Guideline for anti-TNF-{alpha} therapy in psoriatic arthritis

S. Kyle, D. Chandler1, C. E. M. Griffiths2, P. Helliwell3, J. Lewis, I. McInnes4, S. Oliver5, D. Symmons6 and N. McHugh on behalf of the British Society for Rheumatology Standards Guidelines Audit Working Group (SGAWG)

Royal National Hospital for Rheumatic Diseases, Bath, 1 Board of Trustees and Management Committee, Psoriatic Arthropathy Alliance, 2 University of Manchester and Salford Royal Hospitals NHS Trust, Manchester, 3 University of Leeds, Leeds, 4 Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, 5 RCN Rheumatology Steering Committee, and 6 East Cheshire NHS Trust and ARC Epidemiology Unit, University of Manchester, Manchester, UK.

Correspondence to: Dr. Neil McHugh, Royal National Hospital for Rheumatic Diseases, Upper Borough Wells, Bath, BA1 IRL. E-mail: Neil.McHugh{at}rnhrd.tr.swest.nhs.uk

Scope and purpose

Background
Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy with a prevalence between 0.1 and 1% and an equal sex distribution [1]. Psoriasis affects 1–3% of the population, with approximately a third of patients developing PsA [2]. The course of PsA is variable and unpredictable ranging from a mild non-destructive disease to a severe debilitating erosive arthropathy. Erosive and deforming arthritis occurs in 40–60% of PsA patients (followed at hospital clinics), and is progressive from within the first year of diagnosis [3, 4].

The classification of PsA is an area of ongoing international discussion. The five subgroups proposed by Moll and Wright [5] are still frequently used, although considerable overlap between these groups is now recognized. For the purpose of these guidelines we have differentiated between peripheral joint disease in PsA and axial disease alone. Psoriatic spondylitis is similar to ankylosing spondylitis (AS), although it is often less symptomatic, less limiting and radiologically tends to be asymmetrical and less severe [6]. However, despite these differences, until such time as there is evidence that psoriatic spondylitis responds in a different manner from AS to TNF-{alpha} blockade, we recommend that AS guidelines for anti-TNF-{alpha} treatment are used for the management of psoriatic spondylitis [7].

Much like rheumatoid arthritis (RA), PsA can lead to chronic joint damage, increased disability [8, 9] and increased mortality [10, 11]. Social and financial implications are also important, both in terms of personal loss and the impact of direct (e.g. medical care) and indirect (e.g. inability to work) costs to the state.

It is recognized that psoriasis is associated with an increased risk of non-melanoma skin cancers [12], most probably a result of excessive exposure to sunlight and enhanced by use of psoralen and ultraviolet A (PUVA) therapy [13]. The guidelines recognize that these risks that may be potentiated by anti-TNF-{alpha} treatment and specific recommendations have been made accordingly (see sections headed Exclusion criteria and Monitoring and Toxicity).

Need for guideline
Although PsA was once thought to be a benign condition, it is now well recognized as a potentially destructive erosive arthropathy [3, 4, 14]. Traditional standard therapy is aimed at symptomatic relief with the introduction of second-line agents for more severe cases. However, most longitudinal studies of PsA have shown steady progression of the condition despite use of such medication. Disease-modifying anti-rheumatic drugs (DMARDs) used to treat RA are also used in PsA, but there is a serious deficit of therapeutic trials in PsA. A Cochrane systematic review concluded that only two agents had documented efficacy in PsA: sulphasalazine and high-dose parenteral methotrexate [15] (the latter at a dose considered too toxic by today's standards).

Recently there has been interest in the pivotal role that TNF-{alpha}, a proinflammatory cytokine, plays in inflammation of skin and synovium [16] and it is a logical target for treatment in RA. Preliminary studies and trials have shown that TNF-{alpha} blockade is effective in the treatment of PsA [17, 18]. In 2003 etanercept was licensed for treatment of PsA and it is expected that other TNF-{alpha} blockers, such as infliximab, will be licensed for the treatment of PsA.

Cost implications
TNF-{alpha} blockers have the potential to provide symptomatic relief and help prevent disease progression in PsA. Although these drugs are relatively expensive, concerns over an increased drug budget must be balanced against the potential long-term cost savings. At the present time there are no health economic studies concerning the role of TNF-{alpha} blockade in PsA. However, possible long- term benefits include:

In order to achieve maximum benefit to patients with PsA within a limited health resource, there is a need for evidence-based guidelines in the prescribing of TNF-{alpha} blockers for this condition.

Remit
Objectives
These guidelines offer systematic and reviewed recommendations for the prescribing of licensed anti-TNF-{alpha} therapies in adult PsA patients with peripheral joint involvement. The guidelines provide a stepwise management plan giving clear inclusion/exclusion and response criteria. The guidelines also set out monitoring requirements.

Target audience
The guidelines have been developed to give assistance to rheumatologists and involved prescribing clinicians. They will also assist nurses in the application, assessment and monitoring of the treatment.

The guidelines have been drawn from the evidence base available, and in areas of insufficient evidence consensus opinion has been sought and is clearly documented.

The remit of these guidelines does not include:

Stakeholder involvement

The guidelines have been developed by a multidisciplinary Working Party set up by the BSR. Any conflicts of interest among the Working Party were fully declared.

The guidelines were presented for comment at the 20th BSR Annual Meeting (20–23 April 2004) prior to submission for publication.

Rigour of development

Literature review
The evidence in these guidelines was compiled from a comprehensive literature search, including electronic bibliographic databases (Medline, Embase) and systematic review databases (Cochrane) back to 1990. Key words were the following: psoriasis; arthritis; anti-TNF-{alpha}; biologics; etanercept; infliximab; trials.

No related guidelines were found in other guideline databases (e.g. RCP, SIGN, NICE).

Level of evidence
The literature was reviewed and quality of evidence was graded by the Working Party according to the Royal College of Physicians’ ‘Concise Guidance to Good Practice’. Grading of recommendation was given as follows:

Updating
The Working Party acknowledges that there is a lack of high-quality evidence on which to base the recommendations.

These guidelines cover a rapidly evolving area of therapeutic intervention.

Guidelines for anti-TNF-{alpha} therapy in adults with psoriatic arthritis

Treatment algorithm for psoriatic arthritis (Fig. 1)
Standard therapy
Management of PsA is aimed at suppressing joint, tendon and entheseal inflammation. NSAIDs and corticosteroid injections remain an important initial intervention but current practice is aimed at early diagnosis and early use of potential DMARDs to suppress persistent inflammation. Sulphasalazine or methotrexate is widely used in clinical practice as DMARD therapy. Efficacy has been proven for sulphasalazine, and methotrexate is being further evaluated in a current multicentre UK randomized controlled trial. Patients with a poor clinical response are changed to an alternative DMARD or are commenced on combination therapy.



View larger version (40K):
[in this window]
[in a new window]
 
FIG. 1. Treatment algorithm for PsA patients.

 
Failure to respond to therapy
In order to fail standard therapy patients should have active disease and have had adequate therapeutic trials of at least two of the above standard DMARDs individually or in combination. An adequate therapeutic trial is defined as:



View larger version (45K):
[in this window]
[in a new window]
 
FIG. 2. Algorithm of patient's considerations and choices.

 
Licensed anti-TNF-{alpha} therapy
At present only one compound is licensed for use in active PsA in the UK. Etanercept (Enbrel; Wyeth) is a recombinant human TNF receptor:Fc fusion protein consisting of a dimer of the extracellular portion of two p75 receptors fused to the Fc portion of human IgG1. Etanercept is administered subcutaneously at a dose of 25 mg twice weekly.

Infliximab (Remicade; Schering-Plough) is a chimeric human–murine monoclonal antibody usually administered by slow intravenous infusion at weeks 0, 2 and 6 and 8-weekly thereafter at a dose of 5 mg/kg in combination with methotrexate. Despite a supporting body of evidence [22–26], infliximab is not currently licensed for PsA.

NICE is currently undertaking a technology appraisal of etanercept and infliximab in PsA.

Exclusion criteria
Exclusion criteria have been adapted from those used for anti-TNF-{alpha} treatment in RA and are shown in Appendix 2 (may be viewed at Rheumatology Online).

The Working Party recommends specific caution in:

In accordance with the updated BSR guidelines for prescribing TNF-{alpha} blockers in adults with RA [28], caution is recommended in:

Clinical efficacy
Active disease. The most widely used method for assessing peripheral joint disease activity in PsA is the American College of Rheumatology (ACR) joint count, which in some studies has been modified for PsA [17, 18]. There has been some validation of the ACR joint count when applied to patients with PsA [31]. The DAS 28 is an instrument used for assessing the severity of RA but may not be appropriate for PsA as it does not include some of the joints that are frequently involved (e.g. distal interphalangeal joints). Published evidence has used tender and swollen joint counts as a marker of disease activity.

Table 1 shows the eligibility criteria for entry into clinical trials and the median or mean scores for baseline tender and swollen joints.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Eligibility criteria for entry into PsA trials and the median or mean baseline tender and swollen joint scores

 
All clinical trials show a far higher mean or median tender and swollen joint count than the required inclusion criteria. However, setting a high threshold for involved joint count as an inclusion criterion for anti-TNF-{alpha} treatment would exclude a large number of patients with PsA from effective treatment, including those patients with resistant oligoarthritis. At present there is no evidence to differentiate between treatment options for mono/oligo-arthritis or polyarthritis in PsA patients.

Two specific clinical features of PsA, dactylitis and enthesitis, proved an area of debate. How could these entities be included in a PsA activity score? At present there is no validated measure for clinical assessment of dactylitis. Although scoring indices exist for enthesitis [32, 33] none have been proven for PsA. The Working Party came to the following consensus opinions:

Response to therapy
Joint response. Two main instruments have been used for measuring clinical response in PsA, the PsARC and the ACR20 (including ACR50 and ACR70).

The PsARC is a response criterion adapted from the Veterans Affairs Cooperative Study of sulphasalazine [34].

Response is defined as improvement in two factors (with at least one being a joint score) with worsening of none of the following four factors:

Although a large placebo response is often seen in trials of therapies for PsA, trials of anti-TNF-{alpha} treatment have shown a statistically significant difference in the numbers achieving the PsARC and ACR 20 compared with placebo (Table 2).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Clinical responses in anti-TNF-{alpha} trials

 
Skin response. From the patient's perspective, PsA and psoriasis are seen as different manifestations of the same condition. Therefore, the impact of any treatment for PsA should include a skin assessment. The psoriasis area and severity index (PASI) is a scoring system to evaluate baseline and response to therapy in psoriasis (Appendix 4; may be viewed at Rheumatology Online). In the clinical trials of biologic therapies in PsA it has been proved to be a reliable measure of improvement in psoriasis [31].

Quality of life. The Working Party felt further information on quality of life should be obtained using the SF-36 General Health Survey. These data can be adjusted to Quality-Adjusted Life Years, a useful outcome for the required health economic studies in PsA.

Radiological outcome. Despite evidence that radiographic progression was inhibited by etanercept at 12 months in patients with PsA (A) [18], the Working Party believes that the measures for assessing radiographic progression in PsA need further validation and are beyond the scope of these guidelines and should be reserved for clinical trials only.

Withdrawal of therapy
As for the anti-TNF-{alpha} for RA guidelines treatment will be withdrawn in the event of adverse events:

Assessment
Assessment of PsA patients for anti-TNF-{alpha} treatment will be based on those used for RA and should include a full musculoskeletal history and examination, a clinical assessment of cardiopulmonary status and further investigations if required, as well as the following salient points (specific recommendations for PsA patients are in italics).

Monitoring and toxicity
Table 3 shows a full list of required data collection at baseline, 3 months, 3 months and thereafter at 3-monthly intervals. After the first 6 months monitoring data can be collected simultaneously with that required for a register.


View this table:
[in this window]
[in a new window]
 
TABLE 3. Required data collection at baseline, 3 months, 6 months and thereafter 6-monthly

 
Table 4 shows the currently required data collection for the BSR Biologics Register.


View this table:
[in this window]
[in a new window]
 
TABLE 4. Data collection required for register

 
Data collection

Blood tests (Table 3)

Central Biologics Register. There is evidence that the background risk of patients with PsA with respect to mortality [10, 11], malignancy [12, 13] and cardiovascular disease is not the same as that of patients with RA. The spectrum of adverse events on biologic therapy may also differ between the two diseases.

A biologics register for patients being prescribed anti-TNF therapies for PsA does not currently exist. However, the working group recommends that such a register is set up for these patients, and the BSR is currently pursuing this. In the meantime, the BSR currently recommends that data collection, including updated dosage, outcome and toxicity information, is conducted at a local level. Adverse incidents/serious side-effects arising whilst on anti-TNF therapy should be notified immediately via the yellow card system.

The information required for PsA patients on the Register will be the same as for RA patients on the BSR Biologics Register, the Working Party suggesting the following amendments:

Audit. Local audit of prescribing and monitoring will be required for adherence to the Register and BSR blood monitoring guidelines. Auditing will also be required when NICE has reviewed and commissioned guidance for anti-TNF-{alpha} therapy in PsA patients.

Supplementary information. Supplementary documents downloadable from the BSR website (www.rheumatology.org.uk) which health professionals may find useful include:

Conflict of interest

The Working Party was set up independently of any input or funding from the manufacturers of the new biologic therapies.

Members of the Working Party were asked to clarify their relationships with the manufacturers of biologic therapies for PsA. Members were asked to declare if they, as individuals, had been sponsored to attend scientific or other meetings in the past 24 months or if they had a direct financial stake in the manufacturing companies. They were also asked if their units had received funding from the manufacturers to take part in clinical trials of the biologic therapies for psoriatic arthritis. Organizations were asked to declare if they had received sponsorship from manufacturers of the biologic therapies for activities related to the new therapies (either educational or promotional) or for activities not related to the new therapies.

The following replies were received.

Supplementary data

{keh514i2}

    Supplementary data are available at Rheumatology

    Online.

References

  1. Shbeeb M, Uramoto KM, Gibson LE, O’Fallon WM, Gabriel SE. The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982–1991. J Rheumatol 2000;27:1247–50.[ISI][Medline]
  2. Gladman DD. Psoriatic arthritis. Baillieres Clin Rheumatol 1995;9:319–29.[ISI][Medline]
  3. Gladman DD, Stafford-Brady F, Chang CH, Lewandowski K, Russell ML. Longitudinal study of clinical and radiological progression in psoriatic arthritis. J Rheumatol 1990;17:809–12.[ISI][Medline]
  4. McHugh NJ, Balakrishnan C, Jones SM. Progression of peripheral joint disease in psoriatic arthritis. Rheumatology 2003;42:778–83.[Abstract/Free Full Text]
  5. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973;3:55–78.[CrossRef][Medline]
  6. Helliwell PS, Hickling P, Wright V. Do the radiological changes of classic ankylosing spondylitis differ from the changes found in the spondylitis associated with inflammatory bowel disease, psoriasis, and reactive arthritis? Ann Rheum Dis 1998;57:135–40.[Abstract/Free Full Text]
  7. Keat A, Barkham N, Bhalla A, Gaffney K, Marzo-Ortega H, Paul S, Rogers F, Somerville M, Sturrock R, Wordsworth P. BSR Guideline for anti-TNF-{alpha} therapy in ankylosing spondylitis. Rheumatology 2004. In press.
  8. Sokoll KB, Helliwell PS. Comparison of disability and quality of life in rheumatoid and psoriatic arthritis. J Rheumatol 2001;28:1842–6.[ISI][Medline]
  9. Husted JA, Gladman DD, Farewell VT, Cook RJ. Health-related quality of life of patients with psoriatic arthritis: a comparison with patients with rheumatoid arthritis. Arthritis Rheum 2001;45:151–8.[CrossRef][Medline]
  10. Wong K, Gladman DD, Husted J, Long J, Farewell VT. Mortality studies in psoriatic arthritis. Results from a single clinic. I. Causes and risk of death. Arthritis Rheum 1997;40:1868–72.[ISI][Medline]
  11. Gladman DD, Farewell VT, Wong K, Husted J. Mortality studies in psoriatic arthritis: results from a single outpatient center. II. Prognostic indicators for death. Arthritis Rheum 1998;41:1103–10.[CrossRef][ISI][Medline]
  12. Paul CF, Ho VC, McGeown C et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol 2003;120:211–6.[CrossRef][ISI][Medline]
  13. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA). A meta-analysis. Arch Dermatol 1998;134:1582–5.[Abstract/Free Full Text]
  14. Torre AJ, Rodriguez PA, Arribas CJ, Ballina GJ, Riestra NJ, Lopez LC. Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients. Br J Rheumatol 1991;30:245–50.[ISI][Medline]
  15. Jones G, Crotty M, Brooks P. Interventions for psoriatic arthritis. Cochrane Database Syst Rev CD000212, 2000
  16. Ritchlin C, Haas-Smith SA, Hicks D, Cappuccio J, Osterland CK, Looney RJ. Patterns of cytokine production in psoriatic synovium. J Rheumatol 1998;25:1544–52.[ISI][Medline]
  17. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000;356:385–90.[CrossRef][ISI][Medline]
  18. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264–72.[CrossRef][ISI][Medline]
  19. Spadaro A, Riccieri V, Sili-Scavalli A, Sensi F, Taccari E, Zoppini A. Comparison of cyclosporin A and methotrexate in the treatment of psoriatic arthritis: a one-year prospective study. Clin Exp Rheumatol 1995;13:589–93.[ISI][Medline]
  20. Cuchacovich M, Soto L. Leflunomide decreases joint erosions and induces reparative changes in a patient with psoriatic arthritis. Ann Rheum Dis 2002;61:942–3.[Free Full Text]
  21. Kaltwasser JP, Nash P, Gladman D et al. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 2004;50:1939–50.[CrossRef][ISI][Medline]
  22. Antoni C, Dechant C, Hanns-Martin Lorenz PD et al. Open-label study of infliximab treatment for psoriatic arthritis: clinical and magnetic resonance imaging measurements of reduction of inflammation. Arthritis Rheum 2002;47:506–12.[CrossRef][Medline]
  23. Feletar M, Brockbank JE, Schentag CT, Lapp V, Gladman DD. Treatment of refractory psoriatic arthritis with infliximab: a 12 month observational study of 16 patients. Ann Rheum Dis 2004;63:156–61.[Abstract/Free Full Text]
  24. Cauza E, Spak M, Cauza K, Hanusch-Enserer U, Dunky A, Wagner E. Treatment of psoriatic arthritis and psoriasis vulgaris with the tumor necrosis factor inhibitor infliximab. Rheumatol Int 2002;22:227–32.[CrossRef][ISI][Medline]
  25. Salvarani C, Cantini F, Olivieri I et al. Efficacy of infliximab in resistant psoriatic arthritis. Arthritis Rheum 2003;49:541–5.[CrossRef][Medline]
  26. Provenzano G, Termini A, Le Moli C, Rinaldi F. Efficacy of infliximab in psoriatic arthritis resistant to treatment with disease modifying antirheumatic drugs: an open pilot study. Ann Rheum Dis 2003;62:680–1.[Free Full Text]
  27. Mody GM, Parke FA, Reveille JD. Articular manifestations of human immunodeficiency virus infection. Best Pract Res Clin Rheumatol 2003;17:265–87.[CrossRef][ISI][Medline]
  28. Ledingham J, Deighton C. Updated BSR guideline for prescribing TNF-{alpha} blockers in adults with rheumatoid arthritis. Rheumatology 2004. In press.
  29. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133–40.[Abstract/Free Full Text]
  30. Anker SD, Coats AJ. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 2002;86:123–30.[CrossRef][ISI][Medline]
  31. Gladman DD, Helliwell P, Mease PJ, Nash P, Ritchlin C, Taylor W. Assessment of patients with psoriatic arthritis: a review of currently available measures. Arthritis Rheum 2004;50:24–35.[CrossRef][ISI][Medline]
  32. Mander M, Simpson JM, McLellan A, Walker D, Goodacre JA, Dick WC. Studies with an enthesis index as a method of clinical assessment in ankylosing spondylitis. Ann Rheum Dis 1987;46:197–202.[Abstract]
  33. Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A et al. Assessment of enthesitis in ankylosing spondylitis. Ann Rheum Dis 2003;62:127–32.[Abstract/Free Full Text]
  34. Clegg DO, Reda DJ, Mejias E et al. Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 1996;39:2013–20.[ISI][Medline]
  35. Antoni C, Kavanaugh A, Kirkham B. The infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 2002;46:S381.
  36. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001;357:1842–7.[CrossRef][ISI][Medline]
  37. Leonardi CL, Powers JL, Matheson RT et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003;349:2014–22.[Abstract/Free Full Text]
  38. Rich P, Scher RK. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. J Am Acad Dermatol 2003;49:206–12.[CrossRef][ISI][Medline]
  39. Williamson L, Dalbeth N, Dockerty JL, Gee BC, Weatherall R, Wordsworth BP. Extended report: nail disease in psoriatic arthritis—clinically important, potentially treatable and often overlooked. Rheumatology 2004;43:790–4.[Abstract/Free Full Text]
  40. Fredriksson T, Pettersson U. Severe psoriasis—oral therapy with a new retinoid. Dermatologica 1978;157:238–44.[ISI][Medline]
Submitted 20 August 2004; revised version accepted 9 November 2004.