Differential diagnosis of in \202 ammatory polyarthropathy In \202 ammatory synovitis \200 Rheumatoid arthritis \200 Spondylarthropathy (incl. psoriatic polyarthritis) \200 Post-viral arthritis \200 Infectious (e.g. parvovirus B19, Lyme disease) \200 Crystal arthritides (e.g. gout and CPPDD) \200 In \202 ammatory osteoarthritis \200 Autoimmune Connective Tissue Diseases \200 Vasculitis, Sarcoidosis, Beh ets disease Synovial \202 uid analysis \200 Aspiration and analysis of synovial \202 uid is not particu- larly helpful for diagnosis, but analysis can help rule out infection (gram stain and culture), and crystal-induced art hritis (polarized light microscopy). Usually the \202 uid is straw colored and mildly tur bid, and predominantly comprised of neutrophils with the remainder being lymphocytes. The \202 uid glucose level is normal. Synovial biopsy can be helpful, but is not currently ava ilable in routine clinical practice. Metabolic \200 \200 \200 Hyperparathyroidism Thyroid disorders Haemachromatosis (secondary OA) \200 Chronic infection \200 \200 Other investigations If the diagnosis is unclear, investigation for other causes of polyart hritis is mandatory, such as gout (check urate level), CPPDD (requires metabolic screen, pa rticularly calcium and PTH), SLE (check ANA, ENAs, C3). \200 Infective endocarditis Hepatitis B, HIV Miscellaneous \200 \200 \200 \200 Paraneoplastic phenomenon Multiple myeloma Polymyalgia rheumatica (PMR onset of RA) Septic arthritis (usually monoarthrits) Other tests: thyroid function, creatine kinase, vasculitis screen, serum ACE, complement le vels, and infection screen (including parvovirus B19 and mycoplasma). Full pulmonary functi on tests (if suspicious of lung involvement) and high resolution CT scanning in the prone p osition (pulmonary disease). ECG and transthoracic ECHO (cardiovascular involvement \200 \223 particularly pericardial effusion). Nerve conduction studies (neuropathies, e.g. carpa l tunnel syndrome, ulna nerve irritation, vasculitis). DXA scan (osteoporosis, particularly in post-menopausal women or those who have had fractures). ACR response criteria \200 The ACR response criteria are categorical and allow assessment of improvement or change fro m baseline. ACR responses are expressed as ACR20, 50, 70, and 90 indicating 20%, 50%, 70%, and 90% improvement in the respective variables included in the criteria. They do not, howe ver, allow assessment of the actual state of disease activity at one time point. ACR respon ses are currently the most widely reported outcomes in clinical trials. Investigations to monitor drug therapy (see also p. 529) Monitoring of drug toxicity involv es regular FBC, LFTs, renal function, ESR, CRP, and urinalysis. Hepatitis B and C serology is advisable prior to B-cell depleting treatment. Disease Activity Score (DAS) Special case investigations \200 American College of Rheumatology response criteria for 20% improvement (ACR20) 20% reductio n in the number of tender and swollen joints, plus 20% improvement in 3 of the following 5 parameters: \200 \200 \200 \200 \200 Prior to starting biologic DMARD therapy, especially anti-TNFA agents, Mycobacterium tuberc ulosis (MTB) should be excluded by thorough history and physical examination, CXR tuberc ulin skin test (see p. 566). Patients should be asked about immunity to Varicella zoster an d tested for antibodies if necessary. Physician global assessment of disease Patient global assessment of disease Patient assessm ent of physical function Patient assessment of pain ESR or CRP Differential diagnosis The main differential diagnoses will be psoriatic polyarthritis, in \202 ammatory osteoarthritis, SLE, post-infectious arthritis, and in the elderly, polyarti cular CPPDD or gout. Disease activity assessment Measurement of different aspects of disease in RA has be- come important, particularly the assessment of disease activity and the response to treatment. O wing to the het- erogeneous nature of RA, various composite indices have been developed to assess disease including the American College of Rheumatology (ACR) Response Criteria, The DAS is a composite index of disease activity \200 The DAS is used in clinical trials and is also useful in daily practice as it allows assess ment of the actual state of disease activity at any time point. DAS-CRP may be used as an a lternative to ESR in the calculation of the DAS. RHEUMATOID ARTHRITIS 202 EULAR response criteria have also been developed, based on the DAS and when measured at two time points the patients clinical response can be assessed. EULAR criteria for disease act ivity are based on the DAS28, allowing a continuous measurement of disease activity. Other scores have also been developed that are easier to calculate, such as the simpli \201 ed d isease activity index (SDAI) and the clinical disease activity index (CDAI). The Disease Activity Score (DAS) To calculate the DAS28 one requires: \200 \200 \200 \200 The number of swollen joints out of 28 (SJC28) The number of tender joints out of 28 (TJC28 ) The ESR (measured in mm/hour). An assessment of the patient \200\231s general health (GH) measured on a Visual Analog Scale (VAS) of 100 mm Using these data, the DAS28 can be calcu lated using the following formula: DAS28 = (0.56 \227 sqrt [TJC28]) + (0.28 \227 sqrt [SJ C28]) + Health status and quality of life measures Assessment of disability and overall health stat us is critical in patients with RA. Patient-reported outcomes provide intrinsic knowledge a bout a patient \200\231s symptoms, general health, functional status, satisfaction, prefere nces for treat- ment, and quality of life. (0.70 \227 ln[ESR]) + (0.014 \227 GH) This is not simple, but can easily be calculated using a pre-programmed calculator: \200 The DAS28 provides a number on a scale from 0 to 10 indicating the current activity of dise ase. A DAS28 >5.1 means high disease activity. DAS28 <3.2 indicates low disease activity. R emission is achieved by a DAS28 <2.6. Health Assessment Questionnaire (HAQ) \200 \200 \200 The HAQ is the most frequently used method to measure functional impairment. The HAQ was on e of the \201 rst self-reported functional status measures and is based on \201 ve pati ent-centered dimensions: disability, pain, medication effects, costs of care, mortality. Ty pically, one of two HAQ versions is used: The Full HAQ, which assesses all \201 ve dimens ions, and the Short or 2-page HAQ, which contains only the HAQ disability index (HAQ-DI) an d the HAQ s patient global and pain visual analog scales (VAS). Medical Outcomes Study 36-Item Short Form (SF-36) \200 \200 \200 The SF-36 is a health-based survey of quality of life. Like the HAQ is it patient-derived a nd objective. The SF-36 has been implemented to define disease conditions, to determine the effect of treatment, to differentiate the effect of different treatments, and to compare a cross conditions. SF36 comprises 8 individual subscale scores and physical and mental summa ry scores. Physical component summary includes physical functioning, role-physical, bodily pain and general health. Mental component summary includes vitality, social functioning, ro le-emotional and mental health. Figure 6.2 Joints utilized in a DAS28 joint count. Table 6.2 The EULAR response criteria using the DAS28 Current DAS28 DAS28 improvement >1.2 0.6 \200\2231.2 <0.6 <3.2 Good Moderate No response response response 3.2 \200\2235.1 Moderate Moderate No response response response >5.1 Moderate No No response response response Comparing the DAS28 from one patient on two different time points it is possible to de \201 ne improvement or response. CHAPTER 6 Rheumatoid arthritis 203 The role of aerobic exercise is controversial, but there are some studies supporting a role for regular exercise, although promoting weight-bearing activities on hard surfaces regula rly would be inappropriate. Standards of care developed by The British Society of Rheumatology (BSR) 2005. Standards of care for RA Outcome measures 1. Identi \201 cation of persons with rheumatoid arthritis. 2. Empowering persons with rheumatoid arthritis. Pain relief The primary initial concern of the patient is relief from pain and, therefore, adequate analgesia is critical. NSAIDs are one of the cornerstones of medical therapy. Clinical care of persons with rheumatoid arthritis 3. The multidisciplinary team. 4. Prescr iption and monitoring of treatments used to NSAIDs \200 By decreasing prostaglandin production NSAIDs have analgesic, anti-pyretic and anti-in \202 ammatory effects. NSAIDs do not have disease-modifying effects and therefore should no t be used in isolation, even if symp- toms are greatly improved. NSAIDs account for up to 2 0% of all cases of peptic ulcer hemorrhage and perforation with many being fatal, particula rly in the elderly. Gastrointestinal side effects (e.g. perforations, ulcers, bleeds) appea r to have been reduced with the introduc- tion of the cyclo-oxygenase 2 inhibitors (e.g. Ce lecoxib, Etoricoxib), although the cardiovascular and renal toxici- ties are still problema tic. In the UK, the National Institute for Clinical Excellence (NICE) have recommended the use of COX-2 speci \201 c NSAIDs in patients at risk of peptic disease. There may be indiv idual responses to different NSAIDs; therefore, a trial of different agents may be necessar y to optimize therapeutic effect. manage rheumatoid disease. 5. Annual review. 6. Prevention of steroid-induced osteoporosis. 7. Pain management. 8. Col laboration with orthopedic surgeons. Special clinical circumstances 9. Care of young persons with juvenile idiopathic arthritis/rheumatoid arthritis. 10. Pregnancy in persons with rheumatoid arthritis. Development of patient-centered care 11. Involvement of users and carers. 12. Access to fac ilities. 13. In-patient management. 14. Out-patient services. Treatment Objectives of management Due to the heterogeneity of RA and the variability of it s course no consistent treatment paradigm \201 ts the care plan for all individuals. \200 Non-NSAID analgesics \200 Simple analgesics, such as paracetamol 1 g tds with or without dextropropoxyphene or codein e, are useful, although side effects are common in the elderly. Buprenorphine 3- or 7-day t ransdermal patches are popular with patients and claims that side effects are less than wit h oral therapies seem justi \201 ed. There may be substance to data and claims that \201 sh-oils (e.g. cod-liver oil) can have an NSAID-sparing role. The objectives of management are: \200 \200 \200 \200 \200 \200 The ultimate go al of therapy is the clinical, radiographic, and immunological \200\230cure \200\231, and it appears that long-term remission may be possible in many patients. In The UK, standards of care for patients with RA have been published by the British Society of Rheumatology (se e Appendix 6.1). A multidisciplinary approach is important. the relief of symptoms; slowing of cartilage and bone breakdown; preservation of function; minimizing disability; ameliorating premature mortality; maintaining quality of life. Immunosuppression/disease modifying anti-rheumatic drugs (DMARDs) (see also p. 529) The pha rmacological treatment of RA, especially early dis- ease and undifferentiated early in \202 ammatory polyarthritis, is evolving rapidly. General points/current approach \200 Over the last decade the focus has been to treat RA promptly and aggressively with the most effective medications The traditional treatment pyramid ( \200\230start low, go slow \200 \231) has been abandoned. Early intervention results in minimum risk with maximum bene \201 t when viewed over the long-term. Treatment in the \200\230window of opportunity \200 \231 of early RA/ inflammatory arthritis appears to have the greatest impact and early infl ammatory arthritis should be considered a medical emergency. It is becoming apparent that c ombination DMARD therapy is more effective than sequential monotherapy. The introduction of the \200\230biologic \200\231 DMARDs (e.g. anti- TNFA) has led to a sea change in the tre atment of RA and has spearheaded the endeavor for a disease \200\230cure \200\231. Tight c ontrol of (the in \202 ammatory component of the) disease has also been found to improve o utcomes and Physical and occupational therapy Physiotherapists and occupational therapists are key memb ers of the multidisciplinary team. Therapists should be involved early in the care of RA pa tients. \200 Physiotherapy benefits patients in regard to joint movement, function, and muscle strength. Physiotherapists \200\231 different treatment modalities include heat, ice, wax baths, and hydrotherapy. The use of splints are often necessary for joint protec- tion, to reduce joi nt deformity, and improve hand or \201 nger power and function. Adequate rest with graded exercises improve outcome. Foot orthoses may be required for deformed feet. Access to podi atry or orthotists is key. Occupational therapists should assess patients \200\231 disabili ty and offer aids for daily living, such as appropriately fash- ioned cutlery, taps, long h andled combs, etc. \200 RHEUMATOID ARTHRITIS 204 regular assessment of disease activity allows tailored therapy. One of the main dif \201 c ulties is reviewing patients early after symptom onset and, to this end, early in \202 amm atory arthritis clinics are important. Strict protocols are required in both primary and se c- ondary care to facilitate referral of appropriate patients. EULAR and the BSR have publi shed guidelines on the treatment of early RA (See Appendix 6.1 for BSR guide). DMARDs such as sulphasalazine (SZP), hydroxychloro- quine, and le \202 unomide is best. In practice, rheumatologists use various combinations of DMARDs to achieve the optimal respon se. Ciclosporin, azathioprine, gold salts, and D-penicillamine are now not commonly used ow ing to the availability of more ef \201 cacious and less toxic drugs. Cyclophosphamide may be necessary for associated rheumatoid vasculitis. \200\230Biologic \200\231 DMARDs With greater understanding of the immunological basis of RA novel approaches to treatment has developed. Elucida- tion of the molecules involved in RA immunopathogenesis has facilitated the development of therapy targeted against speci \201 c molecules or molecular interactions. These thera- pies are termed \200\230biologic \200\231 DMARDs or \200\230Biologics \200\231. \200 DMARDs DMARD medications are now utilized much earlier in the treatment paradigm of RA due to their ef \201 cacy in retarding erosive disease. \200 The great challenge is to identify patients most likely to suffer from aggressive disease a nd institute treatment expediently. Due to its tolerability, ef \201 cacy, and speed of on set, MTX is regarded as the foundation upon which other drugs are added. It has also become the benchmark drug in clinical trials. Many patients are not adequately controlled on DMAR D monotherapy, even MTX. Combinations of DMARDs have therefore been used to work synergisti cally without a rise in toxicity. A \200\230step down \200\231 approach is favored, rather than a \200\230step up \200\231 protocol. The optimum combination of drugs has not been c learly de \201 ned; however, emerging evidence suggests that MTX in combination with gluco corticoids (GCs) and/or other Biologics comprise a group of recombinant proteins that include antibodies, cytokines, cyto kine inhibitors, and toxins fused with biological \200\230targeting \200\231 segments. A n umber of biologics are now available with many more in development. The most widely used an d studied so far have been the anti-TNFA agents (in \202 iximab, etanercept, and adalimuma b). In \202 iximab and adalimumab are anti-TNFA antibodies and etanercept is a TNFA recept or fusion protein. These biologics produce rapid and sustained amelioration of the signs an d symptoms of RA, retard radiological progression, and improve quality of life more effecti vely than traditional DMARDs. Table 6.3 EULAR guidelines for early arthritis (see Combe et al. 2007) Final set of 12 recommendations on the management of early arthritis based on both evidence and expert opinion 1 Arthritis is characterized by the presence of joint swelling, associated with pain or sti ffness. Patients presenting with arthritis of more than one joint should be referred to, and seen by, a rheumatologist, ideally within six wee ks after the onset of symptoms 2 Clinical examination is the method of choice for detecting synovitis. In doubtful cases, ultrasound, power Doppler, and MR imaging might be helpful to detect synovitis. 3 Exclusion of diseases other than RA requires careful history taking and clinical examinatio n and ought to include at least the following laboratory tests: complete blood cell count, urinary analysis, liver transaminases, antinuclear antibodies. 4 In every patient presenting with early arthritis to the rheumatologist, the following facto rs predicting persistent and erosive disease should be measured: number of swollen and tend er joints, ESR or CRP, levels of RF and anti-CCP antibodies and radiographic erosions. 5 Patients at risk of developing persistent or erosive arthritis should be started with DMARD s as early as possible, even if they do not yet ful \201 l established classi \201 cation criteria for in \202 ammatory rheumatological diseases. 6 Patient information concerning the disease and its treatment and outcome is important. Educ ation programs aimed at coping with pain, disability and maintenance of work ability may be employed as adjunct interventions. 7 NSAIDs have to be considered in symptomatic patients after evaluation of gastrointestinal , renal, and cardiovascular status. 8 Systemic glucocorticoids reduce pain and swelling and should be considered as adjunctive tr eatment (mainly temporary), as part of the DMARD strategy. Intra-articular glucocorticoid i njections should be considered for the relief of local symptoms of in \202 ammation. 9 Among the DMARDS, methotrexate is considered to be the anchor drug and should be used \201 rst in patients at risk of developing persistent disease. 10 The main goal of DMARD treatment is to achieve remission. Regular monitoring of disease activity and adverse events should guide decisions on choice and changes in treatment strategies (DMARDs including biological agents ). 11 Non-pharmaceutical interventions such as dynamic exercises, occupational therapy and hyd rotherapy can be applied as adjuncts to pharmaceutical interventions in patients with early arthritis. 12 Monitoring of disease activity should include tender and swollen joint count, patient \200\231s and physician \200\231s global assessments, ESR and CRP. Arthritis activity should be assessed at one to three month intervals, for as long as remission is not achieved. Structural damage should be assessed by radiographs of hands and feet every 6 to 12 months during the \201 rst few years. Functional assessment (for exam ple, HAQ) can be used to complement disease activity and structural damage monitoring. CRP, C reactive protein; DMARD, disease modifying anti-rheumatic drug; ESR, erythrocyte sed imentation rate; HAQ, Health Assessment Questionnaire; MR, magnetic resonance. CHAPTER 6 Rheumatoid arthritis 205 Anti-TNFA therapies are currently expensive and require parenteral (intravenous or subcutan eous) admin- istration [ 10 000 ( 12 500 Euros) per year]. Despite being well tolerated t here is an increased incidence of infections and possibly malignancy. Up to 30% of patients do not respond to anti-TNFA DMARDs, and a further 30% may lose ef \201 cacy with time or develop intolerable side effects. Anakinra, an IL-1 receptor antagonist, although effective has fallen out of favor as it is not as effective as anti-TNFA agents. Recently rituximab (an anti-CD20 monoclonal antibody) and the T cell co-stimulatory blocker abatacept have bee n licensed in Europe and N America. Both these biologics have displayed similar ef \201 ca cy to the anti-TNFA agents. The IL-6 receptor antibody tocilizumab has potential for ef \201 cacy and is currently being studied in large RCTs. Many other biologics are being deve loped including p38 MAP kinase inhibitors and B-cell modulators. In the UK, BSR has issued guidance on the use of anti-TNFA Biologics. Given the cost of biologics to a publicly-funde d health system, there are constraints on which patients can be treated with anti-TNFA and Rituximab within the National UK Health Service (see guidance www.nice.org.uk;). NICE have issued guidance in the UK on the use of anti-TNFA drugs and rituximab. An unfavorable revie w of abatacept by NICE will mean that NHS funders are unlikely to allow its widespread use . Two studies have confirmed that remission may be induced with intensive treatment and tha t therapy may even be withdrawn without recrudescence of disease. Further evidence is accru ing that a biologic agent may be necessary to maximally inhibit structural damage even if p atients respond symptomatically to MTX alone The TICORA study showed improved outcomes in p atients who were seen regularly and whose treatment was changed frequently in order to main tain a low disease state. When the tight control was stopped the patients deteriorated. An inherent risk, however, of intensive treatment is the possibility of over-treating patients with self-limiting and/ or milder disease Arthroplasty invariably results in excellent outcomes for end stage joint disease particula rly by reducing pain. Tendon reconstructions are being increasingly offered by Orthopedic U nits, to help hand function. An alternative to surgical synovectomy is chemical syn- ovecto my with osmium or radiation synovectomy using Yttrium-90 (90Y) colloid. The availability of 90Y from radi- opharmaceutical suppliers in the UK and in Europe has become more dif \201 cult recently (currently no UK supplier of 90Y and imported products are not UK licensed). Patient advice/education \200 Education is pivotal. Rheumatology practitioners (such as nurse specialists) are indispensa ble for delivering edu- cation (one-to-one or group-led) to patients and their relatives/ca rers. Both patients and their relatives should be informed of the chronic nature of RA, and the importance of rapid disease control in order to improve prognosis. This should include discussion regarding co-morbidities and lifestyle modi \201 cation, such as optimization of weight, healthy diet, exercise, and cessation of smoking. Risks of long-term disease sho uld be discussed as some stage. An explanation of the need to screen for various morbidity, such as neck disease, osteoporosis, hyperlipi- daemia, over time should be explained. The discussion of the concepts of controlling, rather curing disease is important early on. In the elderly, those with multiple co-morbidities or polypharmacy the role of making judiciou s choices of immunosuppressive medication needs to be emphasized. Prognosis The prognosis of RA has improved enormously over the last decade with early, inte nsive use of ef \201 cacious medica- tions. However, the natural history of disease is var iable. \200 Joint destruction and many extra-articular manifestations may be avoided with appropriate i ntervention. Up to 40% of patients presenting to early in \202 ammatory arthritis clinics, however, have self-limiting disease. In 75% of patients the disease waxes and wanes over a period of years. Pregnancy often relieves the symptoms in the 2nd and 3rd trimester throug h poorly clari \201 ed mechanisms. Currently 50% of patients have given up work after 10 y ears. 75% of patients develop at least moderate impairment of function. Mortality is increa sed in RA with cardiovascular disease accounting for up to 45% of deaths, cancer (especiall y hematological malignancy) 15%, and infections 10%. A clearer understanding of the pathoge nesis will undoubtedly lead to improved treatment and prognosis. Glucocorticoids (GCs) Though very effective at reducing in \202 ammation, long-term toxici ty limits the use of GCs. In many patients, however, small doses are required to stabilize the arthritis. \200 \200 GCs do have a disease modifying effect. Higher doses are occasionally needed for severe \202 ares or extra-articular manifestations. Intra-articular GC injections, following joint aspiration, are frequently used with excellent response and minimal side effects. Sepsis m ust be excluded prior to injection. Guidelines have been developed for the prevention of GC -induced osteoporosis (see p. 408). Poor prognosis patients Factors that have been found to be associated with aggressive disea se include: \200 \200 \200 \200 \200 \200 Insidious onset. Constitutional symptoms. Nodules. Female gender. Multiple swollen and tend er joints at presentation (high disease burden, high DAS). RF positivity with high titres ( especially IgA RF). Surgery \200 Historically surgery is often required for RA patients, although there is some anecdotal ev idence the need for surgery has lessened in recent years. Synovectomy and debridement of ti ssue from \200\230recalcitrant joints \200\231 can be bene \201 cial. RHEUMATOID ARTHRITIS 206 \200 \200 \200 \200 \200 \200 Variation has been identi \201 ed so far in genes coding \200 \200 \200 \200 Anti-CCP antibodies. Smokers. Presence of the shared epitope. High in \202 ammatory marker s (ESR, CRP). Early bone erosions. Poor functionality at 1 year. Socially disadvantaged. HLA subtypes. Folate metabolizing enzymes. TNF and TNFA promoter regions. Fc receptors. Resources Assessment tools DAS on line: www.das-score.nl HAQ: See pdf document at www.chcr. brown.edu/pcoc/ Short From 36 (SF-36): www.SF-36.org Current controversies Diagnosis and prediction \200 The role of MR and US in predicting erosions, disability, and response and/or failure to th erapies. The role of anti-CCP antibodies. Whether composite scores from a combination of cl inical, genetic and biomarker data can predict outcome, particularly in relation to speci \201 c therapies. Guidelines/NICE (UK) NICE: www.nice.org.uk; Advice for UK prescribers on Biologic DMARDs. G uidelines are available for various aspects of RA manage- ment from a variety of sources in cluding the BSR, EULAR, and ACR. \200 Treatment \200 Optimum DMARD regimes at the outset. The role of GCs (e.g. high-dose and tapered as for COB RA or low dose 7.5 mg prednisolone 1 \200\2232 years or avoid!). Whether chronic inflammato ry processes can be permanently and advantageously modified in early disease by early and a ggressive Biologic DMARD use. The restriction of funding for Biologic therapies in the UK i s highly controversial and based only partly on a clinical evidence base. Funding is limite d by cost-effectivity analyzes, which are consistently debated and often disputed. The fund ing of expensive therapies in wholly or part public-funded Health Systems, however, is not a controversy speci \201 c to the UK. Patient organizations National Rheumatoid Arthritis Society: www.rheumatoid. org.uk Arthrit is Care: www.arthritiscare.org.uk Internet sites Arthritis Research Campaign: www.arc.org.uk British Society for Rheumatology : www.rheumatology. org.uk American College of Rheumatology: www.rheumatology. org European League Against Rheumatism (EULAR): www. eular.org Arthritis and Musculoskeletal Alliance: www.arma.uk.net The future Unprecedented advances occurred over the last decade in the understanding and ma nagement of RA and the pros- pects for the next decade are no less exciting. Areas of inten se research include: \200 \200 www.ncbi.nlm.nih.gov/books/bv.fcgi?rid= eurekah.chapter.1416 Article on RA cytokines. Eurek ah Bioscience Coll. Further clari \201 cation of the pathophysiology of RA. Genetic influences, including phar macogenetics and genomics. Co-morbidity management. Re \201 nement of disease assessment. Biomarker identi \201 cation for prognostication. Novel therapeutic targets. ICD-10 codes M05 M06 Seropositive rheumatoid arthritis Other rheumatoid arthritis \200 \200 \200 Further reading Bathon JM, Martin RW, et al. A comparison of etanercept and meth- otrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 1586 \200\22393. Future treatment options The following highlight some of rapidly developing areas: \200 Boers M, Verhoeven AC, et al. Randomized comparison of com- bined step-down prednisolone, m ethotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lan cet 1997; 350: 309 \200\22318. Emerging cytokine and signaling targets, e.g. IL-15, IL-36 and adipokines, MAP kinases. Cel l therapies, including T-regulatory cells, haemopoietic, and mesenchymal stem cells. Gene t herapies. Pre-emptive treatment, including vaccination against human cytokines. Breedveld FC, Weisman MH, et al. The PREMIER study: A multi- center, randomized, double-bli nd clinical trial of combination therapy with adalimumab plus methotrexate versus methotrex - ate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006; 54: 26 \200\22337. \200 Combe B, Landewe R, et al. EULAR recommendations for the management of early arthritis: rep ort of a task force of the European Standing Committee for International Clinical Studies I ncluding Therapeutics (ESCISIT). Ann Rheum Dis 2007; 66: 34 \200\22345. Genetic phenotyping Genetic phenotyping may be used to help identify patients most likely t o: \200 \200 \200 \200 Respond to treatment. Develop adverse events. Suffer disease progression. Carry risk factor s for underlying disease. Goekoop-Ruiteman YP, de Vries-Bouwstra JK, et al. Clinical and radiographic outcomes of fou r different treatment strategies in patients with early rheumatoid arthritis (the BeSt stud y): a rand- omized, controlled trial. Arthritis Rheum 2005; 52: 3381 \200\22390. CHAPTER 6 Rheumatoid arthritis 207 Quinn MA, Conaghan PG, et al. Very early treatment with in \202 iximab in addition to meth otrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging e vidence of sy novitis and damage, with sustained bene \201 t after in \202 iximab with- d rawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arth ritis Rheum 2005; 52: 27 \200\22335. Grigor C, Capell H, et al. Effect of a treatment strategy of tight control for rheumatoid a rthritis (the TICORA study): a single- blind randomized controlled trial. Lancet 2004; 364( 9430): 263 \200\2239. Kennedy T, McCabe C, et al. BSR guidelines on standards of care for p ersons with rheumatoid arthritis. Rheumatology 2005; 44: 553 \200\2236. Van Dongen H, van Aken J, et al. Ef \201 cacy of methotrexate treatment in patients with p robable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthrit is Rheum 2007; 56: 1424 \200\22332. Korpela M, Laasonen L, et al. FIN-RACo Trial Group. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying ant irheumatic drugs: \201 ve-year experience from the FIN-RACo study. Arthritis Rheum 2004; 50: 2072 \200\22381. Weinblatt ME, Keystone EC, et al. Adalimumab, a fully human anti-tumor necrosis factor alph a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomi tant methotrexate: the ARMADA trial. Arthritis Rheum 2003; 48: 35 \200\22345. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumor necrosis factor a lpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomi tant methotrexate: a randomized phase III trial. ATTRACT Study Group. Lancet 1999; 354: 193 2 \200\2239. See also: Organ involvement and rheumatological disease (p. 408); Glucocorticoid induced os teoporosis (p. 408), Medications/drugs used in rheumatic disease (p. 529) O \200\231Dell JR, Leff R, et al. Treatment of rheumatoid arthritis with methotrexate and h ydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medication s: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rhe um 2002; 46: 1164 \200\22370. Smolen JS, van der Heijde DM, et al. Predictors of joint damage in patients with early rheu matoid arthritis treated with high-dose methotrexate with or without concomitant in \202 i ximab: results from the ASPIRE trial. GUIDELINES 208 Guidelines for the management of rheumatoid arthritis (the \201 rst 2 years) 1 A diagnosis of RA should be made as early as possible, on the basis of persistent joint i n \202 ammation affecting at least three joint areas, involvement of the MCP or MTP joints, or early morning stiffness of at least 30 min duratio n. 2 In order to identify and treat patients with RA at an early stage, it is necessary for pa tients with suspected early synovitis to have rapid access to a multidisciplinary team that includes specialists in rheumatology, and includes members from both primary and secondary care in order to provide a seamless service for patients. 3 Access to individual elements of the multidisciplinary service should be available accord ing to patient need. 4 Patients with RA should be provided with a plan of care from diagnosis, which outlines th e principles of management including a commitment to training patients to self-manage some aspects of their disease. 5 Specialist rheumatology nurses can provide the ideal support for patients in accessing el ements of the multidisciplinary team and in providing important lifestyle advice. 6 RA is a signi \201 cant independent risk factor for ischaemic heart disease, with the ri sk related to the severity and duration of in \202 ammation. Control of in \202 ammation should also be accompanied by addressing ea ch patient \200\231s other risk factors for ischaemic heart disease, using the established primary care services where appropriate. 7 All patients should have their disease and its impact assessed and documented at onset, p rior to starting DMARD therapy. Once established on DMARD therapy, all patients should have a formal assessment of treatment response, or lack of it, in order to justify continuing t herapy or changing it. Remission should be de \201 ned and documented when achieved, in or der to plan reduction or maintenance therapy. 8 Patients with RA should be established on disease-modifying therapy as soon as possible a fter a diagnosis of RA is established. Disease modifying therapy should be part of an aggre ssive package of care, incorporating escalating doses, intra-articular steroid injections, parenteral methotrexate and combination therapy, rather than sequential monotherapy, progre ssing to biologic (anti-TNFA) therapy, when required. 9 Systemic glucocorticoid therapy may have an important early role in establishing control of synovitis or bridging disease control between different DMARD therapies but long-term use is not justi \201 ed. 10 Patients with RA require assessment of both pain and optimum effective therapy to ensure early symptom control (grade of recommendation A). Long-term use of NSAIDs should be at the lowest effective dose. 11 Current concern over the potential cardiovascular toxicity of coxibs and NSAIDs suggests that such drugs should be avoided in high risk individuals, and used with caution in others who cannot be managed with analgesia, ste roid injections, and one or more DMARDs. 12 Patients with RA require early assessment of sleep patterns (grade of recommendation A). Early management of sleep disturbance should include tricyclic agents, behavioral therapy and consider also the use of exercise ( grade of recommendation B). Consider the impact of fatigue on quality of life in early RA. 13 The evidence for the effectiveness of complementary therapy is con \202 icting and no \201 rm recommendations can be made. 14 Timing and format (group/individual/written) of education to meet individual needs must be considered in early disease (grade of recommendation A). Patients should be offered a cognitive behavioral approach to patient ed ucation, delivered at the appropriate time in order to promote long-term adherence to manag ement strategies (grade of recommendation C). Patients should be helped to contact support organizations such as National RA Society, Arthritis Care (AC) and the Arthritis Research C ampaign (arc). 15 Patients should be encouraged to pace activities and recognize the potential lower, as w ell as upper limits of physical activity, facilitating a realistic readjustment of the patient \200\231s own expectations, guided by members of the multidisciplinary team. Patients should be helped to participate in exercise programs. 16 Aerobic exercise should be encouraged to help combat the adverse effects of rheumatoid d isease on muscle strength, endurance and aerobic capacity, without, in the short-term, exacerbating disease activity or joint destru ction. 17 Hydrotherapy should be accessible to maximize positive effects on pain, function and sel f-ef \201 cacy. 18 Transcutaneous electrical nerve stimulation use in RA patient may be effective in pain r elief, but trials lack standardization. 19 Heat and cold applications may provide short-term symptomatic relief of symptoms of pain and stiffness. There is no evidence of long-lasting bene \201 t. Paraf \201 n wax baths combined with exercise are bene \201 ci al for hands in arthritic conditions. 20 Joint protection, energy conservation and problem-solving skills training should be taug ht early on in the disease course. 21 Hand function should be maintained and improved with a combination of hand exercises and appropriate devices to improve ef \201 ciency of action. OT can be helpful for those experiencing problems at work when t hese are due to the symptoms of arthritis. Altering work methods, posture, pacing and assis tive devices can improve functional ability. 22 When hands and wrists are painful and/or swollen, splints (hand/wrist resting splints an d functional wrist splints) should be offered, but the role of splinting at other times remains uncertain. 23 The goals of foot care for patients with RA are to relieve pain, maintain function and i mprove quality of life using safe, cost-effective treatments, such as palliative foot care, prescribed foot orthoses, and specialist footwear. An annual foot review and assessment is recommended for patients at risk of developing serious complications in order to detect pr oblems early. Foot orthoses are an important and effective intervention in RA. 24 Health professionals should provide opportunities to discuss sexuality and relationship issues where RA affects these. Problems may include pain, dysfunction and changes in relationships, for example dependence and loss of role. Information and help on sexuality and relationship issues should be given backed up w ith written lea \202 ets and contact details of organizations that can offer support.