improvement in physical function after treatment of patients with rheumatoid arthritis.

OBJECTIVES: To identify factors associated with poor physical function in rheumatoid arthritis and to assess whether baseline joint damage has an impact on improvement in physical function during infliximab treatment. METHODS: 428 patients with active rheumatoid arthritis despite methotrexate treatment received methotrexate alone or with infliximab (3 mg/kg or 10 mg/kg every four or eight weeks) for 54 weeks (the ATTRACT trial). Data on clinical outcomes and physical function (assessed by the health assessment questionnaire (HAQ)) were collected. Structural damage was assessed using the van der Heijde modification of the Sharp score. Odds ratios (OR) for factors associated with severe functional disability (HAQ > or =2.0) at baseline were estimated using multiple logistic regression analyses, and baseline factors related to the change in physical function after treatment at week 54 were determined. RESULTS: Baseline radiographic scores were correlated with baseline HAQ scores. After adjustment for demographic characteristics in the logistic regression model, baseline disease activity scores, radiological joint damage, fatigue, and morning stiffness were found to be associated with severe functional disability (HAQ >2.0), with OR values of 2.00 (1.53 to 2.63), 1.82 (1.15 to 2.87), 1.19 (1.05 to 1.34), and 1.07 (1.01 to 1.13), respectively. In multiple linear regression analysis, physical disability, joint damage, and fatigue at baseline were correlated with less improvement in physical function after treatment. Infliximab treatment was associated with greater improvement in physical function. CONCLUSIONS: Greater joint damage at baseline was associated with poorer physical function at baseline and less improvement in physical function after treatment, underlining the importance of early intervention to slow the progression of joint destruction.

The use of porous polyethylene (Medpor) lower eyelid spacers in lid heightening and stabilisation.

BACKGROUND/AIMS: The management of lower eyelid retraction can be challenging, and established techniques to correct it are not always successful. Previous reports have suggested a role for the ultrathin high density porous polyethylene lower eyelid spacer (Medpor LES) in such patients. The authors report the experience of three surgeons implanting Medpor LES over 1 year, and ascertain whether such implants are a safe and effective alternative to autogenous spacers. METHODS: A prospective, interventional, non-comparative case series of consecutive patients. Surgical indications for Medpor LES were noted. Preoperative and postoperative lower marginal reflex distance (L-MRD), vertical palpebral aperture (PA), lagophthalmos, and scleral show inferior to the limbus (LSS) were recorded, together with major and minor complications. RESULTS: 32 patients (35 eyelids) had a Medpor LES inserted, 22/32 under local anaesthetic, and nine with adjunctive procedures. Mean follow up was 22 months (range 15-28 months). The Medpor LES was effective in reducing the palpebral aperture (p<0.001) and lagophthalmos (p = 0.04) and raising the lower eyelid height by reducing both L-MRD (p = 0.006) and LSS (p<0.001). However there were major complications in 7/32 patients and minor complications in 8/32, most requiring further surgery. Final outcome was good in 24/35 eyelids and satisfactory in 5/35. CONCLUSIONS: Despite a good or satisfactory final outcome in the majority of patients, the value of this technique is limited by complications, and should be reserved for those unsuitable for safer techniques.

Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate.

OBJECTIVE: To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate (MTX) over a 2-year period in patients with rheumatoid arthritis (RA) who previously experienced an incomplete response to MTX. METHODS: Four hundred twenty-eight patients were randomly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks, with an additional year of followup. The protocol was later amended to allow for continued treatment during the second year. Of 259 patients who entered the second year of treatment, 216 continued to receive infliximab plus MTX for 102 weeks. Ninety-four of these 259 patients experienced a gap in therapy of >8 weeks before continuing therapy. Infusions were administered at weeks 0, 2, and 6, followed by treatment every 4 weeks or every 8 weeks (alternating with placebo infusions in the interim 4-week visits) at a dose of 3 or 10 mg/kg for a total of 102 weeks (including the gap in therapy). For safety and efficacy assessments, data on the patients who were randomized to receive treatment, irrespective of whether treatment was administered for 102 weeks, were evaluated using all actual observations available. The efficacy measures included the Health Assessment Questionnaire (HAQ) (physical function), Short Form 36 health survey (SF-36) (health-related quality of life), total radiographic scores (structural damage), and the American College of Rheumatology 20% improvement criteria (ACR20) (signs and symptoms). RESULTS: The infliximab plus MTX regimens resulted in significantly greater improvement in HAQ scores (P < or = 0.006) and SF-36 physical component summary scores (P < or = 0.011) compared with the MTX-only group. There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens. Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen. The proportion of patients achieving an ACR20 response at week 102 varied from 40% to 48% for the infliximab plus MTX groups compared with 16% for the MTX-only group. CONCLUSION: Throughout 102 weeks of therapy, infliximab plus MTX provided significant, clinically relevant improvement in physical function and quality of life, accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone.

Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis.

OBJECTIVE: To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis (RA) receiving infliximab + methotrexate (MTX) versus placebo + MTX over 18 weeks, and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the hands and feet at 54 weeks. METHODS: Patients with early RA (duration <3 years) receiving stable dosages of MTX were randomly assigned to receive blinded infusions of 5 mg/kg infliximab (n = 12) or placebo (n = 12) at weeks 0, 2, 6, and then every 8 weeks until week 46. At baseline and week 18, clinical assessments were performed, and metacarpophalangeal joints were assessed by high-frequency ultrasonography and power Doppler ultrasonography measurements. Radiographs of the hands and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method (vdH-Sharp score). RESULTS: Using changes in the total vdH-Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks, we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX. Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54. Infliximab + MTX treatment abolished these relationships. CONCLUSION: The delay or reversal of inflammatory and joint-destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks.

The risk of complications of uveitis in a district hospital cohort.

AIMS: To establish the frequency and risk factors for visual loss in a primary referral cohort of hospital patients with uveitis. METHODS: 561 consecutive uveitis patients attending three district hospitals were recruited and the acuity at the end of the study period recorded. A retrospective case-control study of risk factors for visual loss (permanent loss of acuity <6/9) was performed. Risk factors examined included type of uveitis, age at onset of uveitis, race, type of systemic inflammatory disease, length of follow up, and treatment variables. RESULTS: Visual loss of at least 6/12 in one eye was found in 111 patients (19.9%). Only four patients (0.7%) suffered severe bilateral visual loss (6/36 or less). Visual loss was associated with age at onset >60 years (odds ratio 3.9, 95% confidence interval (CI) 2.2 to 7.0, long follow up 2.0 (1.2 to 3.3) and a history of cataract surgery 3.9 (2.1 to 7.2). It was less likely in patients with acute anterior uveitis 0.2 (0.1 to 0.3). CONCLUSION: The frequency of visual loss associated with uveitis in a district hospital cohort is less than that found in referral centres and levels of legal blindness are low. Although acute anterior uveitis has a low frequency of visual loss it contributes significantly to the total burden. The ocular co-morbidity of the elderly may contribute to the increased visual loss of late onset uveitis.

Infliximab in active early rheumatoid arthritis.

OBJECTIVE: To examine the impact of the combination of infliximab plus methotrexate (MTX) on the progression of structural damage in patients with early rheumatoid arthritis (RA). METHODS: Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, in which 428 patients with active RA despite MTX therapy received placebo with MTX (MTX-only) or infliximab 3 mg/kg or 10 mg/kg every (q) 4 or 8 weeks with MTX (infliximab plus MTX) for 102 weeks. Early RA was defined as disease duration of 3 years or less; 82 of the 428 patients (19%) met this definition. Structural damage was assessed with the modified van der Heijde-Sharp score. The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group. RESULTS: The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen. Consistent benefit was seen in the joints of both hands and feet. CONCLUSIONS: Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment. Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity.

Consequences of immunogenicity to the therapeutic monoclonal antibodies ReoPro and Remicade.

The clinical consequences of immune antibodies generated to abciximab (ReoPro) and infliximab (Remicade) are described. Abciximab, a chimaeric Fab fragment that binds to the beta3 integrin of the GPIIb/IIIa and alphavbeta3 receptors on human platelets, is approved in the US and Europe for use in percutaneous coronary intervention (PCI) to prevent cardiac ischaemic complications. The effects of induced antibodies upon the safety and efficacy of repeat administration of abciximab have been evaluated in the ReoPro Re-administration Registry Study, in which 5.7% of patients were HACA positive before re-treatment. An interim evaluation of 1000 patients has indicated that re-administration of abciximab can be accomplished in the setting of PCI with an acceptable safety and efficacy profile. Infliximab is a chimaeric IgG1 antibody specific for human TNFalpha, and is approved in the US and Europe for the acute treatment of the signs and symptoms of Crohn's disease and for the chronic treatment of rheumatoid arthritis (RA). The incidence of antibodies to infliximab is reported to be approximately 10%; however, an inverse dose-immunogenicity relationship was observed, indicating that higher doses of infliximab (> or = 3 to 10 mg/kg) could reduce the incidence of immune antibodies. The induction of immune antibodies could also be reduced by concomitant administration of low-dose methotrexate and other immunosuppressant agents. Although antibodies to infliximab appeared to be associated with lower serum infliximab concentrations and a slightly higher incidence of infusion reactions, these immune antibodies were generally not associated with a reduction in clinical efficacy. In addition, the antibodies induced to infliximab are specific for infliximab, and do not cross-react with other currently available therapeutic antibodies.

Polymorphism in the immunoglobulin VH gene V1-69 affects susceptibility to rheumatoid arthritis in subjects lacking the HLA-DRB1 shared epitope.

OBJECTIVE: To investigate the contribution of polymorphism in the immunoglobulin heavy chain variable region V1-69 gene set to genetic susceptibility to rheumatoid arthritis (RA) in Czech and British patients. METHODS: We used V1-69 gene sequence-specific polymerase chain reaction (PCR) and restriction enzyme digestion to study polymorphism in the V1-69 gene set in germline DNA of 109 Czech and 159 British RA patients and 164 ethnically matched controls. Polymorphism was further studied by nucleotide sequencing of the V1-69 gene locus in germline DNA. RESULTS: We found that all patients and controls had at least one V1-69 gene copy. In the Czech RA cohort, the dimorphic nucleotide in codon 73 of V1-69 (GAA or AAA) was present in the homozygous form 73(A/A) in 31 of 109 (28.4%) RA patients vs 12 of 79 (15.2%) controls [odds ratio (OR)=2.22, P<0.001]. When the RA patients and controls were classified according to HLA shared epitope (SE) status, 73(A/A) was found in 18 of 76 (23.7%) SE(+) patients compared with 13 of 38 (34.2%) SE(-) patients, four of 12 (18.2) SE(+) controls and eight of 57 (14%) SE(-) controls. This suggests that homozygosity for the dimorphic sequence 73(A) contributed to susceptibility to RA in SE(-) Czech individuals (OR=3.2, P<0.001). The most striking observation was that none of the 38 SE(-) Czech patients, compared with 11 of 76 (14.5%) SE(+) RA patients, three of 22 (13.6%) SE(+) and 11 of 57 (19.3%) SE(-) ethnically matched controls, were homozygous for the alternative dimorphic sequence 73(G/G) (OR=9.1, P<0.05). These data, however, were not replicated in a Caucasoid British RA population. CONCLUSION: The dimorphic sequence at codon 73 (73(A/A)) of the V1-69 gene contributes to genetic susceptibility in SE(-) Czech RA patients.