Rheumatoid arthritis

Diagnosis of rheumatoid arthritis

Rheumatoid arthritis is a symmetrical small and large joint deforming arthritis that is more common in women. It is characterised by morning stiffness, gradual deterioration in activities of daily living, progressive joint deformity with nodule formation, and a relapsing and remitting course. Early disease is sometimes incorrectly managed with non-steroidals alone which control pain but don’t prevent deformity. The 1987 ARA criteria for rheumatoid arthritis were revised in 2010¹ after criticism that they were insufficiently sensitive (early disease was being missed and consequently under-treated.) The performance characteristics of the new 2010 criteria are still being established, but early studies² suggest that they have improved sensitivity (>90%) at the cost of very low specificity (50% to 60%).

“Definite RA” requires a score of 6 or more points (Add up the numbers in brackets for each step in the figure starting with symptom duration.)These criteria are most useful to rule out the diagnosis (they are highly sensitive) but patients with a number of other conditions may also satisfy them (they are not very specific) A patient with long-standing extensive chronic gout, might have five joints involved, and a raised CRP, which is why it is important to consider other conditions first. ACPA = anti-cyclic citrullinated protein antibody.

In the pattern of joint involvement, to fulfil the criterion of more than 10 joints involved (swelling or tenderness) and score the maximum of 5 points, at least one of the joints must be a small joint. Small joints were defined as MCPs, MTPs (but not 1st MTP), PIPs and wrists. Large joints were shoulders, elbows, hips, knees and ankles. ACPA = anti-citrullinated protein antibody

Differential diagnosis of rheumatoid arthritis.

• Osteoarthritis – occurs predominantly in the weight bearing joints, and in the arms, those taking most mechanical strain. The pain is worse with activity and towards the end of the day. Patients are often overweight. Unlike rheumatoid arthritis, morning stiffness is rare.
• Gout – can, particularly in women on diuretics, present with a small joint arthritis affecting the hands. A history of classical podagra (single hot distal joint) may be absent. It is usually of relatively abrupt onset – ‘attacks’ last a few days or weeks.
• Reactive arthritis. Patients are often relatively young, with both large and small joints involvement that may be asymmetrical. There is often an acute history (but RA has to start sometime…)
• Other conditions worth considering are psoriatic arthritis (check for the skin rash and for fingernail pitting), sarcoidosis (often associated respiratory disease) and SLE and the other collagen-vascular diseases deserve consideration. SLE for practical purposes won’t cause joint deformity. Systemic sclerosis (scleroderma) shouldn’t cause confusion if you think of it – tethered skin and reduced mouth opening.

Prognosis in rheumatoid arthritis

Severe rheumatoid arthritis is a life-threatening condition with mortality rates approaching those for severe ischaemic heart disease and malignancy. Most studies showing these high rates were conducted on specialist clinic referral populations so may not reflect the true epidemiology of the disease.

Therapy in rheumatoid arthritis.

In a symptomatic patient with an established diagnosis of rheumatoid arthritis, specific therapy with DMARDs (disease modifying anti-rheumatic drugs) is indicated. In patients with relatively mild disease, or where monitoring may be problematic, low dose prednisone and chloroquine is a common start, but probably not very effective, and another agent and another agent such as methotrexate should be added early to avoid progression of joint deformity. In terms of safety profile chloroquine in moderate doses is relatively safe if the patient has regular (yearly) eye checks, methotrexate and sulphasalazine are probably next, and all the rest come an uncomfortable third with somewhat different side-effect profiles but a similar need for close monitoring.

Non-steroidal anti-inflammatory agents. Use early in highish doses, and start actively weaning off once the DMARDS are starting to have an effect. It is important to educate patients about what to expect with adequate initial therapy – many patients have been managed for months or years with lowish doses of varying agents, and are quite impressed when you pump up the dose. It is important that they understand early that this is only a bridging process, and because of renal and gastrointestinal side effects, it is necessary to drop the dose after a few months. Try:

• Ibuprofen 600-800 mg 3x/d with food,
• Or diclophenac 50mg 3x/d with food.

Corticosteroids. Both patients and doctors love prednisone. The evidence for harm is long-standing – weight gain, osteoporosis, diabetes and peptic ulceration. Outside the situation of rheumatoid vasculitis corticosteroids should not be used in high doses – a starting dose of 15-20 mg/d of prednisone can be weaned relatively quickly to 10 mg/day and then 7.5 mg/day. It should not be used long term in doses higher than 7.5 mg/day, and even this dose still evokes controversy although some authors maintain it has some ability to slow joint damage.³

Chloroquine. An eye check needs to be performed at least yearly. There are two preparations, a sulphate and a phosphate. Pharmacies often flip between the two and as there is nothing to choose between them pharmacologically: the main issue is to ensure that you are always prescribing the correct dose. Consider prescribing in terms of the base alone – e.g. chloroquine base 150 mg/day. The drug has an inordinately long half-life, and accumulation with eye toxicity will eventually occur. One compromise is to ask the patient to omit the drug on the weekends – i.e. take it only once a day Mondays to Fridays and don’t take it on Saturdays and Sundays.

Sulphasalazine Check LFTs, creatinine and FBC on initiating therapy and then monthly for the first three months while you are escalating doses. Thereafter check every three months unless earlier testing seems needed⁴ (patient unwell or a concerning value on previous test.) Start with 500 mg/day, then increase at fortnightly or monthly intervals to 500 mg 12 hourly, then 500 mg 8 hourly. If tolerated from a GIT perspective try going up to 1g 12 hourly. Efficacy is limited by side effects (up to a quarter withdrew in one meta-analysis)⁵ Note also that this drug is quite costly and can make significant inroads into a hospital drug budget unless used judiciously.

Methotrexate has gained a reputation for being quite effective and safe, especially when used in combination. The drug is easiest to give once weekly orally, and there are probably no advantages to the intramuscular route unless you suspect that there are major problems with compliance. Monitoring – same as for sulphasalazine. Dose: 7.5 mg/week for 2 weeks, then 10 mg/week. The maintenance dose is usually 12.5-25 mg/week – see what is tolerated. Once stabilised, FBC and LFT monitoring probably only needs to be done every 3 months. Give as a single dose on the same day each week. Some patients get an upset stomach that day and may benefit from metoclopramide prophylaxis. Give a single dose of folic acid weekly, at least 24 hours after the weekly methotrexate dose.

Cyclophosphamide and azathioprine are thought to be of value particularly in individuals with evidence of a vasculitis. Standard monitoring as for immunosuppressives – i.e. monthly FBC.

Perspective – safety and efficacy of DMARDs

There are quite a number of studies showing broadly similar results, but many are relatively short term. One looked at results on 2170 patients followed for a mean of 6 years collected in a computer database, and purportedly reflected ‘everyday clinical practice’⁶: the median number of months on treatment before stopping due to inefficacy or a clinically important adverse drug reaction was 96 for methotrexate, 43 for sulphasalazine, 34 for penicillamine and 13 for azathioprine. The total patient years on treatment before a death was reported was 109 for sulphasalazine, 44 for methotrexate, 36 for penicillamine, 31 for azathioprine, and 14 for cyclophosphamide.

Perspective – which strategy for early disease?

There are numerous guidelines and a fair number of adequate quality studies, but few systematic reviews covering the issue of which complex protocol (as opposed to which agent) works best in early disease. One randomised trial from the Netherlands (BeSt study)⁷ did in fact compare four protocols and found that initial combination therapy (tapered higher-dose prednisone, methotrexate and sulphasalazine) performed better than sequential monotherapy or step-up combination therapy without prednisone, and about as well as an initial combination approach including infliximab. However, after one year changes in HAQ score (Health Assessment Questionnaire) were no longer significantly different between the groups. (All strategies at some stage included infliximab and leflunomide.) Interestingly, a recent network meta-analysis⁸ found that a biologic plus one DMARD was not superior in preventing joint damage to 2 DMARDs with or without low dose glucocorticoids, which is reassuring in light of the restricted availability of the biologics.

Perspective – cyclic citrullinated protein antibody

Much of the information on this assay is not of high quality. A systematic review⁹ pooled results which were arguably too heterogeneous for that, but came up with a sensitivity for the diagnosis of RA of 67% (95% CI 62 to 72%) and specificity of 95% (95% CI 94 to 97%.) The sensitivity of RF itself varies around 70%, depending on the study; doing an anti-CCP if the RF is not diagnostic may increase sensitivity to 80%.¹⁰ Like RF, false positive CCPs are described – e.g. in tuberculosis.)

Rheumatoid arthritis – injecting joints.

A single ‘out of step’ joint may respond gratifyingly to corticosteroid injection, but don’t overdo this. If you find yourself tempted to inject more than one or two joints in a patient per year, you probably should rather be reviewing the remmitive therapy.

Big joints can handle up to 40 mg of depot methylprednisolone; for smaller joints 10-20 mg may be adequate. Joints where reasonable success can be achieved are shoulders, acromioclavicular joints, elbows and knees. Dilute with an equal volume of 2% lignocaine, and inject using a sterile no-touch technique. Don’t do an injection near a neurovascular bundle, and inject into a palpable synovial space. If you don’t know the anatomy, read it up first, and don’t inject into tendons or ligaments – they may rupture subsequently. Preferably get taught by example.

Monitoring activity in rheumatoid arthritis.

Clinical – asking the duration of morning stiffness may be problematic – in patients who get up at the same time each day, it is simpler to just ask at what time of the day the stiffness wears off. As about activities of daily living, and consider doing a joint count (how many, and which, joints are painful to palpation)

• CRP
• Rheumatoid factor titre.

Complications of rheumatoid arthritis

Complications of therapy have been alluded to above. Treat as they arise, and consider whether that particularly therapy is still appropriate – it usually can be stopped or replaced with something else. The main complications of the disease itself reflect failed therapy, and include:

• Sudden loss of finger extension due to extensor tendon rupture – prompt repair can save function.
• Rapid worsening of hip discomfort with what is known as protrusio acetabuli where the distorted femoral head pushes into the pelvis through a thinned acetabulum – an indication for relatively rapid hip replacement, if feasible.
• Atlanto-axial instability. Major cervical neurology due to arthritic destruction is relatively rare, but when it occurs, take an X-ray and order a collar while obtaining orthopaedic advice. Often bone stock is so poor that surgical options are limited.
• Sudden back pain due to osteoporotic collapse. Treat symptomatically and consider where steroids are still achieving anything if the patient is still on them.

Referral for surgery

Consider surgery for a few disabled joints in a patient who has otherwise settled and is left with considerable irreversible destruction. Hip and knee joint replacements are most useful, but it is clearly pointless doing an impeccable operation on somebody’s hip if they have major foot disease, so the process does tend to snowball, and the patient should be prepared for quite a long slog. If in doubt, ask. It is sad to condemn a young person to a wheelchair where one or more operations may restore considerable function.

When to stop therapy in rheumatoid arthritis

Many older persons have ‘burnt-out’ disease where there may still be considerable disability and pain secondary to joint destruction. However they have minimal if any evidence of inflammation, and little morning stiffness. Carrying on with aggressive therapy in that situation is inappropriate – withdraw slowly, particularly if the person is a strong believer in the ongoing efficacy of the product. (Every now and then there is still unrecognised ongoing activity.) You should also add in regular paracetamol as a simple analgesic.

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1. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria. Arthritis and Rheumatism 2010; 62(9):2569-2581. DOI 10.1002/art.27584. ↩

2. Kennish L, Labitigan M, Budoff S, et al. Utility of the new rheumatoid arthritis 2010 ACR/EULAR classification criteria in routine clinical care. BMJ Open2012;2:e001117. doi:10.1136/bmjopen-2012-001117 ↩

3. Van Everdingen AA, Jacobs JW, van Reesma DR, et al. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects. Ann Intern Med 2002;136:1-12 ↩

4. Singh JA, Saag KE, Bridges SL, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care and Research 2015. DOI 10.1002/acr.22783 ↩

5. ME Winblatt et al. Sulphasalazine treatment for rheumatoid arthritis: a meta-analysis of 15 randomized trials. J Rheumatol 1999 26: 2123-30 ↩

6. Grove ML, Hassell AB, Hay EM, et al. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice. Q J Med. 2001;94:309-19 ↩

7. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CR, et al. Comparison of treatment strategies in early rheumatoid arthritis. Ann Intern Med. 2007;146:406-15 ↩

8. Graudal N, Hubeck-Graudal T, Tarp S, et al. Effect of Combination Therapy on Joint Destruction in Rheumatoid Arthritis: A  Network Meta-Analysis of Randomized Controlled Trials. PLoS ONE 9(9): e106408.doi:10.1371/journal.pone.0106408 ↩

9. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Annals Int Med 2007; 146(11): 797-808 ↩

10. Lee DM, Schur PH. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 2003;62:870–874 ↩

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