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Abstract
Background Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD).
Methods The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement.
Results Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined.
Conclusion These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.
This paper is freely available online under the BMJ Journals unlocked scheme, see http://ard.bmj.com/info/unlocked.dtl
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The treatment of psoriatic arthritis (PsA) has changed dramatically over recent years, despite the lack of sufficient knowledge on aetiology and detailed pathogenesis. Observations that pro-inflammatory cytokines may play important pathogenetic roles have led to the evaluation of novel therapies; indeed, new synthetic and biological disease-modifying antirheumatic drugs (DMARD) are widely used,1,–,5 with further treatment options anticipated in the near future.6 7 While psoriatic skin and joint disease have many facets in common, the pathways leading to their expression may differ, exemplified in the frequent distinct efficacy of various therapies on skin and joint disease (eg, phototherapy, fumaric acid or alefacept).8,–,12 PsA in itself is heterogeneous by virtue of its broad phenotypes of joint involvement (peripheral and spinal),13 but also its spectrum of extra-articular manifestations, which—aside from skin and nails—comprise dactylitis and enthesopathy.14 15
The complexity of PsA and the relative paucity of randomised controlled clinical studies, let alone strategic trials, contrasts with the situation in rheumatoid arthritis (RA), another chronic and destructive inflammatory joint disease. There are data on the usefulness of synthetic DMARD as well as the efficacy of biological DMARD, particularly tumour necrosis factor (TNF) inhibitors1,–,5 16,–,18 in PsA, and there exist general recommendations for the use of biological agents.19 Recently, recommendations for PsA treatment were presented by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).20 21 These recommendations are comprehensive, with a special focus on skin disease, providing an initial treatment guidance set. However, clinicians can benefit from concise, easy to follow guidance on the optimal use of available therapies and clear treatment strategies for PsA.
Among other aspects, the efficacy of synthetic DMARD and the role of glucocorticoids remain under debate, and combination therapy of synthetic DMARD or synthetic DMARD with biological agents is relatively underresearched.17 22 Moreover, even disease activity assessment of PsA is under scrutiny, given that the measures used in clinical trials are mostly ‘borrowed’ from RA23 with further methods under evaluation. Furthermore, therapeutic targets require definition.24 25
All of these reasons, as well as more recent insights, provided a rationale for the development of European League Against Rheumatism (EULAR) recommendations for the management of PsA. Rheumatologists require evidence-based guidance for the treatment of PsA with regard to synthetic and biological therapies, including the definition of treatment targets and assessment tools.
To address the set task, EULAR convened a group of experts to produce evidence-based recommendations for the management of PsA with non-topical pharmacological therapies on the basis of the EULAR standard operating procedures,26 and to develop a research agenda for future activities.
Methods
The task force aimed at aggregating available information on disease management in PsA into practical recommendations. The basis of its activities were the respective EULAR standardised procedures,26 which suggest the institution of an expert committee in charge of consensus finding, on the basis of evidence provided by a systematic literature review and expert opinion. The taskforce thus followed a similar path as other management recommendations, such as for RA, ankylosing spondylitis and osteoarthritis.27,–,30 One of the aims of EULAR recommendations is to provide clear guidance that is easy to follow in clinical practice.
The expert committee consisted of 28 rheumatologists, two patients, one infectious disease specialist, one dermatologist, one physiotherapist and two rheumatology fellows. The members of this task force came from 14 European countries and from the USA. This inclusive approach aimed at obtaining broad consensus and applicability of the recommendations. The process was both evidenced based and consensus based, as explained in supplementary text 1 (available online only), and included, between January 2010 and December 2010, two expert meetings, systematic literature reviews and extensive discussions. The literature search is published separately.31
A vote was obtained from the experts on the level of agreement with the final recommendations. Votes for agreement or disagreement were performed anonymously, by giving a score from 0 (total disagreement) to 10 (total agreement) for each recommendation; the means and SD of scores from the whole group were calculated.
Results
Overarching principles
Before addressing the actual treatment recommendations, the task force established principles deemed sufficiently important to be conveyed to those affected by PsA or involved with the management of PsA. These principles regarding the care of patients with PsA are of such s generic nature that they were felt to be ‘overarching’. The complete wording and level of agreement are shown in table 1, and the explanatory text is in supplementary text 2 (available online only). The task force voted unanimously on these five principles.
EULAR recommendations for the management of PsA, with levels of evidence, grade of recommendations and level of agreement
Recommendations
The process led to 10 recommendations on drug management and treatment strategies, presented in table 1 with levels of evidence and strengths of recommendations. The 10 recommendations are ordered by means of logical sequence or procedural and chronological hierarchy rather than by any major weight of importance. They also serve as the basis for the algorithm provided in figure 1.
Management of psoriatic arthritis according to the European League Against Rheumatism recommendations. Recommendations have been divided into four phases. Numbers in parentheses indicate the respective items of the recommendation as shown in table 1. Small fonts within the ellipses in phases II and III refer to dose modifications or an alternative therapy, as detailed within the body of the recommendations.
NSAID for relief of signs and symptoms
The task force was unanimous in its view that in the vast majority of PsA patients, NSAID should be used as first-line treatment, although the data regarding the usefulness of NSAID in PsA are limited.31,–,33 NSAID have been shown to be efficacious on joint symptoms, although there is no demonstrated efficacy on skin lesions.31 Of course, cardiovascular and gastrointestinal risk34,–,36 should be taken into account when prescribing NSAID, which explains the use of the word ‘may’ in the wording of the recommendation. Furthermore, not everyone with signs and symptoms requires NSAID treatment, as some patients may respond well to analgesics or may not feel in need of symptomatic therapy. We encourage the lowest dose and the shortest treatment duration possible with NSAID, in view of their potential toxicity. Data suggest that cyclooxygenase 2 inhibitors are as effective as non-selective NSAID in PsA.32 No data were found regarding the possible worsening of skin lesions following NSAID use.
Treatment with synthetic DMARD
To date, there are few data on which to rest for the decision to start a synthetic DMARD. Who should be treated with DMARD? When to treat with DMARD? This should be addressed by future research. Based on the prognostic factors shown in the literature, the group considered that patients with active disease and potential poor prognosis should be started on DMARD. Active disease was defined globally as one or more tender and inflamed joint and/or tender enthesis point and/or dactylitic digit and/or inflammatory back pain; however, for the introduction of synthetic DMARD only joint involvement is taken into account. Poor prognosis refers here to the number of actively inflamed joints (defined here as five or more), elevated acute phase reactants, radiographic damage that is progressing, previous use of glucocorticoids, loss of function and diminished quality of life.31 37
Delay in the start of DMARD therapy may lead to worse outcomes, similar to RA,38 although data are scarce in this respect in PsA.20 39 Obviously, patients who have active disease despite previous NSAID therapy should receive a synthetic DMARD (this is stated as ‘at an early stage’ in the recommendation; although the term ‘early’ was not precisely defined, it is common to regard ‘early’ as a few weeks to a maximum of 1 year). Regarding the choice of a DMARD, here again there are few data and almost no head-to-head comparisons. Based on the available literature, the experts recommended methotrexate as the first-choice DMARD. This group decision was based in particular on broad therapeutic dose ranges, different application forms (by mouth, subcutaneous) and available data in PsA and in other inflammatory diseases.39,–,42 It is worth noting here that synthetic DMARD do not appear to be efficacious for treating enthesitis and axial disease (more details under recommendations 6 and 7, see table 1).
When treating with methotrexate, careful consideration must be given to the prescription of an efficacious dose. While the most efficacious dose has not been determined for PsA and low doses may not be effective, it is evident in RA that doses in the order of 25 mg per week are more appropriate than lower doses.43 Other drugs to be considered include sulfasalazine, leflunomide and ciclosporin A (although the use of this latter drug is limited by long-term toxicity issues).4 22 31 44,–,46 The order presented here is not a ranking order. Clinical efficacy on joint involvement has also been published for gold salts and azathioprine, although for these drugs the level of evidence was low.31 None of the synthetic DMARD have been tested for (eg, ciclosporin, leflunomide) and/or have demonstrated (eg, methotrexate, sulfasalazine, gold salts, azathioprin) structural efficacy in PsA.31 Although there is a lack of evidence on the efficacy of synthetic DMARD combinations, these may be considered.47 48
As a result of the potential for increased hepatic toxicity of methotrexate in PsA compared with other rheumatic conditions,49 50 transaminase enzymes should be carefully monitored in patients with PsA who receive treatment with methotrexate or leflunomide, especially in cases of alcohol consumption, obesity, type II diabetes and non-alcoholic steatohepatitis or concurrent therapy with other potentially hepatotoxic drugs (eg, statins). In some patients, a liver biopsy has been recommended.51
Choice of synthetic DMARD in the presence of clinically relevant psoriasis
Some DMARD have shown efficacy in psoriasis. This is especially the case with methotrexate, but also ciclosporin A, leflunomide and sulfasalazine.31 52 In patients with ‘clinically relevant’ psoriasis, defined as psoriasis with impact on quality of life, these data should be taken into account for the choice of DMARD. In trials, the extent of psoriasis is measured through composite indices such as the PASI (Psoriasis Area and Severity Index). However, these recommendations are mainly aimed at rheumatologists, who usually do not measure psoriasis by PASI. The extent of psoriasis (percentage of skin body surface) is an indicator of psoriasis severity; however, there are cases when the extent may not be important, but the consequences on quality of life are important (eg, face/hand/genital involvement). Therefore, we suggest considering the choice of DMARD in the light of patient-perceived severity of psoriasis (through its impact on quality of life). This would correspond in dermatological terms to moderate to severe psoriasis. Better understanding the patients' perspective in PsA was set on the research agenda.
Local and systemic glucocorticoids
Glucocorticoid injections may be a useful adjunctive therapy in localised disease (oligoarticular forms, enthesitis or dactylitis).53 Intra-articular steroids are efficacious for mono/oligoarthritis or single joint flares, in otherwise well-controlled polyarthritis. Glucocorticoid injections may also be performed in dactylitis (tendon sheath/peritendinous injections) and in entheseal areas, for example, elbow, or retrocalcaneal bursa in Achilles enthesitis.20
Systemic steroids in psoriasis are feared, as it has been reported that skin flares may occur.54 However, the literature search performed to inform the present recommendations found few data (other than case reports) supporting the assertion that skin psoriasis may flare in glucocorticoid-treated PsA patients.31 Furthermore, registry data reveal that systemic steroids are, in fact, widely used in PsA (up to 30% of patients in the German national database), usually at low doses (≤7.5 mg/day),55 although there is no evidence from clinical trials on the efficacy of systemic glucocorticoids in PsA (level of evidence 4; table 1). Nevertheless, the task force considered that systemic glucocoritcoids are a therapeutic option, although they should be used with caution, keeping in mind the possibility of a skin flare. Greater caution should perhaps be used in patients with severe/extensive skin involvement, and/or not taking concomitant DMARD (expert opinion). This stems partly from the observation that PASI scores in PsA trials are generally much lower than in clinical trials of psoriasis.
In PsA as in other chronic diseases, the long-term use of glucocorticoids can lead to major adverse events;56 therefore, thought should be given to tapering glucocorticoids when feasible. When tapering, attention should be paid to the potential worsening of skin disease (rebound). The safety of glucocorticoids is also an important aspect of the EULAR recommendations on the management of glucocorticoid therapy.57
TNF inhibitors
This recommendation deals with patients for whom a synthetic DMARD (usually methotrexate because of its effects on joints and skin, but also leflunomide, sulfasalazine or others, see above) is not efficacious or not well tolerated. A patient should be considered a treatment failure when in spite of therapy for a length of time appropriate to the drug profile (usually 3–6 months), the patient fails to demonstrate achievement of the treatment target low disease activity. Treatment failure could not be defined more precisely given the lack of appropriate trials. In these patients TNF inhibitor treatment (with or without continuation of previous synthetic DMARD therapy) can be considered if the disease is active, ie, if there is evidence of active arthritis in terms of swollen joints and/or at least moderate disease activity by a composite disease activity measure and/or active disease with impaired function or quality of life. However, the definition of (residual) active disease is still pending in PsA, and is part of the research agenda.
This item refers to the use of biological agents. TNF inhibitors (adalimumab, etanercept, golimumab and infliximab) have demonstrated efficacy in PsA, both for skin and joint involvement, as well as in preventing radiographic damage.2 5 6 16 31 There were no evident differences regarding the efficacy of the different TNF inhibitors on the joints, although no head-to-head comparisons exist.58 However, for skin involvement, it seems that the efficacy of the TNF receptor construct etanercept on psoriasis may be lower, or at least be of slower onset, than for the antibodies targeting TNF (although there are, again, no head-to-head comparisons available).2 Also, ustekinumab was tested against etanercept in patients with psoriasis and demonstrated superior skin outcomes after 12 weeks.59 This information may be taken into consideration for the choice of TNF inhibitors in patients with clinically significant skin involvement.
Other biological agents have been assessed in PsA but there were too few data (ustekinumab, rituximab, abatacept, tocilizumab) and/or too low response rates (alefacept) to consider these drugs in this recommendation.31 The list of biological agents must of course be updated regularly, as new data are published.
To date, there are no data showing the superiority of TNF inhibitors in combination with synthetic DMARD versus TNF inhibitor monotherapy.3 5 31 Of note, in all trials of TNF inhibitors in PsA, methotrexate was allowed but not required, and approximately half the patients in these studies took TNF inhibitor monotherapy without concomitant methotrexate. The data for patients receiving and not receiving methotrexate were comparable.60 This was added to the research agenda. TNF inhibitors also improve enthesitis and axial disease (see also recommendations 6 and 7).
Regarding the safety of biological agents in PsA, there are significantly fewer data available than in RA.31 61,–,63 Indeed, there are few data available regarding even the background risk of infectious disease morbidity in PsA/psoriasis. Given the paucity of safety data on biological agents in PsA, one option is to extrapolate from either the RA or psoriasis experience with these therapies. In RA, there is now a wealth of safety data from randomised controlled trials and, most importantly, from large observational studies (registry data). In comparison, however, there is a lack of long-term safety data on TNF inhibitors in the psoriasis setting. Data to date suggest that the biological agents are likely to have a similar risk profile in PsA and psoriasis with regard to serious adverse events (eg, elevated infectious risk), but that the absolute risks of infection and malignancy (and perhaps other serious adverse events) are probably lower than in RA, due to underlying pathophysiological differences between RA and psoriasis. Long-term registry or other observational data will be important to establish the safety profile of these drugs in PsA or psoriasis. However, to date, the literature review did not find any apparent specific safety signals of concern in PsA, compared with RA. As stated in this recommendation, in patients with active arthritis, TNF inhibitors should be ‘considered’; of course, we recommend careful assessment of potential contraindications to TNF inhibitors and careful weighing of the benefit/risk/cost ratio before any treatment decision is made (please see also recommendation 10, see table 1).
Enthesitis and/or dactylitis and TNF inhibitors
This recommendation deals with the subgroup of patients with predominant enthesitis/dactylitis. In these patients, TNF inhibitors might be considered even if no synthetic DMARD have been tried, after failure of local or non-specific anti-inflammatory therapy, because DMARD have not been proved efficacious, even though they have been little studied.31 There are very few data regarding this subgroup of patients, but the efficacy of TNF inhibitors on these manifestations of PsA has been reported in several trials, generally as secondary endpoints.31 The diagnosis of enthesitis can be challenging; several instruments have been proposed for the assessment of enthesitis.14 There is no data-driven definition of ‘active’ disease in this case; we suggest to focus on quality of life in this regard. Therefore, physicians must apply clinical judgement when faced with dactylitis/enthesitis, aiming at the improvement of physical disability and quality of life, which can be severely impaired in some situations, such as enthesitis of the Achilles tendon. The group is of course not suggesting that all such patients should be treated with TNF inhibitors, as this would lead to the inappropriate use of TNF inhibitors in some situations. This recommendation, and recommendation 8, received the lowest agreement within the group (see table 1).
Axial disease and TNF inhibitors
Recommendation 7 deals with the subgroup of patients who have predominant axial disease. In these patients, TNF inhibitors can be considered even if no synthetic DMARD have been tried. This was extrapolated from data in ankylosing spondylitis,27 which also included patients with psoriasis. In PsA, the efficacy of TNF inhibitors on axial disease has been reported only in observational studies.64 Active disease, here, refers to Bath ankylosing spondylitis disease activity index (BASDAI) levels equal to or above 4.65 66 The group suggests following established recommendations for ankylosing spondylitis.65 66
TNF inhibitors exceptionally for a very active patient naive of disease-modifying treatment
In certain, very rare and thus highly selected patients, there may be a place for TNF inhibitors as first-line treatment. This recommendation is mere expert opinion because there are no data in this regard. In TNF inhibitor trials, some patients were in fact DMARD-naive but the results regarding efficacy and safety have never been presented separately for these patients.
Some criteria to help select the patients who may need TNF inhibitors early were discussed, such as contraindications to synthetic DMARD or poor prognostic factors in conjunction with severe skin disease or severe extra-articular manifestations with a professional need for very rapid improvement. This item received the second lowest agreement and warrants further research.
Switching to another TNF inhibitor agent
This recommendation is derived from some studies indicating a good efficacy of a second TNF inhibitor in PsA.67 68 The recommendation is also extrapolated from the data available regarding switches in RA.69 To date, the group could not identify randomised trials in which switching was appropriately compared between different TNF inhibitors, and therefore a preference for a particular TNF inhibitor in this situation cannot be established.
Accounting for comorbidities and safety issues
Treatment of patients with PsA should be tailored according to the current manifestations of the disease (such as peripheral joint, skin, axial, entheseal symptoms or dactylitis), the level of current symptoms, clinical findings and prognostic indicators; but also according to the general clinical status (age, gender, comorbidity, concomitant medications, psychosocial factors). For each treatment, a careful choice must be made, taking into account efficacy, safety and cost issues.
The recommendations reflect the balance of efficacy and safety and do not deal in detail with the toxicity of DMARD and biological agents. In this regard, the most important pieces of information are provided in the separate publication on the systematic literature reviews,31 which indeed are part and parcel of these recommendations, because they provide their bases. Therefore, the recommendations shown here primarily deal with agents whose toxicity appears to be manageable, assuming that users are either aware of the respective risks or will adhere to the information provided in the package inserts. When deemed of particular importance, safety issues were especially mentioned (liver toxicity on methotrexate, infections with biological agents), but clearly safety has not been comprehensively addressed.
Some comorbidities require further exploration and were put on the research agenda; these include the cardiovascular risk in PsA, which has been little studied: cardiovascular diseases and their risk factors appear more common in patients with PsA than in controls.70,–,72 The contribution of alcohol consumption, type II diabetes, obesity and steatohepatitis to hepatotoxicity in PsA is also a relevant question, particularly in the light of the high prevalence of methotrexate use in this disease.50
Graphic representation of the recommendations
The recommendations and the algorithm they imply are summarised in figure 1.
The figure attempts to capture the most important aspects of the recommendations and explanatory text. While it does not account for all therapeutic eventualities nor ought to be representative for all variations of the disease, the relatively high level of agreement obtained within the group (see supplementary text 3, available online only) suggests that it has validity for a large majority of patients with PsA.
Research agenda
One of the objectives of this initiative was to develop a research agenda, to guide future research funding by EULAR. An extensive research agenda was developed and the summary is presented in table 2.
Research agenda for PsA
Discussion
The task force has formulated 10 statements on the management of PsA. These statements were based on systematic literature reviews, but also on expert opinion with subsequent consensus finding on the wording of the recommendations. By this process and by stating the respective levels of evidence and strength of recommendation for each item, the committee adhered to the EULAR standardised operating procedures for the development of recommendations. Moreover, when evidence was lacking and the task force had to use only expert opinion, a research agenda was formulated to expedite the generation of evidence in the future.
The reasoning behind each statement and, particularly, behind the recommendations' specific wordings is explained in detail in the Results section. Importantly, the overall agreement with these statements, assessed anonymously several weeks after their formulation, was very high.
It is worth noting that the task force felt the best evidence for efficacy was available for three synthetic DMARD (methotrexate, leflunomide and sulfasalazine; statement 2) and four TNF inhibitors (adalimumab, etanercept, golimumab, infliximab; statements 5–7). Some additional synthetic DMARD agents are mentioned in the text only, because although effective in RA, their efficacy appeared to be lower or toxicity higher than that of other agents in their general class, and the data were often sparse.
The task force was convinced that modern therapy of PsA should be target oriented and governed by a strategic treatment approach. Remission or at least low disease activity, if remission cannot be attained, was affirmed as the therapeutic goal, in line with recommendations in RA.30 However, the literature review found few data regarding the natural history, prognosis, treatment targets and treatment strategies in PsA,31 contrary to the situation in RA. Still, there are some data supporting low disease activity or minimal disease activity as a therapeutic goal.75,–,79 Furthermore, monotherapy with all TNF inhibitors usually leads to complete cessation of erosion progression at the group level; these agents appear to induce an arrest in disease progression.31 Finally, treatment targets constitute yet another part of the research agenda.
Glucocorticoids had a special place in the discussion (statement 4). Although there is a fear of psoriasis flares related to systemic glucocorticoids in PsA (and especially their cessation), we did not find supportive data in this regard, and the experience of rheumatologists and dermatologists may be different, possibly related to different forms of PsA (with low to moderate skin involvement on the one hand vs important or severe skin involvement on the other). Indeed, the experts in the group did not report their patients having experienced skin flares; and registry data show us that systemic glucocorticoids are in fact widely used at low doses in PsA.55
The present EULAR recommendations have been developed by experts (mainly rheumatologists, a dermatologist, an infectious disease specialist, a health professional and two patient representatives) from 14 European countries and the USA. It is therefore a true international document, meant to serve physicians in Europe and the world, although we are aware of the fact that not all agents mentioned here are available or accessible everywhere.
Beyond physicians, the document is also aimed at patients with PsA so they are informed on current treatment goals, strategies and opportunities. Importantly, patient representatives also participated in the task force. Finally, this document is also meant to inform officials in governments, social security agencies and reimbursement agencies.
The recommendations on the management of PsA provided here by the EULAR task force, when compared with those provided by GRAPPA,20 are of lesser complexity and thus more easy to adhere to; moreover, they cover additional aspects of drug therapies as well as therapeutic strategies and goals. A graphic representation (see figure 1) captures most of the important items.
The limitations of the present recommendations include that juvenile PsA and patients with psoriasis and some joint pain but without a definitive diagnosis of PsA are outside their scope; that topical treatments including topical NSAID and topical steroids are not taken into account and that non-pharmacological therapy is not considered. However, the group did state that non-pharmacological therapy was an important component of PsA treatment.
These recommendations reflect the current state of evidence and thought in the area of PsA management. The five overarching principles and 10 practical recommendations have a high level of face validity and feasibility, and the development of a scientific agenda will guide future research. However, several of the recommendations are strongly based on expert opinion, which in turn is based on clinical practice that has emerged in certain institutions, rather than available evidence. This is due to the paucity of data in the field of PsA. Therefore, the research agenda developed is extensive.
Finally, as has been the case over the past decade, it is to be anticipated that new data on existing or new drugs or therapeutic strategies will emerge over the next few years. Therefore, we will carefully observe the developments in the field and assume that an amendment of these recommendations may be needed in 2–5 years.
References
Supplementary materials
Supplementary Data
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Footnotes
LG and JSS contributed equally to the study (joint first authors)
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Funding This study was supported by EULAR.
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Competing interests The following authors declare that they have no potential conflict of interest: CG-V, ZA, HD, MM, DB. The following authors declare a potential conflict of interest having received grant support and/or honoraria for consultations and/or for presentations as indicated: LG: Abbott, BMS, Chugai, MSD, Pfizer, Roche, Schering-Plough, UCB, Wyeth; JSS: Abbott, BMS, Chugai, MSD, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Wyeth; HM-O: Abbott, Centocor, Chugai, MSD, Pfizer; DVDH:Abbott, Amgen, Astra Zeneca, BMS, Centocor, Chugai, Eli lilly, GSK, Merck, Novartis, Otsuka, Pfizer, Roche, Schering-Plough, UCB, Wyeth; OF: Abbott, BMS, Pfizer, Merck, UCB; DA: Abbott, Roche, Schering-Plough, BMS, UCB, Sanofi-Aventis; MB: Roche, Abbott, BMS, Wyeth; PB: Abbott, Pfizer, Roche, Sonobite, Wyeth; JB: Abbott, Centocor,Chugai, Merck, MSD, Novartis, Pfizer, Roche, UCB; FCB: Abbott, Schering-Plough, Wyeth; GB: Abbott, BMS, Chugai, MSD, Pfizer, Roche, Sanofi-Aventis, Schering Plough, UCB, Wyeth; JDC: Abbott, BMS, MSD, Roche; MdeW: Abbott, Roche, Wyeth; KdeV: Abbott, BMS, Celgene, Novartis, Pfizer, UCB; MD: Abbott, BMS, Novartis, Nordic Pharma, Pfizer, Roche, UCB, Wyeth; PH: Abbott, BMS, Pfizer, Schering Plough, UCB, Wyeth; AK: Abbott, Amgen, Centocor, Roche, UCB; TKK: Abbott, BMS, MSD, Pfizer, Roche, UCB; RL: Abbott, Amgen, BMS, Centocor, Merck, Pfizer, Schering-Plough, UCB, Wyeth; TL: Abbott, Almirall-Hermal, Basilea, BiogenIdec, Ceries, Galderma, Innéov, Janssen-Cilag, Leo Pharma, Maruho, MSD, Novartis, Palau Pharma, Pfizer, Shionogi, Symrise, Wolff; DMcG: Merck, Pfizer, Roche, Schering-Plough, Wyeth; INMcH: Abbott, Schering-Plough; IBMcI: Abbott, BMS, Merck, Pfizer, Roche; CR: Abbott, Amgen, BMS, Centocor, Pfizer, UCB; JS: Abbott, BMS, Centocor, MSD, Pfizer, Roche, Sanofi-Aventis, UCB; PPT: Abbott, Amgen, Centocor, Pfizer, Schering-Plough, Wyeth; GV: Abbott, BMS, Roche, MSD, Schering-Plough, UCB, Wyeth; JV: Abbott, BMS, MSD, Pfizer, Roche, UCB; KLW: Genentech, Wyeth; AZ: Abbott, Amgen, BMS, Essex/Schering-Plough, Merck, Pfizer, Roche, Sanofi-Aventis, UCB, Wyeth; PE: Abbott, BMS, Centocor, Pfizer, Roche, Sanofi-Aventis, Schering-Plough,UCB, Wyeth.
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Provenance and peer review Not commissioned; externally peer reviewed.