10.0 Musculoskeletal and joint diseases

10.1.1 Non-steroidal anti-inflammatory drugs (NSAIDs)

First line treatment

GREEN     Ibuprofen                                                                                                                                                                                        tablets 200mg, 400mg, 600mg                                                 

           syrup 100mg/5mL                              

GREEN      Naproxen                                                                                                                                                                            tablets  250mg, 500mg                                                       

Gastrointestinal toxicity and cardiovascular toxicity are the two most important safety concerns for non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors (coxibs). Clinical trial and epidemiological data have given important information on the level of risk with individual medicines. However, these data are complex and there are no robust comparisons for many NSAIDs. Most evidence relates to the coxibs, naproxen, ibuprofen, and diclofenac.  The National Prescribing Centre (NPC) has summarised up-to-date prescribing advice and information in relation to NSAIDs, which is available through their website (www.npc.nhs.uk).

Thrombotic risks

In October 2006, the Commission on Human Medicines (CHM) gave advice on the latest evidence for cardiovascular thrombotic risks: 

• Diclofenac 150 mg daily has a thrombotic risk profile similar to that of at least one coxib (etoricoxib) and possibly others
  
• Naproxen 1000 mg daily has a lower thrombotic risk than coxibs and, overall, epidemiological data do not suggest an increased risk of myocardial infarction
  
• For ibuprofen at high doses (eg, 2400 mg daily) there may be a small thrombotic risk, but at lower doses (eg, 1200 mg daily or less) epidemiological data do not suggest an increased risk of myocardial infarction

Less evidence is available for other NSAIDs, but they may be associated with a small risk of thrombotic events, especially with long duration of treatment and high doses.

Cardiovascular risks

Results of two recently published epidemiological studies lend support to the view that some increase in thrombotic cardiovascular risk may apply to all NSAID users, irrespective of their baseline risk, and not only to chronic users. The absolute increase in risk for 'healthy' users is very low. Current advice remains that patients should use the lowest effective dose and the shortest duration of treatment necessary to control symptoms. Overall evidence continues to indicate that naproxen is associated with a lower thrombotic risk than coxibs. For ibuprofen, no significant increase in risk has been identified for doses of up to 1200mg daily.

Reference: Drug Safety Update, Volume 2 Issue 7, February 2009.

Gastrointestinal risks

The Committee on Safety of Medicines (now the Commission on Human Medicines) has reviewed the relative gastrointestinal risks of NSAIDs on several occasions.  Recently, we have highlighted the high gastrointestinal risks with piroxicam, ketoprofen, and ketorolac.  Of the traditional NSAIDs, low-dose ibuprofen offers the lowest risk. Coxibs are associated with reduced gastrointestinal risk relative to most NSAIDs at equivalent doses. However, coxibs (like NSAIDs) may vary in their effects, and evidence for a reduction in the most clinically important gastrointestinal risks for etoricoxib is weak.  Proton pump inhibitors reduce the gastrointestinal risks associated with NSAIDs, and may reduce the risks to a similar level as use of a coxib alone.

Other NSAIDs

GREEN      Diclofenac

                   injection 25mg/mL

                   suppositories 12.5mg, 25mg, 50mg, 100mg

GREEN      Mefenamic acid

                   capsules 250mg

                   tablets 500mg                                                                             

Indometacin is usually recommended only for ankylosing spondylitis and gout.

GREEN      Indometacin

                   capsules 25mg, 50mg                                                                  

                   suppositories 100mg

Patients over 65 years who are in high risk groups for developing ulcers (history of peptic ulcer or bleeding, cardiovascular disease) should be given protection for the stomach when prescribed NSAIDs. NSAIDs and PPIs (Section 1.3.5) are often used together for these at risk patients.

Cox IIs (cyclo-oxygenase II selective inhibitors)

The MHRA has issued the following general advice concerning all selective COX-2 inhibitors (Feb-05):

•  Patients with established ischaemic heart disease, cerebrovascular disease or peripheral arterial disease should be switched to alternative treatment
  
• For all patients the balance of gastrointestinal and cardiovascular risk should be considered before prescribing a COX-2 inhibitor, particularly for those with risk factors for heart disease and those taking low dose aspirin, for whom gastrointestinal benefit has not been clearly demonstrated.
  
• The lowest effective dose of COX-2 inhibitor should be used for the shortest necessary period.  Periodic re-evaluation is recommended, especially for osteoarthritis patients who may only require intermittent treatment.
  
• Gastro-protective agents should be considered for patients switched to non-selective NSAIDs.

GREEN       Celecoxib

                   capsules 100mg, 200mg                                                     

GREEN      Meloxicam

                   tablets 7.5mg, 15mg                                                             

AMBER     Etoricoxib (Rheumatology initiation only)

                   tablets 60mg, 90mg, 120mg                                               

Osteoarthritis - NICE Clinical Guideline 177 February 2014

Treatment and management

Core treatment:

There are three core interventions which should be considered for every person with osteoarthritis:

• access to appropriate patient information sources,
  
• activity and exercise,
  
• interventions to achieve weight loss if person is overweight or obese.                                              

If further treatment is required then adjunctive treatments should be considered;   

Pharmacological:

• Paracetamol (regular dosing may be required). AND/OR
  
• Topical non steroidal anti-inflammatory drugs (NSAIDs) or topical capsaicin for knee or hand osteoarthritis

If above agent/s are ineffective or insufficient then consider;

• substitution or addition of an oral NSAID or COX-2 inhibitor (but NOT eterocoxib) OR
  
• Opioid analgesics 

Consider intra-articular corticosteroid injections if pain is moderate to severe.

Treatment with oral NSAIDs/COX-2 inhibitors:

All oral NSAIDs/COX-2 inhibitors have similar analgesic effects but vary in their gastrointestinal, liver and cardio-renal toxicity. This should be taken into account when choosing the drug and dose for an individual patient.

Treatment with oral NSAIDs/COX-2 inhibitors:

• Prescribe the lowest effective dose for the shortest possible period of time,
  
• ALWAYS co-prescribe a proton pump inhibitor (PPI) - choose one with the lowest cost.
  
• Assess patient risk factors for gastrointestinal, liver and cardio-renal toxicity,
  
• Consider ongoing monitoring of patient risk factors,
  
• Use an alternative analgesic if patient is taking low-dose aspirin.

Treatment with opioids:

• Consider the risks and benefits particularly in elderly people.
  
• Adverse effects: constipation, nausea, itchiness, drowsiness and confusion

Non-pharmacological:

• Application of heat or cold to the site of pain.
  
• Transcutaneous electrical nerve stimulation (TENS).
  
• Manipulation and stretching, particularly for hip osteoarthritis.
  
• Assessment for bracing/joint supports/insoles for people with biomechanical joint pain or instability.
  
• Assistive devices (for example, walking sticks and tap turners) for people with specific problems with daily activities. Expert advice may be required.

Treatments not recommended

DO NOT prescribe:

• rubefacients
  
• intra-articular hyaluronan injections
  
• electro-acupuncture
  
• chondroitin or glucosamine products

 

10.1.2 Corticosteroids

10.1.2.2 Local corticosteroid injections

These are given by intra-articular injection or by injection into soft tissue or the tendon sheath and         should be considered as an adjunct to core treatments for the relief of moderate to severe pain in people with osteoarthritis.

GREEN      Hydrocortisone acetate injection 25mg/mL                                                        

GREEN      Methylprednisolone injection 40mg/mL                                                               

GREEN      Triamcinolone acetonide injection 40mg/mL                                                      

RED           Triamcinolone acetonide injection 10mg/mL                                               

RED           Triamcinolone hexacetanide 20mg/mL (Lederspan®) – unlicensed import for use in chronic                            juvenile arthritis only.

10.1.2.3 Other local injections

Hyaluronan injections for osteoarthritis- Updated Feb 2014 CG177

NICE states ‘ Do not offer intra-articular hyaluronan injections for the management of osteoarthritis'

BLACK - Hyaluronan injections.

10.1.3. Drugs which suppress the rheumatic disease process

These are sometimes called disease modifying anti-rheumatic drugs (DMARDs). They are used when NSAIDs alone are not sufficient and they should only be initiated by a specialist. They require 4-6 months of treatment for a full response. If there is no benefit after 6 months they should be discontinued on specialist advice.

AMBER     Azathioprine tablets 25mg, 50mg

AMBER     Ciclosporin (Neoral®)

                   capsules 25mg, 100mg

                   oral solution 100mg/mL

RED          Cyclophosphamide injection 500mg, 1g

AMBER     Hydroxychloroquine tablets 200mg       

AMBER     Leflunomide tablets 10mg, 20mg

RED           Leflunomide tablets 100mg (used for initial loading doses only)

Secondary care will prescribe and supply leflunomide for the first three months, the primary care prescriber may then take over prescribing and the associated monitoring.

Methotrexate                                                                                                                                                                 All new patients started on methotrexate will be supplied with 2.5mg tablets only. Prescribers are reminded to follow the monitoring guidance outlined in the shared care protocol available here .

AMBER     Methotrexate tablets 2.5mg only

RED           Methotrexate injection, for s/c or i/m use (Metoject®, Ebetrex®)

Methotrexate should be prescribed once weekly as a single dose on the same day each week. Folic acid 5mg should normally be taken the day after methotrexate dosing.

AMBER     Penicillamine tablets 125mg, 250mg

AMBER     Sodium aurothiomalate injection 10mg, 20mg, 50mg

AMBER     Sulfasalazine tablets e/c 500mg

Cytokine modulators                                                                                                                                                     These drugs should be prescribed byspecialists only, and in line with any relevant NICE guidance. 

Certolizumab, rituximab and tocilizumab (inc. Abatacept, Adalimumab, Etanercept, Golimumab and Infliximab) - NICE guidance for rheumatoid arthritis (TAG 130, 186, 195, 198, & 225).

Treatment pathways for highly active rheumatoid arthritis in adults who have failed to respond to at least two standard disease modifying anti-rheumatic drugs (DMARDs) including methotrexate. These drugs should be prescribed according to the guidelines of the British Society for Rheumatology under the supervision of consultant rheumatologist.                                                                                                         Please refer to the full guidelines for further information.

Etanercept - NICE guidance for juvenile idiopathic rheumatoid arthritis (TAG 35)

For children aged 4 to 17 years who have active JIA in at least five joints and whose condition has not responded adequately to or have been unable to tolerate treatment with methotrexate. Only a consultant who regularly sees children and young adults with JIA and who runs specialised paediatric rheumatology clinics should prescribe etanercept.                                                                                                                      Please refer to full guidelines for further information.  

Secukinumab is recommended, within its marketing authorisation, as an option for treating active ankylosing spondylitis in adults whose disease has responded inadequately to conventional therapy (non-steroidal anti-inflammatory drugs or TNF‑alpha inhibitors) as per NICE TA407

RED       Secukinumab solution for injection 150mg/1mL

Adalimumab, Certolizumab pegol , Etanercept, Golimumab and Infliximab - in line with NICE Guidance for Ankylosing spondylitis and non-radiographic axial spondyloarthritis (TA 383).              

(Replaces NICE technology appraisal guidance on adalimumab, etanercept and infliximab for ankylosing spondylitis (TA143) and golimumab for the treatment of ankylosing spondylitis (TA233).  

These drugs are for people with severe active ankylosing spondylitis or severe non‑radiographic axial spondyloarthritis who have tried non‑steroidal anti‑inflammatory drugs (NSAIDs), but they have not worked

RED           Adalimumab pre-filled pen/syringe 40mg

RED           Certolizumab pegol pre-filled syringe 200mg

RED           Etanercept vial for injection 25mg                                                                                                                                           pre-filled pen/syringe 25mg, 50mg                 

RED           Golimumab pre-filled pen/syringe 50mg,100mg

RED           Infliximab vial for infusion 100mg

Adalimumab, Etanercept, Infliximab, Certolizumab pegol, Golimumab, tocilizumab and abatacept - NICE Guidance for Rheumatoid arthritis not previously treated with DMARDS or after conventional DMARDS only have failed are receommended as an option by NICE. NICE TA375.                                           Please refer to full guidelines for further information. 

Belimumab is recommended as an option as add-on treatment for active autoantibody-positive systemic lupus erythematosus in adults as per NICE TA397 

RED     Belimumab ( Benlysta®)

                   powder for concentrate for solution for infusion 120mg, 400mg 

Adalimumab, Etanercept, Golimumab and Infliximab - NICE guidance for psoriatic arthritis (TAG199 & 220)

Treatment options for adults with severe active psoriatic arthritis who: 

• have peripheral arthritis with three or more tender joints, and
  
• three or more swollen joints, and
  
• other disease modifying anti-rheumatic drugs (DMARDs) administered individually or in combination have not worked.                                                                                                                

 Please refer to the full guidelines for further information.

Belimumab is recommended as an option as add-on treatment for active autoantibody-positive systemic lupus erythematosus in adults as per NICE TA397 

RED     Belimumab ( Benlysta®)

                   powder for concentrate for solution for infusion 120mg, 400mg 

Abatacept (Orencia), adalimumab (Humira), etanercept (Enbrel) and tocilizumab (RoActemra) are recommended as possible treatments for people with polyarticular juvenile idiopathic arthritis. Full guidance - NICE TA373

• Adalimumab and etanercept are recommended as possible treatments for people with enthesitis-related juvenile idiopathic arthritis.
  
• Etanercept is recommended as a possible treatment for people with psoriatic juvenile idiopathic arthritis 

Abatacept                                                                                                                                                                        Abatacept may be considered as a second line option for rheumatoid arthritis if either rituximab or methotrexate is contraindicated or an adverse reaction has been experienced (see NICE guidance). Infusion to be administered in hospital. (NICE TA195)

Abatacept for treating Rheumatoid Arthritis after failure of conventional disease modifying anti-rheumatic drugs (NICE TAG280) (rapid review of TAG234) - recommended as an option by NICE in adults whose disease has responded inadequately to two conventional DMARD's including methotrexate if used in accordance with recommendations for other biologicals (TAG130) and PAS is provided

RED           Abatacept vial for infusion 250mg

RED           Abatacept pre-filled pen/syringe 125mcg

Adalimumab                                                                                                                                                                   Adalimumab is recommended either alone or in combination for the treatment of psoriatic arthritis and ankylosing spondylitis. It is also a treatment option for rheumatoid arthritis (see NICE guidance). Patients should be trained to self administer the injection.

RED           Adalimumab pre-filled pen/syringe 40mg

Apremilast - NICE TA433 (relaces TA372)

Apremilast, alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is recommended as an option for treating active psoriatic arthritis in adults only if:

¤     they have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints and

¤     their disease has not responded to adequate trials of at least 2 standard DMARDs, given either                    alone or in combination and

¤     the company provides apremilast with the discount agreed in the patient access scheme

RED        Apremilast tablets 10mg, 20mg, 30mg (Otezla®)

Certolizumab                                                                                                                                                                 Certolizumab pegol in combination with methotrexate is indicated for the treatment ofmoderate to severe, active rheumatoid arthritisin adult patients when the response to conventional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate, has been inadequate (see NICE guidance). Patients should be trained to self administer the injection

RED           Certolizumab pre-filled syringe 200mg

Certolizumab   and Secukinumab as per NICE TA445                       CCG Commissioned  The response to certolizumab pegol and secukinumab after 12 weeks and 16 weeks of treatment respectively and should only be continued if there is clear evidence of response.

Certolizumab pegol alone, or in combination with methotrexate, is recommended as an

option for treating active psoriatic arthritis in adults only if:

it is used as described in the NICE technology appraisal guidance on on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis  (recommendations 1.1 and 1.2) or  the person has had a tumour necrosis factor (TNF)-alpha inhibitor but their disease has stopped responding after the first 12 weeks. Certolizumab pegol is only recommended if the company provides it as agreed in the patient access

Secukinumab alone, or in combination with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults only if: it is used as described in the NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (recommendations 1.2 and 1.2) or  the person has had a TNF‑alpha inhibitor but their disease has not responded within the first 12 weeks or has stopped responding after 12 weeks or TNF‑alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).                                      Secukinumab is only recommended if the company provides it as agreed in the patient access scheme RED            Certolizumab pre-filled syringe 200mg

RED            Secukinumab pre-filled syringe 150mg/1mL

Certolizumab                                                                                                                                                                 Certolizumab is recommended for the treatment of adults withactive and progressive psoriatic arthritis in line withNICE TA199, that is when the person has peripheral arthritis with three or more tender joints and three or more swollen joints and their psoriatic arthritis has not responded to adequate trials of at least two standard disease-modifying antirheumatic drugs, administered either individually or in combination.

Certolizumab should be used in combination with methotrexate where possible, however can be given as monotherapy in the case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate

RED            Certolizumab pre-filled syringe 200mg

Certolizumab                                                                                                                                                                   An option as  as a second line anti-TNF (tumour necrosis factor) in psoriatic arthritis (PsA) following discontinuation of first anti-TNF due to an adverse event or primary or secondary inefficacy.

RED             Certolizumab pre-filled syringe 200mg

Certolizumab                                                                                                                                                                 Certolizumab pegol is licensed for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to, or are intolerant to non-steroidal anti-inflammatory drugs (NSAIDs)  (in line with NICE TA143)

RED            Certolizumab pre-filled syringe 200mg

Certolizumab                                                                                                                                                                 Certolizumab pegol  is recommended as an option for treating rheumatoid arthritis after inadequate response to a TNF-alpha inhibitor -  NICE TA415

RED            Certolizumab pre-filled syringe 200mg      (CCG commissioned )              

Etanercept                                                                                                                                                                     Etanercept is recommended either alone or in combination with methotrexate for the treatment of active polyarticular juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis. It is also a treatment option for rheumatoid arthritis (see NICE guidance). Patients should be trained to self administer the injection.

RED           Etanercept vial for injection 25mg

                   pre-filled pen/syringe 25mg, 50mg

Golimumab                                                                                                                                                                   Treatment option for adults with severe active psoriatic arthritis only if used as described for other tumour necrosis factor (TNF) inhibitors and the manufacturer provides the 100mg dose of Golimumab at the same cost as the 50mg dose.                                                                                                                           Please refer to the full guidelines for further information.

RED         Golimumab pre-filled pen/syringe 50mg,100mg    

Infliximab                                                                                                                                                                       Infliximab may be considered as an option to treat rheumatoid arthritis where:

• certolizumab, adalimumab and etanercept are contraindicated, or
  
• methotrexate is contraindicated or not tolerated, or
  
• the patient cannot self inject (see NICE guidance). 

It is also a treatment option for psoriatic arthritis. Infusion to be administered in hospital.

RED           Infliximab vial for infusion 100mg

Rituximab                                                                                                                                                                       Rituximab in combination with methotrexate is recommended as a second line option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to, or are intolerant of, other disease modifying anti-rheumatic drugs (DMARDs), including at least one tumour necrosis factor (TNF) inhibitor. Treatment with rituximab should be given no more frequently than every 6 months (see NICE guidance). Infusion to be administered in hospital.

Pre-medication 30-60 minutes before hand with methylprednisolone is necessary to reduce infusion-related reactions. Rituximab should be prepared by a pharmacist or healthcare professional observing aseptic techniques. As per BSR guidelines for anti-TNFs, treatment should be withdrawn following adverse events or where there is an inadequate response at 3 months following initiation of treatment. Rituximab should be funded via 'pass through funding' under payment by results, booked out to individual patients in pharmacy and recharged directly to the PCTs. A New Drug review for rituximab in rheumatoid arthritis is available - click here.

RED           Rituximab vial for infusion 100mg, 500mg

Tocilizumab                                                                                                                                                                   Tocilizumab in combination with methotrexate is recommended third line for the treatment of moderate to severe active rheumatoid arthritis in people whose condition (NICE TA198):

• has responded inadequately to one or more tumour necrosis factor alpha (TNFα) inhibitors; and
  
• has responded inadequately or are contraindicated to rituximab, or when rituximab is withdrawn because of an adverse effect as per NICE guidance. 

Tocilizumab in combination with methotrexate is recommended for some children with juvenile idiopathic arthritis where all other treatments have failed (NICE TA238).

Infusion to be administered in hospital.

RED           Tocilizumab vial for infusion 80mg, 200mg, 400mg

Subcutaneous Tocilizumab is recommended for use as an alternative to intravenous Tocilizumab              providing the patient meets the prescribing criteria as set out in NICE technology appraisals for                1st, 2nd and 3rd  line use to treat active rheumatoid arthritis (RA) and the agreed Lancashire  Rheumatology Alliance flex for use as monotherapy. CLICK here to link to the recommendation.

 RED      Tocilizumab injection 162mg pre-filled syringe         

10.1.4 Gout and cytotoxic-induced hyperuricaemia

Acute attacks of gout                                                                                                                                               High doses of NSAIDs are usually used.

Colchicine is an alternative. The BNF dose of colchicine is known to cause gastrointestinal side effects, particularly in patients with impaired renal function. Local rheumatologists recommend colchicine be given at a dose of 500micrograms twice daily for acute gout.

GREEN      Colchicine tablets 500 micrograms

Long term control of gout                                                                                                                                           Long term control to reduce formation of uric acid can be achieved with allopurinol. It should not be started during an acute attack. For approximately the first 6 weeks of therapy NSAIDs or colchicine should also be given.

GREEN      Allopurinol tablets 100mg, 300mg

Febuxostat                                                                                                                                                                      NICE TA164 advises febuxostat, within its marketing authorisation, as an option for the management of chronic hyperuricaemia in gout only for people who are intolerant of allopurinol or for whom allopurinol is contraindicated.                                                                                                                                                         Intolerance of allopurinol is defined as adverse effects that are sufficiently severe to warrant its discontinuation, or to prevent full dose escalation for optimal effectiveness as appropriate within its marketing authorisation.                                                                                                                                   Annual treatment costs for febuxostat are approximately £318 while for allopurinol they are approximately £16.                                                                                                                                                       MHRA alert June 2012 advises to stop treatment if signs and symptoms of severe hypersensitivity occur. See Drug safety update

GREEN     Febuxostat tablets 40mg, 80mg

Hyperuricaemia associated with cytotoxic drugs

RED           Rasburicase 1.5mg (Consultant Haematologist use only)