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The Pharmaceutical Journal 145

A FIFTY-TWO-YEAR-OLDwoman is referred to the earlyarthritis outpatient clinic by herGP. The GP’s letter states she hasa four-week history of pain in herfinger and lower limb joints. Thepatient reports “walking like adisabled person” and that she hasnever had this problem before.Blood tests (performed by theGP) show a raised ESR(erythrocyte sedimentation rate).Her previous medical historyincludes hypertension, uterinefibroids and iron-deficiencyanaemia. Her medication consistsof:

•Amlodipine 5mg od

• Ferrous fumarate 210mg tds

•Diclofenac 50mg tds

•Co-codamol 8/500 ii qds prn

The medical registrar takes abrief medical history and carriesout an examination, which revealssynovitis in the wrists,metacarpophalangeal (MCP)joints and proximalinterphalangeal (PIP) joints ofboth hands, and synovitis in bothankles. The patient complains of

Rheumatoid arthritis: a patient’s journey (I)This case study aims to help you understand the diagnosis of rheumatoid arthritis, the different medicines that may be prescribed and the support you can give patients

TINA HAWKINS IPRESC, MRPHARMS, ADVANCED CLINICAL PHARMACIST — RHEUMATOLOGY, LEEDS TEACHING HOSPITAL NHS TRUST

(Vol 292) 8 February 2014www.pjonline.com

early-morning stiffness thatpersists for up to two hours. Herhands and wrists have beentender and swollen for twomonths. Swelling and pain inboth knee joints and her feet havemade walking difficult.

The registrar performs anumber of blood tests, including afull blood count (FBC), liverfunction tests (LFTs), urea andelectrolytes (U&Es),inflammatory markers andantibodies associated withautoimmune inflammatory jointdiseases. He also performs aninfection screen to rule this out asa cause.

The patient’s disease activityscore 28 (DAS28) is calculatedand she is sent for X-rays of herhands, feet and chest. This showsearly erosive change at the fifthmetatarsal head but no otherabnormalities.

A provisional diagnosis ofrheumatoid arthritis (RA) ismade and the patient is asked to

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REFLECT

The scoring system consists of four categories. A score of at least 6 outof 10 is required for diagnosis.

Joint involvement1 large joint 02–10 large joints 11–3 small joints (with or without involvement of large joints) 24–10 small joints (with or without involvement of large joints) 3>10 joints (at least one small joint) 5

Serology (at least one positive result is needed for classification)Negative RF and negative ACPA 0Low-positive RA or low-positive ACPA 2High-positive RA or high-positive ACPA 3

Acute phase reactants (at least one abnormal result needed)Normal CRP and normal ESR 0Abnormal CRP or abnormal ESR 1

Symptom duration< six weeks 0≥ six weeks 1

Key: RF = rheumatoid factor; ACPA = anti-citrullinated protein antibodies; CRP = C-reactiveprotein; ESR = erythrocyte sedimentation rate* Adapted from the American College of Rheumatology and EULAR classification criteriafor rheumatoid arthritis

PANEL 1: CLASSIFICATION CRITERIA FOR RA*

X-rays show inflamed and swollen joints as well as erosive changes in rheumatoid arthritis (DU CANE MEDICAL IMAGING LTD/SCIENCE PHOTO LIBRARY)

diabetes mellitus andhypertension. Low-dose oralprednisolone may be usedintermittently if the diseasecannot be controlled by othermeans. For severe disease,particularly where there are extra-articular manifestations, pulsedIV infusions ofmethylprednisolone may begiven, although with theintroduction of newer therapiesthis is now less common. Patientswith repeated exposure tocorticosteroids are at high risk ofglucocorticoid-inducedosteoporosis. The fall in bonemineral density associated withcorticosteroids is highest withinthe first few months.Consideration should be given tothe need for bone protection witha bisphosphonate and calciumplus vitamin D supplementation.

the prescriptionThe patient takes her prescriptionto the hospital pharmacy. Sheasks the pharmacist if she shouldtake the new medicines inaddition to her usual painkillers.

What are the importantdifferences between the non-steroidal anti-inflammatorydrugs? The differences in anti-inflammatory effects of thevarious NSAIDs are small, butthere is wide variation in theincidence of side effects andpatients differ in their response. Ifa patient does not respond to oneNSAID he or she might respondto another. However, it isimportant to give a chosenNSAID an adequate therapeutictrial before switching. Pain-relieving benefits begin after thefirst dose, but maximumanalgesia takes up to a week todevelop and anti-inflammatoryaction up to three weeks.

Gastrointestinal bleeding andperforation occur in around 1 percent of patients and result insignificant morbidity andmortality. Piroxicam, ketoprofen,indometacin, naproxen anddiclofenac are all associated withan intermediate risk ofgastrointestinal side effects;azapropazone is associated withthe highest risk and ibuprofen thelowest. The cyclo-oxygenase-2(COX-2) selective agentsetoricoxib and celecoxib are aseffective as traditional NSAIDsbut have a lower incidence ofgastric side effects. The optionsfor reducing gastric side effectsdue to NSAIDs are to avoid them

and use simple analgesia; to usean NSAID with the fewestassociated gastrointestinal sideeffects and at the lowest possibledose; to prescribe agastroprotective agent (protonpump inhibitors are probablybest); or to prescribe a selectiveCOX-2 inhibitor. All NSAIDs,including the COX-2 inhibitors,however, are contraindicated inthe presence of active peptic ulcerdisease. Concomitant aspirintherapy greatly increases thegastrointestinal risks of NSAIDsand severely reduces anygastrointestinal safety advantagesof COX-2 selective agents.

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return to the clinic two weekslater to start treatment with adisease-modifying antirheumaticdrug (DMARD). She is given adepot intramuscular injection of120mg methylprednisoloneacetate and a prescription for:

•Naproxen 500mg bd

•Tramadol 50mg qds prn

What common symptoms areassociated with ra? RA is achronic autoimmune condition. Itpresents as a polyarthritis,sometimes developing acutelyover a few days or, morecommonly, over weeks to months.Fatigue and diffusemusculoskeletal pain may occurbefore there is visible swelling ofthe joints. The disease commonlypresents with swelling, tendernessand stiffness in joints, usuallythose of the hands, wrists, knees,ankles and feet. Morning stiffnessis a common early feature.“Boggy” synovial tissue may befelt on examination. However, RAis not purely a disease of thejoints and extra-articularmanifestations can affect thelungs, skin, blood, eyes and otherorgans. The European LeagueAgainst Rheumatism (EULAR)uses a score-based algorithm indiagnosing RA (see Panel 1).

What is the role of corticos-teroids in managing ra? Corticosteroids are often used asa bridging therapy to reducesymptoms and disease activitywhen waiting for the therapeuticonset of a DMARD or whenchanging from one DMARD toanother.

Owing to the long-term sideeffects associated withcorticosteroids it is not ideal touse them for long but in resistantcases it may be necessary toinclude them because the diseasecannot be controlled withstandard biologic and DMARDtherapy alone.

Depending on the number ofaffected joints, corticosteroidsmay be injected directly into thejoint (intra-articular), or given asan IM depot injection or as short-term oral therapy, tapered asrapidly as clinically feasible. Theyproduce rapid relief ofinflammatory symptoms and mayhave a role in diseasemodification, but their use, athigh dose in particular, isrestricted because of their long-term side effects, such asosteoporosis, peptic ulceration,

Methotrexate is highly effective in the management of RA, both as amonotherapy and on the basis of its ability to increase the efficacy ofbiologic medicines (see Part II, to be published next week). No otherDMARD has shown superiority in terms of clinical efficacy and meta-analyses have confirmed tumour necrosis factor inhibitor (TNFi)monotherapy (also called anti-TNF) is not superior to methotrexate inimproving signs and symptoms of RA.

Methotrexate is generally used as a first-line agent (unlesscomorbidity precludes its use). It has an onset of action of about amonth, and can be given orally or by subcutaneous or IM injection. Ittends to be given by injection when patients are unable to tolerate oraldoses because of gastric side effects, or where doses of 25mg or moreare being given. The starting dose tends to be 7.5–10mg once a week,then gradually adjusted according to response and tolerance. Patientsshould be clearly counselled that methotrexate should only be takenonce a week.

Common side effects include mouth ulcers (stomatitis) and nausea.Folic acid is commonly prescribed to counteract these, at 5mg oncedaily, although other regimens are used. Most will omit the dose on theday of methotrexate therapy to avoid any potential impact on the latter’sefficacy.

The use of methotrexate has been associated with haematological,hepatic and pulmonary toxicity. Because of the drug’s potential tosuppress bone marrow and cause liver toxicity it is essential thatcertain blood tests are performed regularly. All patients should havebaseline FBC, U&E and LFTs and these should then be performedregularly throughout treatment.

Panel 3: methotrexate iS firSt choice

DAS28 is a disease activity score based on a 28-joint count. It iscalculated from the number of tender and swollen joints, the patient’sESR or CRP and a self-determined patient assessment of general healthstatus according to a 100mm visual analogue scale. A score of morethan 5.1 indicates high disease activity; ≥3.2 and up to 5.1 indicatesmoderate disease activity; between 3.2 and 2.6 indicates low diseaseactivity; and <2.6 indicates remission.

DAS28 is often used to determine when treatment with a biologicshould be started, and to evaluate the patient’s response. An adequateresponse is defined as an improvement in the DAS28 of 1.2 points ormore. A drawback associated with using DAS28 as an indicator forchanging therapy is that some patients may not have particularly highinflammatory markers, but still have severe disease.

DAS28 may also be raised by the perception and reporting of pain bypatients and the presence of pre-existing long-term damage. Variationsin the score will be caused by different individuals making theassessment, and any sensory, communication or learning difficulties apatient may have.

Panel 2: DaS28 anD itS Significance

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The Pharmaceutical Journal 147

Recent epidemiological studieslend support to the view thatsome increased cardiovascularrisk may apply to all NSAIDsirrespective of their baseline risk,and not only to chronic users.The greatest concern relates tochronic users of high doses,especially of the COX-2-selectiveagents and diclofenac. Diclofenacshould no longer be prescribed inpatients with establishedischaemic heart disease,peripheral arterial disease,cerebrovascular disease orcongestive heart failure (NYHAII-IV). Evidence suggests thatnaproxen is associated with alower thrombotic risk than boththe COX-2 selective agents anddiclofenac. Patients should usethe lowest effective dose and theshortest duration of treatmentnecessary to control theirsymptoms. For ibuprofen the riskis low for doses below 1,200mgper day, but doses of 1.6–2.4gdaily are needed in RA.

All NSAIDs are contraindicatedin severe heart failure and shouldbe used with caution in patientswith renal impairment.

It also should be noted thatalthough NSAIDs may inhibit theexcretion of methotrexate (seelater), leading to toxicity, thisusually remains a theoreticalconcern. NSAIDs are oftenprescribed with methotrexate butpatients are carefully monitored.

How might new pain reliefchange the current prescription?In view of this patient’s history ofhypertension it is appropriate toswitch to an NSAID associatedwith a lower thrombotic risk, suchas naproxen.

The combination of tramadolwith co-codamol 8/500 isinappropriate and needs to bediscussed with the prescriber, asdoes the need for gastricprotection.

Paracetamol, used incombination with a weak opiatesuch as dihydrocodeine, canprovide simple pain relief.Although they have no anti-inflammatory properties and willnot affect the disease process,such simple analgesiccombinations do have a place inboth early and late stages of RA.

The World HealthOrganization’s analgesic ladder isa good starting point for anydecision on analgesia. Note thatcodeine in doses of 8mg, as in co-codamol 8/500, has not beenshown to confer any additional

benefit over standardparacetamol. The patient maybenefit from a prescription ofparacetamol 1g qds combinedwith a separate weak opioid such as dihydrocodeine 30mg qds. It is important to avoid theco-prescription of two weakopioids, for example, tramadoland co-codamol, because this isunlikely to provide additionalanalgesia and will predispose thepatient to unwanted side effects.A laxative, to prevent opiate-induced constipation, may beneeded.

Day 14On Day 14 the patient returns toclinic to be reviewed by arheumatology nurse specialist.The results from her blood testsare as follows:

•Haemoglobin 11.1g/dl (11.5–16.0)

•Red blood cells 4.85×1012/L(3.80–5.80)

•White blood cells 4.18×109/L(4.00–11.00)

•Neutrophils 2.22×109/L (2.00–7.50)

• Plasma viscosity 1.90mPa/s(1.50–1.72)

• Platelets 323×109/L (150–400)

•Mean cell volume 78fl (78–100)

•U&E and LFT levels and liverfunction unremarkable

•Urate 239mol/L (140–360)

• Infection screen negative

•C-reactive protein (CRP)57mg/L (<10.0)

•Rheumatoid factor (RF)250IU/ml (<20)

•Anti-cyclic citrullinated peptide(anti-CCP) assay 318 (CCPquantitive result >10: positive)

•Anti-neutrophil cytoplasmicantibody (ANCA) screennegative

What is DAS28? The patient stillhas a number of swollen andtender joints. The DAS28 iscalculated and recorded (seePanel 2).

The patient reports that theinjection and painkillers she wasgiven reduced some of her painand stiffness.

A formal diagnosis ofseropositive RA is made. Thenurse explains what RA is andhow it is managed. She gives thepatient a prescription for aDMARD and a form to haveblood tests (FBC, U&Es, LFTs and inflammatory markers)two weeks later. The patient is asked to return to clinic after fourweeks.

What is the significance of RFand anti-CCP? RF and anti-CCPare antibodies directed againstone or more of an individual’sown proteins. These auto-antibodies may be detected in theblood of patients with RA and,along with other tests, are used indiagnosis.

Sulfasalazine Sulfasalazine (enteric-coated) is indicated in mild-to-moderate disease. It has an onset of action of six to 12 weeks. In orderto reduce nausea the dose is usually titrated up from 500mg od,increasing at weekly intervals to 1g bd. Haematological abnormalitieshave occurred with sulfasalazine and, although these are rare, patientsshould be advised to report unexplained bleeding, bruising, sore throat,fever or malaise. Patients should also be warned that sulfasalazine cancolour urine red and stain contact lenses. Baseline FBCs and LFTsshould be performed and repeated intermittently throughout treatment.

Leflunomide Leflunomide inhibits the synthesis of pyrimidinenucleotides in response cells (particularly T-cells) and reduces pro-inflammatory cytokines. Studies have shown it to be at least as effectiveas sulfasalazine and methotrexate, and for quality-of-life measuressome evidence suggests superiority. When given as a loading dose of100mg od for three days followed by a maintenance dose of 10–20mgdaily its therapeutic effect starts after four to six weeks, and furtherimprovement may be seen for up to six months. However, many centresdo not use this loading dose regimen because patients are unable totolerate the gastrointestinal side effects associated with it.

Leflunomide use has been associated with both haematological andhepatotoxic side effects. An FBC and LFTs must be performed beforetherapy is initiated, and then every two weeks for the first six months,followed by every eight weeks. When leflunomide and methotrexate areused in combination extra caution is advised. Leflunomide can alsocause hypertension — blood pressure should be checked before startingleflunomide and regularly after — and men and women are required touse adequate contraceptive measures during treatment, and a washoutprotocol must be followed for any patient considering starting a family.

Gold Although injectable gold (sodium aurothiomalate) has been shownto be efficacious in the management of RA, its use is limited due to itsunfavourable side effect profile. Due to the risk of anaphylaxis an initial10mg test dose should be given in the first week of treatment, followedby a maintenance dose of 50mg the following week. Administration is bydeep IM injection. Patients should be monitored for 30 minutes followingeach dose. FBC and urine (for proteinuria) should be checked after sixdays, just before giving the next full dose of 50mg IM. The maintenancedose of 50mg every week is given until the first signs of remissionoccur. At this point the interval between injections should be extended totwo weeks until full remission occurs. The interval between injectionscan then be increased progressively to three weeks, four weeks andthen, after 18 months to two years, to six weeks.

Azathioprine Azathioprine is an oral purine analogue that inhibitslymphocyte proliferation. It becomes biologically active aftermetabolism by the liver to 6-mercaptopurine. Bone marrow suppressionand liver toxicity are associated with its use and FBCs and LFTs shouldbe performed during treatment. Renal function should also bemonitored because the drug is renally excreted. Azathioprine may alsobe used for steroid-sparing.

Ciclosporin Ciclosporin works by impairing the function of B- and T-lymphocytes. Dose-related hypertension and nephrotoxicity arecommon side effects. FBCs should be performed during treatment andliver and renal function monitored. Ciclosporin drug levels are notroutinely measured when it is used for the management of RA.

PANEL 4: OTHER DMARD OPTIONS

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RF is the initial defining auto-antibody in RA. It is an antibodyagainst a portion (Fc) of IgG. RFand IgG combine to formcomplexes that contribute to thedisease process. However, apositive result may have anothercause and a negative result doesnot rule out RA. Around 80 percent of patients with RA will bepositive for RF and this mayprecede symptom onset byseveral years. The presence of RFis associated with a poorerprognosis. Other conditionsassociated with an elevated RFinclude chronic hepatitis, primarybiliary cirrhosis, chronic viralinfection, bacterial endocarditis,leukaemia, infectiousmononucleosis, systemic sclerosisand systemic lupuserythematosus.

Raised anti-citrullinated proteinantibodies (ACPA; also known asanti-CCP) has been relativelyrecently recognised as a markerfor RA. Post-transitionalmodification of arginine residuesto citrulline is the antigenrecognised and it has a higherspecificity for distinguishing RAfrom other rheumatic diseases.The presence of ACPA may alsoprecede symptoms of RA bymany years and it is highlypredictive of the futuredevelopment of RA in healthyindividuals and patients withundifferentiated arthritis. ACPA-positive RA is associated withincreased joint damage and lowerremission rates. ACPA-positiveand ACPA-negative RA areassociated with different geneticand environmental risk factorsand are increasingly viewed astwo distinct disease entities.

When should a DMARD bestarted and which are commonlyused? All patients with confirmedRA should be started on aDMARD immediately. Severalstudies have shown thatirreversible damage occurs in thefirst two years of RA — magneticresonance imaging indicates ithappens within weeks and earlytherapeutic intervention with canimprove patient outcome andreduce disease progression.

DMARDs do not provide painrelief but do suppress the diseaseprocess. They also have a delayedonset of action — it can take sixweeks before the patient starts tosee a response, and up to sixmonths for a full response.

Recommendations vary onwhether a patient should be

started on a single DMARD orwhether it is more appropriate toprescribe a combination. CurrentNational Institute for Health andCare Excellence guidancerecommends that all patients withnewly diagnosed active RAshould be offered two DMARDsas first-line treatment, ideallywithin three months of the onsetof persistent symptoms. However,European guidance suggests thatDMARD monotherapy may bemore appropriate in DMARD-naive patients. Reasons includevariations in glucocorticoid use intrials comparing DMARDcombination and monotherapy,which resulted in non-comparative treatment arms, plusdifficulties in evaluating toxicityand efficacy when two DMARDsare started together. Physiciansmay, therefore, prefer to start witha single agent with closemonitoring and rapid doseescalation, with early addition of asecond agent where appropriate.

The precise mechanism ofaction of DMARDs is unclear.There is good evidence that theyinhibit the activity ofinflammatory cytokines. Certaincytokines have been shown toplay an important role in thepathogenesis of RA. Activated T-cells also play a role in the earlyinduction of RA. Methotrexateand leflunomide have both beenshown to inhibit T-cells.

The agent of choice ismethotrexate (see Panel 3, p146).This is considered the “anchor”drug in RA, but its use may becontraindicated in some patientsor therapy may have to bediscontinued due to side effects.Other currently recommendedDMARDs include sulfasalazine,leflunomide and injectable gold(see Panel 4). Azathioprine andciclosporin may be usedoccasionally for progressivedisease refractory to otherDMARDs, or where a biologic iscontraindicated.

The antimalarialshydroxychloroquine andchloroquine may also be of use inmilder disease. They show someefficacy as a monotherapy withrespect to the signs andsymptoms of RA but they havenot been shown to inhibitstructural damage sufficientlycompared with other DMARDs.They may also be combined withother DMARDs in themanagement of RA, but it is notestablished if they conferadditional efficacy.

Penicillamine is no longer usedin the management of RA due toits poor side effect profile andlack of efficacy compared withother agents.

New prescriptionThe patient visits the outpatientpharmacy with a prescription fororal methotrexate 10mg once aweek for two weeks, then 15mgonce each week for two weeks inconjunction with folic acid 5mgdaily, except on the day themethotrexate is taken.

What counselling would you givewith methotrexate? Althoughmethotrexate is a safe medicinewhen used appropriately, deathshave occurred as a consequenceof patients taking it incorrectly.The patient must understandhow and when to take themedicine, plus the need forregular blood monitoring. It mustbe clear that methotrexate is takenonly once a week and all patientsprescribed it should berecounselled every time they areissued with a prescription,irrespective of how long they havebeen receiving treatment.

Important points to cover whencounselling a patient prescribedmethotrexate are listed in Panel 5.National Patient Safety Agencyguidance recommends that allpatients taking methotrexateshould be issued with a corepatient information leaflet and ahand-held monitoring booklet.The prescriber should providethe patient with informationabout the benefits and risks oftreatment. “As directed” shouldnot be used and patients shouldbe clear on the number of tabletsthey are taking and on which dayof the week. There should also beconsistency on the strength of thetablet issued — ideally, patientsshould be supplied with only the2.5mg strength to avoidconfusion. When dispensing theprescription it should be clearlypointed out which is themethotrexate container and whichis the folic acid container, so thepatient is able to differentiatebetween the two.

Part 2Find out what happened next —follow this case in part II, to bepublished in The Journal nextweek. Part II will focus onbiologic agents used for RA:when it is appropriate to usethem, checks needed, associatedrisks and switching options.

Learning &developmentUnless stated otherwise,Learning & developmentmaterial is commissionedby The Journal and is notpeer-reviewed

Points to cover:

•Why the methotrexate isprescribed

•How long it will take to work

• The dose and the frequency

• The importance of regularblood monitoring

• Side effects, includingwarning symptoms thatnecessitate urgent referralto the doctor (eg, increasedbreathlessness, a drypersistent cough or vomitingand diarrhoea

• Interactions with themedicine, including over-the-counter products and herbalremedies

• The need for adequatecontraception (men andwomen)

PANEL 5: ADVICEWITH METHOTREXATE

This article has been adaptedfrom a chapter in ‘Drugs in use’, available from ThePharmaceutical Press.