CME Rheumatology

Management of Medical management appears to have Rheumatologists now use DMARDs as most to offer in the early stages of the early as possible in the natural history of disease, with the aim of preventing joint the disease. Recent guidelines for the early rheumatoid damage and loss of function. Simple management of RA published by the analgesics and non-steroidal anti-inflam- American College of Rheumatology arthritis matory drugs (NSAIDs) can be used for Subcommittee on Rheumatoid Arthritis pain control but they do not control the Guidelines (2002 update)4 state that: inflammation and joint damage. Shirish Dubey MBBS MRCP(I), Specialist the majority of patients with newly diag- Other drugs, used for control of sys- Registrar, Rheumatology nosed RA should be started on a temic inflammation, are known as dis- disease-modifying antirheumatic drug Karl Gaffney FRCP FRCP(I), Consultant ease-modifying antirheumatic drugs Rheumatologist within three months of the diagnosis. (DMARDs); they include methotrexate, Norfolk and Norwich NHS Trust sulphasalazine, leflunomide, ciclosporin, gold and antimalarials (eg hydroxy- Early inflammatory arthritis Clin Med 2005;5:211–4 chloroquine) and were previously con- sidered as second-line agents. Recently, a A number of factors lead to delay in diag- new class of DMARDs (‘biologics’) has Background nosis and treatment, including: emerged. This group of drugs includes • delay on the part of the patient in Rheumatoid arthritis (RA) is a systemic the anti-tumour necrosis factor agents seeking medical care (discussed in the accompanying article autoimmune disorder of unknown delay in primary care aetiology characterised by symmetrical Beyond methotrexate: biologic therapy • waiting time to be assessed in polyarthritis of the small and large joints. in rheumatoid arthritis). • secondary care The cardinal history features of active RA Traditionally, the treatment of RA are: revolved around control of symptoms, • time to initiation of a DMARD in secondary care. pain with painkillers and NSAIDs, the more • ‘toxic’ agents being used once these drugs Research shows that any delay in initi- early morning stiffness (lasting more • had failed to control the symptoms of ating DMARDs can lead to substantial than 30 min) arthritis (hence, the concept of differences in long-term outcome.5,6 As a • joint swelling second-line agents). Unfortunately, result, the concept of early inflammatory • limitation of function. studies have shown that NSAIDs and arthritis has emerged. The first early Additional features include malaise analgesics have no disease-modifying arthritis cohort was established in 1957 in and fatigue. effects and that irreversible erosive Bath but the concept of early arthritis Chronic synovitis, with its attendant changes occur early in the course of the clinics emerged only in the late 1980s.7 In synovial proliferation, can lead to ero- disease. Within three months of disease recent years, a number of studies have sions, destruction of the cartilage and onset, 10–26% of patients will have joint focused on early inflammatory arthritis, instability of the joint, leading in turn to erosions evident on X-ray2 – the figure addressing whether early treatment with considerable disability. Furthermore, may be greater with imaging modalities DMARDs improves outcome. In several about a third of patients with RA will like magnetic resonance imaging and placebo-controlled studies in early stop working due to disease progression ultrasound. Within five years, about 95% arthritis (duration <2 years) using agents within five years.1 In the US, the esti- of patients are likely to have erosive dis- like methotrexate, sulphasalazine, gold mated yearly cost of RA is $9 billion, with ease.3 With increasing knowledge about and hydroxychloroquine, patients treated $4 billion in lost earnings alone. long-term prognosis and the risks of with DMARDs showed significant reduc- Consequently, RA has a profound impact delaying potentially disease-modifying tion in signs and symptoms and improved on patients, families and society in therapy, there has been a marked change patient function.8 Similar results are seen general. in the management of early RA. with oral prednisolone, which seems to have both symptom controlling and dis- 9 Key Points ease-modifying effects. Analysis of delayed treatment trials (extensions of placebo-controlled treatment investiga- For patients in whom inflammatory arthritis is suspected, the presence of polyarticular symptoms, particularly with hand or foot involvement and morning tions in which the placebo group is stiffness more than 30 minutes warrants specialist opinion switched to active treatment at the end point of the initial study) shows that the Disease-modifying antirheumatic drugs (DMARDs) are started early in the treatment early treatment group had significantly of inflammatory arthritis, sometimes even before the confirmation of diagnosis better efficacy parameters, including KEY WORDS: disease-modifying antirheumatic drugs (DMARDs), early arthritis, improved patient function (reduced rheumatoid arthritis, treatment Health Assessment Questionnaire

Clinical Medicine Vol 5 No 3 May/June 2005 211 CME Rheumatology

scores), decreased swollen joint counts, taken further. Patients with early arthritis • joint swelling of three or more joints and reduced or slowed radiographic were divided into two groups and • metacarpophalangeal or progression.10–12 outcomes assessed separately: metatarsophalangeal involvement In addition to monotherapy with • very early RA (VERA): duration less • morning stiffness of more than 30 DMARDs, a number of DMARD combi- than three months minutes. nations have been studied and may have • late early RA (LERA): duration less superior efficacy compared with than one year. monotherapy in early disease, but those Baseline investigations (Table 2) Although the inflammatory markers that do not include methotrexate fail to and swollen joint counts were no dif- Baseline laboratory investigations should show the same levels of efficacy. The ferent, patients in the VERA group had include: combinations include: better control of symptoms and signs full blood count methotrexate/sulphasalazine/ • • and better retardation of radiological erythrocyte sedimentation rate steroids13 • progression.16 These studies highlight (ESR) methotrexate/hydroxychloroquine • the importance of an early aggressive C-reactive protein methotrexate/ciclosporin approach in improving both the disease • • rheumatoid factor methotrexate/leflunomide. course and outcome. • • renal function tests Further support for early intervention • liver function tests (including comes from a review of primary trial Practical management of early • hepatic enzymes, alkaline data from 14 randomised controlled inflammatory arthritis phosphatase and albumin) trials of DMARD therapy in early RA. This indicated that disease duration was Referral • urinalysis. In certain instances, a synovial fluid a significant determinant of response to The therapeutic studies in early arthritis analysis may be deemed necessary to treatment, patients with shorter disease studies suggest a ‘window of opportu- 8,14 exclude other differential diagnoses like duration responding more favourably. nity’ in RA when DMARDs are more septic arthritis or crystal arthritis. The likely to be successful. Unfortunately, it assessment of renal and hepatic function can be hard to diagnose RA early in the Safety of early intervention tests is necessary as a number of treat- course of the illness (Table 1) and may ments (including NSAIDs) can cause An inception cohort (wherein a selection take some months before the classifica- renal and/or hepatic damage and may be of new patients are followed from tion criteria are fulfilled. Delays in con- contraindicated in the presence of presentation onwards) of 622 patients firming the diagnosis might mean that impairment of these organs. with newly diagnosed RA were followed any ‘therapeutic window of opportunity’ for up to 10 years to evaluate patient is missed. Baseline clinical assessment mortality, functional ability and prog- should include symptoms of active dis- Prognosis nostic factors for mortality.15 This ease (history of joint pain and swelling, In addition to these baseline laboratory cohort, treated early and aggressively duration of morning stiffness, diurnal investigations, the patient should be with DMARDs, showed no excess mor- variation of symptoms), functional assessed for comorbid conditions, and a tality within the first 10 years, and func- status and examination evidence of validated tool used to assess pain, disease tional ability remained constant after an synovitis. initial improvement from baseline. The clinical criteria that should In a recent prospective study, the con- prompt referral to a rheumatologist and cept of early inflammatory arthritis was to the early arthritis clinic are:8 Table 2. Baseline assessment of patients with inflammatory arthritis.

Symptoms of active disease Table 1. American College of Rheumatology 1987 revised criteria for classification of Functional status (eg HAQ) rheumatoid arthritis.17 Clinical evidence of synovitis Extra-articular disease Morning stiffness lasting more than 1 hour Radiographic damage Arthritis of 3 or more joint areas Need to be present for at least 6 weeks Laboratory investigations including: } Arthritis of hand joints – FBC, ESR, U&Es, LFTs, RF Symmetric arthritis – Urinalysis Rheumatoid nodules Rheumatoid factor positivity ESR = erythrocyte sedimentation rate; FBC = full blood count; HAQ = Health Radiographic changes or erosions on joint X-rays Assessment Questionnaire; LFTs = liver function tests; RF = rheumatoid factor; At least four of the seven criteria need to be fulfilled for classification of rheumatoid arthritis. U&Es = urea and electrolytes.

212 Clinical Medicine Vol 5 No 3 May/June 2005 CME Rheumatology activity and quality of life. Poor prog- newly diagnosed inflammatory arthritis 2 Harrison BJ, Symmons DP. Early inflam- nostic markers should be identified, are started on DMARD therapy as soon matory polyarthritis: results from the including early age of disease onset, high as is practical in a bid to improve overall Norfolk Arthritis Register with a review of the literature. II. Outcome at three titre of rheumatoid factor, elevated ESR long-term prognosis. As discussed above, years. Review. Rheumatology (Oxford) 2000; and swelling of more than 20 joints.17 A treatment may include low-dose oral 39:939–49. worse prognosis is indicated by extra- prednisolone, single or combination 3 Hulsmans HM, Jacobs JW, van der Heijde articular manifestations of RA including: DMARDs (Table 3). Treatment of DM, van Albada-Kuipers GA et al. The inflammatory arthritis is an iterative course of radiologic damage during the first • rheumatoid nodules six years of rheumatoid arthritis. Arthritis sicca syndrome process and continuous reassessment of Rheum 2000;43:1927–40. • patients is extremely important. interstitial lung disease 4 American College of Rheumatology • Subcommittee on Rheumatoid Arthritis • eye involvement (episcleritis, scleritis Guidelines. Guidelines for the management and, in later stages, scleromalacia Conclusions and the future of RA: 2002 update. Arthritis Rheum perforans) 2002;46:328–46 Early inflammatory arthritis offers a 5 Yelin EH, Such CL, Criswell LA, Epstein • interstitial lung disease window of opportunity for treatment WV. Outcomes for persons with rheuma- • pericardial involvement intervention. Early aggressive treatment, toid arthritis with a rheumatologist versus a • systemic vasculitis. frequently with combined therapy, may non-rheumatologist as the main physician enable much improved outcomes for for this condition. Med Care 1998;36: 513–22. patients with RA. Early referral for spe- Treatment 6 Solomon DH, Bates DW, Panush RS, Katz cialist advice is therefore critical. The JN. Costs, outcomes, and patient satisfac- Treatment of early inflammatory arthritis advent of the biologic treatments raises tion by provider type for patients with begins with patient education (the dis- the question of how these new agents rheumatic and musculoskeletal conditions: should be incorporated into early a critical review of the literature and pro- ease, the risks of joint damage and dis- posed methodologic standards. Review. Ann ability, the available forms of treatment inflammatory arthritis management Intern Med 1997;127:52–60. and their risks and benefits). Patients are strategies. 7 Emery P, Gough A. Why early arthritis referred to physiotherapists, occupational clinics? Br J Rheumatol 1991;30:241–2. therapists and social workers as part of a 8 Emery P, Breedveld FC, Dougados M, References Kalden JR et al. Early referral recommenda- multidisciplinary approach. 1 Scott DL, Pugner K, Kaarela K, Doyle DV et tion for newly diagnosed rheumatoid NSAIDs and glucocorticoids (intra- al. The links between joint damage and dis- arthritis: evidence based development of a articular or low-dose oral) can be used ability in rheumatoid arthritis. Review. clinical guide. Review. Ann Rheum Dis for symptom control. Most patients with Rheumatology (Oxford) 2000;39:122–32. 2002;61:290–7. 9 Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Table 3. Dosages and approximate time to benefit of disease-modifying Low-Dose Glucocorticoid Study Group. antirheumatic drugs used in the treatment of rheumatoid arthritis. N Engl J Med 1995;333:142–6. Approximate time 10 Egsmose C, Lund B, Borg G, Pettersson H et Drug to benefit Usual maintenance dose al. Patients with rheumatoid arthritis ben- efit from early 2nd line therapy: 5 year fol- Adalimumab Few days to 12 weeks 40 mg s/c every fortnight lowup of a prospective double blind placebo controlled study. J Rheumatol 1995;22: Anakinra 2–12 weeks 30–150 mg/day s/c 2208–13. Azathioprine 8–16 weeks 2.5 mg/kg/day oral 11 Tsakonas E, Fitzgerald AA, Fitzcharles MA, Ciclosporin 8–16 weeks 2.5–4 mg/kg/day oral Cividino A et al. Consequences of delayed D-penicillamine 12–24 weeks 250–750 mg/day oral therapy with second-line agents in rheuma- toid arthritis: a 3 year followup on the Etanercept Few days to 12 weeks 25 mg s/c twice a week hydroxychloroquine in early rheumatoid Hydroxychloroquine 8–24 weeks 200 mg twice a day oral arthritis (HERA) study. J Rheumatol 2000; Gold: 27:623–9. oral 16–24 weeks 3 mg twice a day 12 van der Heide A, Jacobs JW, Bijlsma JW, intramuscular 12–24 weeks 50 mg every 4 weeks Heurkens AH et al. The effectiveness of early treatment with ‘second-line’ Infliximab + methotrexate Few days to 16 weeks 3 mg/kg iv every 8 weeks antirheumatic drugs. A randomized, con- Leflunomide 4–12 weeks 10–20 mg/day oral trolled trial. Ann Intern Med 1996;124: Methotrexate: 699–707. oral 6–12 weeks 7.5–30 mg once a week 13 Landewe RB, Boers M, Verhoeven AC, injectable 6–12 weeks 7.5–30 mg once a week Westhovens R et al. COBRA combination Sulphasalazine 6–12 weeks 1 g 2–3 times a day oral therapy in patients with early rheumatoid arthritis: long-term structural benefits of a iv = intravenous; s/c = subcutaneous. brief intervention. Arthritis Rheum 2002; 46:347–56.

Clinical Medicine Vol 5 No 3 May/June 2005 213 CME Rheumatology

14 Anderson JJ, Wells G, Verhoeven AC, Felson Classification DT. Factors predicting response to treat- Management of ment in rheumatoid arthritis: the impor- This article focuses mainly on SSc (scle- tance of disease duration. Arthritis Rheum systemic sclerosis roderma with systemic involvement), 2000;43:22–9. but the spectrum of scleroderma encom- 15 Kroot EJ, van Leeuwen MA, van Rijswijk MH, Prevoo ML et al. No increased mor- passes Raynaud’s phenomenon and Voon H Ong MRCP, Clinical Research Fellow tality in patients with rheumatoid arthritis: localised subtypes of skin fibrosis such as up to 10 years of follow up from disease Geraldine Brough FRCP, Associate morphoea (Table 1). The extent of skin onset. Ann Rheum Dis 2000;59:954–8. Specialist in Rheumatology involvement defines the disease subset in 16 Nell VP, Machold KP, Eberl G, Stamm TA Christopher P Denton PhD FRCP, Senior cutaneous SSc (Fig 1):2 et al. Benefit of very early referral and very Lecturer in Rheumatology early therapy with disease-modifying • diffuse cutaneous SSc (dcSSc): skin anti-rheumatic drugs in patients with early Centre for Rheumatology, Royal Free involvement proximal to the elbows rheumatoid arthritis. Rheumatology Hospital, London and knees, and (Oxford) 2004;43:906–14. 17 Arnett FC, Edworthy SM, Bloch DA, limited cutaneous SSc (lcSSc): skin Clin Med 2005;5:214–9 • McShane DJ et al. The American involvement distal to these joints. Rheumatism Association 1987 revised cri- A subset of patients has the clinical fea- teria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. Pathogenesis tures of isolated Raynaud’s phenomenon, 18 Scott DL. Prognostic factors in early with evidence of microvasculopathy rheumatoid arthritis. Review. The pathogenesis of systemic sclerosis based upon nailfold capillaroscopy Rheumatology (Oxford) 2000;39(Suppl 1): (SSc) remains incompletely understood. and/or serum autoantibodies against 24–9. The earliest events occur in the microcir- nuclear antigens (autoimmune Raynaud’s culation with endothelial cell activation, phenomenon). They have a 10–15% like- followed by perivascular inflammation lihood of developing a defined connective with monocytes and later lymphocytes. tissue disease (including SSc) during Subsequently, fibroblasts become acti- long-term follow-up. vated and deposit increased extracellular The term limited SSc has recently been matrix in lesional tissues including the applied to another group of patients who skin and internal organs.1 The resulting lack definite skin involvement but who architectural disruption leads to the harbour specific antibodies against hall- morbidity, and ultimately mortality, mark antigens or have scleroderma- associated with SSc. There is evidence to associated capillaroscopic changes.3 support genetic factors in the develop- In addition, a small number of ment of SSc but few candidate suscepti- patients with vascular symptoms and bility or severity genes have yet been SSc-specific antibodies develop major identified. organ-based complications in the

Key Points

Appropriate management of systemic sclerosis (SSc) requires accurate disease subsetting, staging of the disease within each subset and risk stratification for major organ-based complications, based upon clinical features and serology

All patients with SSc should be screened for major complications to facilitate early intervention

Hypertensive renal crisis can occur in any patients with SSc; angiotensin-converting enzyme inhibitors should be instituted as early as possible in these cases

Significant reduction in transfer factor on lung function tests may reflect either interstitial lung disease or pulmonary hypertension (PAH). Doppler echocardiography and high-resolution computed tomography of the chest are indicated

PAH should be confirmed by right heart catheterisation before considering advanced therapy for symptomatic cases

KEY WORDS: pulmonary fibrosis, pulmonary hypertension, Raynaud’s phenomenon, renal crisis, scleroderma, systemic sclerosis

214 Clinical Medicine Vol 5 No 3 May/June 2005