M.C.W. Creemers

Survival during treatment with tumour necrosis factor blocking agents in rheumatoid arthritis

Tumour necrosis factor (TNF) blocking agents are an important advance in the clinical treatment of rheumatoid arthritis (RA). They were introduced into clinical practice while limited safety information was available. This means that intensive monitoring is needed early in the life cycle of these new drugs. Setting up large cohort studies to monitor efficacy, safety, and tolerability in long term use of these so-called biological agents will provide information about the consequences of using TNF blocking agents in chronic rheumatic disease like RA. Currently, a Dutch multicentre registry on biological agents in RA is being set up. This study aimed at investigating the efficacy and toxicity of TNF blocking agents in patients with RA at one participating academic centre by a drug survival analysis. Since 1997 230 patients with RA at the centre have been treated with TNF blocking agents for the first time (94 with adalimumab, 120 with infliximab, and 16 with etanercept). No differences in drug survival between the three TNF blocking agents were found despite the diversity in selection and patient numbers. Adverse events which occurred, leading to discontinuation, were similar to those from previous reports.

The tumour necrosis factor receptor superfamily member 1b 676T>G polymorphism in relation to response to infliximab and adalimumab treatment and disease severity in rheumatoid arthritis

Objective: To assess the effect of a functional polymorphism (676T>G, M196R) in the tumour necrosis factor receptor super family 1b (TNFSF1b) gene on disease activity, radiological joint damage and response to infliximab and adalimumab treatment in patients with rheumatoid arthritis (RA). Methods: Two cohorts of patients with RA were genotyped for the 676T>G polymorphism (rs1061622) in exon 6 of the TNFSF1b gene by restriction fragment length polymorphism analysis. One cohort (n = 234) included patients from the Dutch Rheumatoid Arthritis Monitoring register with detailed information on their response to anti-TNF therapy (infliximab and adalimumab), the other cohort comprised patients from a long-term observational early inception cohort at our centre (n = 248). Results: The 676T>G polymorphism was not associated with anti-TNF response after 3 or 6 months of treatment. Linear regression analysis showed no significant difference in the progression of radiological joint damage during the first 3 and 6 years of disease between the three genotype groups (TT, TG and GG). Additionally, no difference in mean disease activity between genotypes was seen after 3 and 6 years of disease. Conclusion: Despite its demonstrated functionality, the 676T>G polymorphism in the TNFSF1b gene does not have a major role in either the response to anti-TNF therapy or in the disease severity or radiological progression in RA.

Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis.

IntroductionThe aim of this study was to determine the prevalence of gastrointestinal and behavioural symptoms occurring before (anticipatory/associative) and after methotrexate (MTX) administration, termed MTX intolerance, in rheumatoid (RA) and psoriatic arthritis (PsA).MethodsMethotrexate Intolerance Severity Score (MISS), previously validated in juvenile idiopathic arthritis patients, was used to determine MTX intolerance prevalence in 291 RA/PsA patients. The MISS consisted of four domains: abdominal pain, nausea, vomiting and behavioural symptoms, occurring upon, prior to (anticipatory) and when thinking of MTX (associative). MTX intolerance was defined as ≥6 on the MISS with ≥1 point on anticipatory and/or associative and/or behavioural items.ResultsA total of 123 patients (42.3%) experienced at least one gastrointestinal adverse effect. The prevalence of MTX intolerance was 11%. MTX intolerance prevalence was higher in patients on parenteral (20.6%) than on oral MTX (6.2%) (p < 0.001).ConclusionBesides well-known gastrointestinal symptoms after MTX, RA and PsA patients experienced these symptoms also before MTX intake. RA and PsA patients on MTX should be closely monitored with the MISS for early detection of MTX intolerance, in order to intervene timely and avoid discontinuation of an effective treatment.

Appropriate infliximab infusion dosage and monitoring: results of a panel meeting of rheumatologists, dermatologists and gastroenterologists.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Infliximab is an effective treatment for rheumatoid arthritis, ankylosing spondylitis, Crohns disease (both adult and paediatric), ulcerative colitis, psoriatic arthritis and plaque psoriasis and national and international guidelines have been developed for each indication. WHAT THIS STUDY ADDS This study is the first study which compared current international, national and local guidelines from the medical specialties involved in the treatment with infliximab on the following topics: indication, dosage, synergy and monitoring of vital signs. AIMS Infliximab, an anti-TNF biologic agent, is currently indicated and reimbursed for rheumatoid arthritis, ankylosing spondylitis, Crohns disease (both adult and paediatric), ulcerative colitis, psoriatic arthritis and plaque psoriasis. Development of national and international guidelines for rheumatology, gastroenterology and dermatology, was mostly based on clinical studies and expert opinion. The aim of this study was to compare available guidelines and local protocols for rheumatology, dermatology and gastroenterology, regarding dosage of infliximab, synergy of infliximab with concomitant medication and monitoring of vital signs during infliximab administration, for achieving optimal care. METHODS Current international, national and local guidelines on the use of infliximab were reviewed and compared, differences and shortcomings were identified, and optimal treatment schedules discussed during a meeting (July 2008) of clinical experts and researchers from three departments of a Dutch university hospital. RESULTS Recommended dosages of infliximab are not equal for different indications. Loss of response to infliximab is a common problem encountered within the three medical specialties, but indications for adjustments in treatment schedules are lacking in all of the guidelines. Monitoring of vital signs (blood pressure, pulse, temperature) during infusion with infliximab is common practice and recommended by some guidelines. Routine measurement of vital signs is not of any value in predicting or recognizing acute infusion reactions, in our experience, and this is confirmed by literature on inflammatory bowel disease. CONCLUSION Different indications encompass different dosing schedules. National and internal guidelines do not provide advice regarding loss of response. Routine measurement of vital signs during infusion is not valuable in detecting acute infusion reactions and should only be performed in case of an acute infusion reaction. These topics need to be studied in future studies and covered in future guidelines.

Pseudoporphyria due to Naproxen: A cluster of 3 cases

Pseudoporphyria is a photo-induced blistering disorder with increased skin fragility, caused among others by nonsteroidal antiinflammatory drugs. Lesions heal with scarring and milia. Porphyrin screen studies are normal in this disease. Histology and immunofluorescence resembles porphyria cutanea tarda. In this report we describe a cluster of three cases of naproxen-induced pseudoporphyria, and review briefly previously reported cases induced by naproxen. The majority of reported cases involve children. Physicians should be aware of this reversible skin disorder.

Coxiella burnetii infection (Q fever) in rheumatoid arthritis patients with and without anti-TNFα therapy

Q fever is a zoonosis caused by the intracellular bacterium Coxiella burnetii. The Netherlands experienced a major Q fever outbreak between 2007 and 2010, with an estimate of more than 40 000 infected individuals.1 Initial infection is asymptomatic in over 50% of the infected individuals or causes a mostly self-limiting febrile disease.2 However, chronic Q fever may develop months to years after initial infection. This serious, life-threatening condition presents mostly as endocarditis or infection of an aortic aneurysm or vascular prosthesis, and is accompanied by high IgG antibody titres against phase I C burnetii .3 Individuals most at risk for chronic Q fever are those with pre-existing valvulopathy, vascular aneurysm or prosthesis and yet undefined types of immune suppression.4 ,5 Tumour necrosis factor-α (TNFα) plays an important role in the defence against intracellular bacteria such as C burnetii . In vitro studies show that TNFα is involved in internalisation and intracellular killing of C burnetii in monocytes.6 ,7 In addition, C burnetii- infected TNFα knockout mice develop early bacteraemia and severe …

A tailored-guided internet-based cognitive-behavioral intervention for patients with rheumatoid arthritis as an adjunct to standard rheumatological care: results of a randomized controlled trial

Abstract For patients with chronic pain conditions such as rheumatoid arthritis (RA), who experience elevated levels of distress, tailored-guided internet-based cognitive-behavioral treatment may be effective in improving psychological and physical functioning, and reducing the impact of RA on daily life. A multicenter, randomized controlled trial was conducted for RA patients with elevated levels of distress as assessed by a disease-specific measure. The control group (n = 71) received standard care and the intervention group (n = 62) additionally received an internet-based tailored cognitive-behavioral intervention. Main analyses were performed using a linear mixed model estimating differences between the intervention and control groups in scores of psychological functioning, physical functioning, and impact of RA on daily life at preassesment and postassessment, and at 3, 6, 9, and 12 months. Patients who received the internet-based intervention reported a larger improvement in psychological functioning compared with the control group, indicating less depressed mood (P < 0.001, d = 0.54), negative mood (P = 0.01, d = 0.38), and anxiety (P < 0.001, d = 0.48) during the course of the 1-year follow-up period. Regarding physical functioning, a trend was found for the intervention group reporting less fatigue than the control group (P = 0.06, d = 0.24), whereas no effect was found on pain. No effects were found for the impact of RA on daily life, except for the intervention group experiencing fewer role limitations due to emotional problems (P < 0.001, d = 0.53). Offering guided internet-based cognitive-behavioral therapy is a promising development to aid patients with psychological distress particularly in improving psychological functioning. Further research on adherence and specific intervention ingredients is warranted.

High-dose intravenous pulse methotrexate in patients with eosinophilic fasciitis

Importance Eosinophilic fasciitis (EF) is a connective tissue disorder in which conventional treatment leads to disappointing results in a proportion of patients. Therefore, we investigated high-dose intravenous (IV) pulse methotrexate (MTX) as a treatment for EF. Objective To examine safety and effects of monthly high-dose IV pulse MTX in EF. Design, Setting, and Participants For this prospective single-arm study, we recruited 12 patients diagnosed with biopsy specimen-proven EF between 2006 and 2009 from the Department of Dermatology and Rheumatology at the Radboud University Medical Centre. Interventions Intravenous MTX (4 mg/kg) monthly for 5 months with folinic acid rescue 24 hours after MTX administration. Main Outcomes and Measures The primary outcome was improvement of the modified skin score at month 5 vs baseline. Secondary outcomes were durometry, range of motion, visual analog scale scores for disease activity, and 36-Item Short Form Survey health questionnaires. Results Overall, 12 patients (11 women between 37-69 years old) received a median (range) monthly dose of 288 (230-336) mg MTX. Median (range) modified skin score improved from 17.5 (8.0-24.0) at baseline to 8.5 (1.0-20.0) at month 5 (P = .001). Secondary outcome measures improved significantly, except for durometer scores and range of motion of the elbows. Adverse events included gastrointestinal symptoms (n = 9), mild stomatitis (n = 5), and alopecia (n = 4). Conclusions and Relevance High-dose IV pulse MTX is a safe and effective treatment option in EF. Trial Registration clinicaltrials.gov Identifier: NCT00441961.

Measuring the Therapeutic Relationship in Internet-Based Interventions

exists to measure internet-specific aspects of the therapeutic relationship during internet-based interventions. In this letter we describe the following: (1) the sensitivity to change, (2) the associations with pre-treatment patient characteristics and (3) the associations with patient-reported treatment outcome of an instrument to measure the therapeutic relationship during an internet intervention. We report on data from 98 psoriasis and rheumatoid arthritis patients who participated in the treatment arm of two ongoing trials between July 2010 and May 2014. Patients were asked to fill out a paper-and-pencil version of the Internet-Specific Therapeutic Relationship Questionnaire (ITRQ) together with the Dutch translation of the short form of the Working Alliance Inventory (WAIS) [8, 9] , firstly after an instruction session of the treatment website and again at treatment completion. The WAI-S is generally used for assessing the face-to-face treatment alliance. Also, at the pretreatment session several questionnaires on general well-being were assessed ( table 1 ). To assess whether the ITRQ may be related to treatment outcome, the patients were asked to rate their own progress on coping and complaints at the end of treatment and to give a general mark on a scale from 1 to 10 on treatment satisfaction. A full description of both trials and the inclusion criteria for participants were drawn from and can be found at http://www. trialregister.nl/trialreg/admin/rctsearch.asp (trial No. NTR2100 and NTR2436). Of the 98 patients, 72 pre-treatment and 75 posttreatment measurements of the questionnaire assessing internetspecific aspects of the treatment were available and 52 patients completed both questionnaires. Treatment consisted of an internet-based cognitive-behavioural treatment tailored to the individual’s goals and characteristics as established during one or two face-to-face intake sessions. Patients received online assignments from one to four treatment modules (pain or itch, fatigue, negative mood, or social functioning) and personalized feedback from the therapist. Treatment ended with a relapse prevention module. The ITRQ was constructed after a review of the literature on the specific characteristics of internet-based psychological treatments. For an overview of the English translation of the items on the questionnaire and results of the factor analysis, see Appendix. A team of psychologists, researchers and patient research partners aided in the generation of the items and the construction of the questionnaire. The ITRQ contains 9 items, consisting of two subscales of 4 items each. Because 1 item was highly associated with both subscales (item 7), this item was not included in either subscale. The first scale, including items on the time lag aspects in communication and receiving sufficient attention by the E-coach therapist, was termed ‘internet-specific time and attention’ (Cronbach’s α = 0.92). The second scale, including items reflecting the sharing of information with the therapist and the home as the treatment environment, was termed ‘internet-specific reflection and comfort’ (α = 0.87); the internal consistency of the total scale was also satisfactory (α = 0.89). The use of the internet for the provision of health care is on the rise, with increasing evidence of comparable effectiveness of psychological internet and face-to-face treatments [1, 2] . It is well known that the quality of the therapeutic relationship during faceto-face treatment contributes at least modestly to an effective treatment outcome [3] . A recent review [4] further suggests that the patient evaluation of the therapeutic relationship in internet-based therapy is comparable to that of face-to-face treatments. However, there might be specific issues of a therapeutic relationship during internet interventions that have been neglected so far. For example, patient evaluations and uptake of internet-based treatments suggest problems in building a therapeutic relationship during internetbased treatments [5] . Internet-based treatments may have incorporated fewer features to develop and maintain a therapeutic relationship compared to face-to-face treatments. On the other hand, internet-based treatments may offer unique characteristics that impact on the therapeutic relationship that face-to-face treatments do not provide [6] . Some studies have indicated that interventions with the support of a therapist to motivate patients have lower drop-out rates and may be more effective [7] . Finally, little is known about which patient pre-treatment characteristics contribute to a better therapeutic relationship during internet interventions. In previous studies on the therapeutic relationship in internet interventions, instruments were used that are commonly used in face-to-face treatment. To our knowledge, no instrument currently Received: March 21, 2015 Accepted after revision: June 15, 2015 Published online: November 27, 2015

OP0343-HPR An economic evaluation of a tailored guided internet-based cognitive behavioural intervention for patients with rheumatoid arthritisas an addition to usual care

Background Within the field of rheumatoid arthritis (RA), patients report decreased health-related quality of life (HRQoL) as a result of living with physical factors such as pain and psychological factors such as negative mood. As these factors are associated with the disease trajectory, health care utilisation, and workplace disability of patients, these factors lead to significant societal health expenses. In a recent randomised controlled trial, improvements in especially psychological functioning (e.g., depressed mood) were found by offering tailored, therapist guided cognitive behavioural therapy online.1 Although internet-based cognitive behavioural therapy holds promise for implementation and cost-reductions, scarce research is available on the cost-effectiveness of these treatments. Objectives A cost-effectiveness study from a societal perspective was conducted alongside a randomised controlled trial on a tailored and therapist-guided internet-based cognitive behavioural intervention (ICBT) for patients with elevated levels of distress, as an addition to usual care alone in order to inform stake-holders on implementation of this treatment. Methods Data were collected at baseline/pre-intervention, 6 months/post-intervention, and three-monthly thereafter during one year follow-up. Effects were measured in quality-adjusted life years (QALYs) and costs from a societal perspective including healthcare sector costs (including healthcare use, medication, and intervention costs), patient travel costs for healthcare use, and costs associated with loss of labour. Results The intervention improved quality of life compared to usual care alone (Δ QALYs=0.059), but also led to higher costs (Δ=€ 4.211,44), which reduced substantially when medication costs were left out of the equation (Δ=€ 1.862,72). Most (93%) of the simulated ICERS were in the north-east quadrant, suggesting a high probability that the intervention is effective in improving HRQoL, but at a greater monetary cost for society compared to usual care alone. Conclusions A positive effect on quality-adjusted life years is seen in the intervention group compared to the control group. However, cost-ratios show that this comes at a greater cost to society. The substantial costs in this population are generated by medication costs, for which no group differences could be found. The cost-benefit ratio improves when the costs for medication are not taken into account. Based on the effects for improvement of quality of life, implementation of the intervention is recommended, yet on the side of costs, further study is warranted. Reference [1] Ferwerda M, van Beugen S, van Middendorp H, Spillekom-van Koulil S, Donders ART, Visser H, Taal E, Creemers MCW, van Riel PCLM, Evers AWM. A tailored-guided internet-based cognitive-behavioural intervention for patients with rheumatoid arthritis as an adjunct to standard rheumatological care: Results of a randomized controlled trial. Pain2017;158(5):868–78. PMID: 28106666 Disclosure of Interest None declared