24th February 2025

Joint Disorders Part II

Spondyloarthritis

Overview of spondyloarthropathies

These are a heterogeneous group of seronegative inflammatory conditions, with common features including inflammation of the axial (spine) and peripheral joints, enthesitis (inflammation of tissue attaching ligaments and tendons to bone), a link to HLA-B27 and responsiveness to NSAIDs.

They include:

• Axial spondyloarthritis – ankylosing spondylitis (AS) when there is radiographic ankylosis (joint fusion)
• Psoriatic arthritis (PsA)
• Reactive arthritis 
• Enteropathic (inflammatory bowel disease) arthritis

They typically affect patients under 45, often with a delay in diagnosis. AS affects men twice as often, while the others have equal sex distribution. The prevalence of AS may be up to 0.23% in Caucasian populations, PsA in up to 10% with psoriasis and enteropathic arthritis in up to 15% with IBD. Some with PsA never get psoriasis.

Reactive arthritis occurs in up to 4% 1-4 weeks after certain gastrointestinal and genitourinary infections, including Chlamydia, Campylobacter, Salmonella, Shigella and Yersinia. The synovitis is sterile, so distinct from septic arthritis.

Up to 95% with AS and 30% with enteropathic arthritis have HLA-B27, which carries a 5 times higher risk of reactive arthritis. It may cause abnormal T-cell responses, interplaying with abnormal environmental exposure to microorganisms (through the skin in psoriasis and bowel in IBD).

AS and PsA are progressive, though can be relapsing and remitting. Reactive arthritis is of acute onset, with 70% recovering in 6 months. Enteropathic arthritis can improve with IBD remission.

Signs and symptoms of spondyloarthropathies

These include:

• Inflammatory back pain with features of:
  • Chronic or recurrent pain >3 months
  • Morning stiffness relieved with exercise and NSAIDs
  • Pain at night
  • Buttock pain
  • Reduction in spinal mobility due to fusion 
• Synovitis, usually affecting the asymmetric larger joints in the lower limbs (hips and knees)
• Enthesitis, most commonly causing Achilles tendonitis and plantar fasciitis 
  • In AS this can occur at the costochondral joints with pain and reduced chest expansion
• Dactylitis, with swelling of fingers and toes

AS classically has more axial features, and the other spondyloarthropathies have more peripheral features.

PsA in particular, has a number of different patterns; alongside spine-predominant, enthesopathic-predominant, and asymmetric arthritis are also:

• Symmetrical polyarthritis
• DIPJ (distal interphalangeal joint)-predominant disease 
• Arthritis mutilans in 5% with erosive arthropathy of the hands (‘telescope fingers’)

Other features are:

• Systemic fatigue, weight loss, low-grade fever, anaemia
• Non-musculoskeletal features (Table 1)

Table 1 Non-musculoskeletal features of spondyloarthritides

* The classic triad of post-infection arthritis, urethritis and conjunctivitis (‘Reiter’s syndrome’) is only seen in a minority.

General complications can include osteoporosis, fractures, nerve root entrapment and renal involvement from NSAID use.

Investigation of spondyloarthropathies

Bloods will often show a raised ESR and CRP, but negative RF and ACCP (anti-citrullinated protein) antibodies. 

In reactive arthritis genitourinary and stool cultures should be taken, but are often negative.

Imaging may include: 

• Pelvic (AP) and spinal X-rays showing sacroiliitis with sclerosis and erosions. Persistent sacroiliitis and enthesitis cause bony growth with syndesmophytes (spurs) and intervertebral ligament calcification. There is eventual ankylosis (fusion) of the sacroiliac and spinal facet joints (‘bamboo spine’).
• MRI can show sacroiliitis not seen on X-ray.
• Hands and feet X-rays in PsA, which may show erosion of the DIPJs (‘pencil-in-cup appearance’) with periarticular bone formation.

Box 1 Distinguishing spondyloarthropathies from rheumatoid arthritis

Management of spondyloarthropathies

First-line therapy involves NSAIDs. These can be contraindicated in IBD and sometimes cause rebound skin symptoms in psoriasis. Alongside this are analgesia adjuncts, physiotherapy and smoking cessation. Corticosteroid injections are recommended for localised inflammation.

If there is poor response of peripheral disease or severe symptoms, second-line treatment may involve the DMARDs sulfasalazine or methotrexate. Leflunomide and ciclosporin are sometimes used in PsA.

With poor response to the above or severe axial symptoms, the biological DMARD TNF-α (tumour necrosis factor) inhibitors can be considered (adalimumab, infliximab, etanercept, golimumab). NICE has also licensed Ustekinumab, an IL-23 inhibitor, in PsA for non-responders.

Management of cardiovascular comorbidities is important.

References

• Chan A, Sacks S. Ankylosing spondylitis [Internet]. BMJ Best Practice. BMJ Publishing Group; 2022 [cited 2022 July 25]. Available from: https://bestpractice.bmj.com/topics/en-gb/366 
• Michet C. Psoriatic arthritis [Internet]. BMJ Best Practice. BMJ Publishing Group; 2022 [cited 2022 July 25]. Available from: https://bestpractice.bmj.com/topics/en-gb/524 
• Carter J. Reactive arthritis [Internet]. BMJ Best Practice. BMJ Publishing Group; 2022 [cited 2022 July 25]. Available from: https://bestpractice.bmj.com/topics/en-gb/597 
• National Institute for Health and Care Excellence. Ankylosing spondylitis [Internet]. NICE. 2019 [cited 2022 July 27]. Available from: https://cks.nice.org.uk/topics/ankylosing-spondylitis/ 
• National Institute for Health and Care Excellence. Psoriasis [Internet]. NICE. 2022 [cited 2022 July 27]. Available from: https://cks.nice.org.uk/topics/psoriasis/ 
• Clunie, Gavin and others (eds), Oxford Handbook of Rheumatology, 4 edn, Oxford Medical Handbooks (Oxford, 2018; Oxford Academic, 1 July 2018)
• Kumar, P. J., & Clark, M. L. (2002). Kumar & Clark clinical medicine. Edinburgh, Saunders

Infections and rheumatic disease

Overview of infections and rheumatic disease

A number of microorganisms are linked to inflammatory rheumatic diseases. Pathogenesis can be through direct local infection and indirectly (‘reactive’) through pathogen-specific immune response and autoimmunity.

Viral

Often there is arthralgia or polyarthritis with viral infections, due to direct toxicity or immune complex deposition. Erythrovirus B19 (parvovirus, causes slapped cheek syndrome, usually in children), rubella and hepatitis B commonly give an acute symmetrical polyarthritis of the small joints of the hands, which resolves in a few weeks.

Bacterial

Common conditions with direct joint damage include septic arthritis, gonococcal arthritis and tuberculosis. The most common conditions with indirect damage are Lyme disease and rheumatic fever.

Other bacteria with rare rheumatological symptoms include meningococcus, brucello

Septic arthritis 

Overview of septic arthritis

This is an emergency, requiring rapid management to prevent joint destruction and with a mortality of 22%.

It describes bacterial infection in the joint, usually through haematogenous spread but sometimes local infection. 

In developed countries, incidence is 10 times higher with joint disease or prosthetic joints. Other risk factors include IV drug use, immunosuppression (immunodeficiency, alcoholism, diabetes, CKD, age >80), recent surgery and skin infection. 

A large majority of cases are caused by Staphylococcus aureus (including MRSA [methicillin-resistant Staphylococcus aureus]) and Streptococcus species, but Gram-negative bacilli can be causative in IVDU or immunosuppression and Salmonella in sickle cell disease. Neisseria gonorrhoea will be discussed.

Signs and symptoms of septic arthritis

Septic arthritis should be considered in any acutely painful, hot, swollen or immobile joint. Most people are febrile and unwell, but in the elderly or immunosuppressed, it may be insidious. The knee is most commonly infected (>50%), alongside the wrist, ankles and hips. In 20% it affects more than 1 joint, with higher mortality.  

Investigations in septic arthritis

Joint aspiration should be attempted before antibiotic treatment, though one must not delay this. Aspirate should be sent for Gram stain, cell count/differential, microscopy and culture. Bloods usually show leukocytosis. Blood cultures should be sent, and potentially wound/sputum/throat swabs and urine culture.

Management of septic arthritis

The joint must be aspirated to dryness to remove infection and relieve pressure. Surgical involvement may be needed, particularly with prosthetic joints. Empiric antibiotic therapy should be started immediately. This is often 2 weeks of IV flucloxacillin QDS (four times daily) ± IV gentamicin, followed by an oral switch. Rest is advised initially, with early physiotherapy.

Gonococcal arthritis

Overview of gonococcal arthritis

This is caused by Neisseria gonorrhoea, a sexually transmitted infection, and is the commonest cause of septic arthritis in fit young adults. There is likely a reactive element as well.

Signs and symptoms of gonococcal arthritis

It can present as an acute monoarthritis but is often a migratory asymmetric polyarthritis. It is associated with tenosynovitis, and lower limb pustular dermatitis; this is known as arthritis-dermatitis syndrome. Patients can be unwell if disseminated. 

Investigations in gonococcal arthritis

Synovial fluid analysis is often sterile and cultures negative. NAAT (nucleic acid amplification test) can be positive.

Management of gonococcal arthritis

Treatment is according to the local antibiotic regimen, with awareness of resistance. Discussion with sexual partners is important.

Mycobacterium

Overview of mycobacterial joint infection

Mycobacterium tuberculosis can invade the synovium and disc space, with tissue destruction. In developed countries, this occurs in <5% of TB cases. Risk factors include pre-existing joint disease and immunosuppression. Atypical mycobacteria are rarer causes.

Signs and symptoms of mycobacterial joint infection

Infection is usually low-grade and slowly progressive, without warmth or erythema. It is usually monoarticular, affecting the spine in 50% (Pott’s disease) and then the hip, knee, ankle and sacroiliac joint. Spinal cord compression is a serious complication.

Investigations in mycobacterial joint infection

Synovial fluid analysis is usually sterile, and tissue biopsy may be needed. Biopsy shows caseating granulomas.

Management of mycobacterial joint infection

Treatment is with the local anti-TB regimen for 9 months, with initial joint rest and acute spine immobilisation.

Lyme disease

Overview of Lyme disease

Lyme disease is caused by the spirochaete Borrelia, with a tick vector (Ixodes) found in grassy and wooded areas. 

Signs and symptoms of Lyme disease

About 25% develop arthralgia, with arthritis less common. This arthritis is often migratory, with brief attacks of swelling in one or more joints; it can become chronic if untreated. Other symptoms are divided into 3 stages, including an early erythema migrans rash and later cardiovascular and neurological complications.

Investigations in Lyme disease

There is an ELISA (enzyme-linked immunosorbent assay) test for antibodies.

Management of Lyme disease

Treatment is with antibiotics for all with erythema migrans or a positive ELISA, with a cure rate of 95%. This is usually doxycycline 100 mg BD for 21 days (or 28 days with arthritis) with a Jarisch-Herxheimer reaction in 15%. This presents with fevers, vasodilation with flushing, tachycardia, headaches and myalgia; hypotension is not a usual feature. Prevention of tick bites is important. In the UK, antibiotic prophylaxis is not routine.

Rheumatic fever

Overview of rheumatic fever

This is a delayed immune response to pharyngeal infection with group-A β-haemolytic Streptococcus. It is uncommon in the UK but the major worldwide cause of valvular heart disease.

Signs and symptoms of rheumatic fever

Arthritis is usually in large joints, with little inflammation and self-limits in 2-3 weeks. Other features can include erythema marginatum (an annular pink rash on the trunk and proximal limbs that can fade and reappear), painless subcutaneous nodules, carditis (with cardiomyopathy and conduction defects), Sydenham’s chorea, and valvular heart disease (of the mitral valve) 10-20 years later.

Investigations in rheumatic fever

Diagnosis is based on clinical features with detection of group-A Streptococcus: throat cultures or antistreptolysin O (ASO) titre. The Jones criteria can be used. CXR and ECG look for cardiac involvement.

Management of rheumatic fever

Treatment is with 10 days of penicillin with NSAIDs. Some patients may receive long-term secondary prophylaxis with phenoxymethylpenicillin (recurrence risk).

Table 2 Overview of key rheumatological manifestations of infection

References

• Kumar, P. J., & Clark, M. L. (2002). Kumar & Clark clinical medicine. Edinburgh, Saunders
• National Institute for Health and Clinical Excellence. Gonorrhoea [Internet]. NICE. 2022 [cited 2022 July 26]. Available from: https://cks.nice.org.uk/topics/gonorrhoea/
• National Institute for Health and Clinical Excellence. Lyme disease [Internet]. NICE. 2022 [cited 2022 July 26]. Available from: https://cks.nice.org.uk/topics/lyme-disease/  
• Alexiou A. Septic arthritis [Internet]. BMJ Best Practice. BMJ Publishing Group; 2022 [cited 2022 July 26]. Available from:  https://bestpractice.bmj.com/topics/en-gb/3000116 
• Koirala J. Lyme disease [Internet]. BMJ Best Practice. BMJ Publishing Group; 2022 [cited 2022 July 26]. Available from: https://bestpractice.bmj.com/topics/en-gb/224  
• Webb R. Rheumatic fever [Internet]. BMJ Best Practice. BMJ Publishing Group; 2022 [cited 2022 July 26]. Available from: https://bestpractice.bmj.com/topics/en-gb/404  
• Clunie, Gavin and others (eds), Oxford Handbook of Rheumatology, 4 edn, Oxford Medical Handbooks (Oxford, 2018; online edn, Oxford Academic, 1 July 2018)

Biologics

Overview of biologics

Biological disease-modifying anti-rheumatic drugs are proteins which are derived from human genes and genetically engineered to inhibit specific parts of the immune system. There are four main inflammatory targets: tumour necrosis factor (TNF) inhibitors (most common), B cell inhibitors, interleukin inhibitors and T cell inhibitors.

They are more precise and rapid-acting than conventional DMARDs, which have a broad immune-suppressing effect. However, they are more expensive, so are only used after these (often 2 options) have failed to work and as per NICE criteria. They are often given with methotrexate to reduce loss of efficacy from anti-drug antibody formation.

As with conventional DMARDs, there are a variety of side effects. In general, these include: an increased risk of infection (active bacterial or severe viral infection is a contraindication), blood dyscrasia, gastrointestinal upset, fatigue, myalgia and headaches. There has been debate about risk of malignancy (current is a contraindication), but evidence only suggests an increased risk of skin cancers, particularly melanoma, with TNF inhibitors.

Specific biologics and side effects

Table 3 Examples of different sub-classes of biologic, their uses, route of administration and side effects
*TNF inhibitors should not be prescribed in those with multiple sclerosis or severe heart failure (NYHA grade 3-4)
**Mainly with infliximab and adalimumab

Monitoring of biologics

In general, monitoring requirements are:

• At baseline: FBC, U&Es, LFTs, CRP, ESR, lipids, HIV, hepatitis B and C, urinalysis (for protein), blood pressure and CXR with QuantiFERON for TB
• Patients should be treated if found to have latent TB
• FBC, U&Es and LFTs at 3-4 months, then every 6 months
• Lipid profile at 1-2 months
• Rituximab may also need Igs and CD19 monitoring 6 monthly 
• Further infection screens, if clinically indicated 

Patients should be offered vaccinations before starting treatment: influenza, pneumococcal and covid. Live vaccinations should be avoided. Education should be given about skin cancer prevention and infection risk.

There are guidelines for use in pregnancy and breastfeeding, but little data.

References

• National Institute for Health and Clinical Excellence. DMARDs [Internet]. NICE. 2021 [cited 2022 July 27]. Available from: https://cks.nice.org.uk/topics/dmards/ 
• Kumar, P. J., & Clark, M. L. (2002). Kumar & Clark clinical medicine. Edinburgh, Saunders
• Clunie, Gavin and others (eds), Oxford Handbook of Rheumatology, 4 edn, Oxford Medical Handbooks (Oxford, 2018; online edn, Oxford Academic, 1 July 2018)
• Joint Formulary Committee. British National Formulary. Edition 83 ed. London: BMJ Group and Pharmaceutical Press; 2022