24th February 2025

Joint Disorders Part I

Osteoarthritis (OA)

Overview of OA

OA is a common chronic degenerative condition of the joint cartilage, affecting millions of patients across the UK, resulting in a significant economic impact due to lost working days. The pathogenesis is thought to be a dynamic process of cartilage loss, synovial inflammation and bone remodelling, mediated by matrix metalloproteinases. OA is characterised by pain and, as the disease progresses, deformity and loss of function. It typically affects the large, weight-bearing joints such as the knees, hips and spine.

Risk factors for OA include: female gender, advancing age, family history, obesity, previous trauma and vitamin D deficiency. Secondary OA can occur due to endocrine (acromegaly), metabolic (haemochromatosis, hyperparathyroidism), inflammatory (crystal arthropathy) and neuropathic (diabetes mellitus) conditions.

Signs and symptoms of OA

The most common symptom is pain, which typically improves with rest and worsens with activity, but OA sufferers also complain of stiffness, joint instability and reduced range of movement. In advanced cases deformity occurs, including the classical findings of Bouchard’s nodes (at the proximal interphalangeal joints) and Heberden’s nodes (at the distal interphalangeal joints) in generalised nodal OA (see Figure 1). In lower limb OA, compensation in gait due to antalgia can result in muscle wasting and, consequently, weakness, contributing to the risk of falls.

Image source: Wikimedia Commons (2006). Heberden-Arthrose, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Heberden-Arthrose.JPG (Accessed: 17 January 2024).

Investigation of OA

The mainstay of diagnosis in OA is a comprehensive clinical assessment, where the history and examination findings are correlated, augmented by radiological studies. Of note, the radiological findings of X-rays correlate poorly with the described severity of symptoms and, indeed, the function of the joint in terms of daily living activities. The typical X-ray findings are: loss of joint space, subchondral sclerosis, subchondral cysts and osteophyte formation (see Figure 2).

Image source: Wikimedia Commons (2012). Osteoarthritis left knee, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Osteoarthritis_left_knee.jpg (Accessed: 17 January 2024).

Laboratory investigations are rarely required, and if they are, it is to exclude other causes, such as crystal arthropathy (where joint aspiration for microscopy may be indicated) or RA (where inflammatory markers will be raised and auto-antibodies likely detected).

Management of OA

The effective management of OA requires a coordinated, holistic, multidisciplinary approach, aiming to minimise symptoms and maximise function. Unless there is a secondary cause, there are no pharmacological therapies that can halt or reverse the disease process. The impact of OA cannot be overstated in terms of poor quality of life and mental health, namely the deleterious effect on the ability to work, enjoy leisure activities, self-care and sleep. Important aspects of care include:

• Functional assessment by both physiotherapists and occupational therapists for joint supports, walking aids and adaptations to the home environment. Exercises can be taught to optimise joint function and reverse muscle wasting, helping with mobility and, importantly, overall cardiovascular health. 
• Weight loss should be encouraged, particularly if central, weight-bearing joints are primarily affected, as ongoing mechanical stress will cause progressive joint damage.
• Analgesia should be titrated in a stepwise manner, taking into account the distribution of joints affected, patient comorbidities and potential drug reactions, as comorbidity is common. The management of patient expectations regarding pain relief is an important consideration of chronic pain management.
  • Step 1: Regular Paracetamol 1 g, four times a day, with a topical NSAID gel such as diclofenac (particularly for hand and knee disease).
  • Step 2: Switch topical for oral NSAIDs such as ibuprofen, if not contraindicated (either relatively due to age or absolutely due to cardiovascular, gastrointestinal or renal disease). The risk may be reduced by co-administering a proton pump inhibitor. Alternatively, for disease predominantly affecting a specific joint, intra-articular corticosteroid injections may be beneficial (up to 3-4 injections per year). There is no evidence for oral or injected viscosupplements.
  • Step 3: In refractory cases or where previous therapies are contraindicated, weak opiates such as codeine may be used, with or without neuropathic agents such as gabapentin or pregabalin.
  • Step 4: NICE does not recommend strong opiates such as morphine for refractory pain, otherwise difficult to manage; therefore, the next step is referral to Orthopaedics for the consideration of a joint replacement, especially if there is a significantly reduced quality of life.

References

• Clunie, G, Wilkinson N, Nikiphorou E, Jadon D. Oxford Handbook of Rheumatology. Fourth Edition. Oxford: Oxford University Press; 2018
• Badlissi F. Osteoarthritis [Internet]. BMJ Best Practice. BMJ Publishing Group; 2023 [Cited 2023 August 17]. Available from: https://bestpractice.bmj.com/topics/en-gb/192

Rheumatoid arthritis (RA)

Overview of RA

RA is an autoimmune disease that typically affects patients from their fifth decade and, like most autoimmune diseases, has a 3:1 female-to-male predominance.

The pathophysiology is due to an immune response triggered between both B and T lymphocytes and fibroblasts of the synovial membranes, generating an inflammatory cascade mediated by TNF-ɑ and IL-6. The deposition of immune complexes causes cartilage degradation and, thus, joint pain. In certain cases, the inflammatory cascade is so pronounced that multi-system extra-articular manifestations can occur and so close monitoring for complications is required.

The treatment consists of combinations of immunosuppressive therapies, known as disease-modifying antirheumatic drugs (DMARDs, such as methotrexate) and biologics (first line are anti-TNF-ɑ) to dampen down the immune response and thus the symptomology, though they all require close monitoring and do not come without their own side effects.

Signs and symptoms of RA

RA is typically polyarticular, symmetrical and may be fleeting and migratory. The intra-articular features are pain, erythema, swelling and early morning stiffness of the small joints, typically of the hands, causing significant loss of function and deformity over time. The classic skeletal deformities include ulnar deviation of the wrist, swan-neck and Boutonnière deformities of the fingers (see Figures 3-4) and atlanto-axial subluxation of the cervical spine.

Image source: Wikimedia Commons (2010). Rheumatoid Arthritis, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Rheumatoid_Arthritis.JPG (Accessed: 17 January 2024).

Image source: Wikimedia Commons (2015). RheumatoideArthritisAP, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:RheumatoideArthritisAP.jpg (Accessed: 17 January 2024).

Constitutional symptoms may include fatigue, malaise, weight loss and rashes. Specific extra-articular manifestations can be classified by system:

Table 1 Extra-articular manifestations of RA (not an exhaustive list)

Complications of established RA include anaemia of chronic disease, osteoporosis, septic arthritis (due to immunosuppressive therapies), cardiovascular sequelae due to chronic inflammation (think of Virchow’s triad) and consequential mental health issues of living with this chronic, often relapsing and remitting condition. Interestingly, malignancy rates (particularly Hodgkin’s lymphoma) are elevated in those with RA.

Given the varied and widespread possible signs and symptoms with RA, a thorough clinical history and examination is crucial in making the diagnosis and a high index of suspicion is required, especially in the context of pre-existing autoimmune disease.

Investigation of RA

RA is essentially a clinical diagnosis; however, specific auto-antibodies are useful investigations which can confirm or refute the provisional diagnosis: rheumatoid factor (RF; 69% sensitivity, 85% specificity) and anti-cyclic citrullinated peptide (anti-CCP; 67% sensitivity, 95% specificity). If both RF and anti-CCP are positive, there is a 100% positive predictive value for a diagnosis of RA. Interestingly, a diagnosis of seronegative RA can be made without positive auto-antibodies if the clinical features and other investigations are suggestive of RA. This can be challenging as other diagnoses, such as spondyloarthritis (including psoriatic arthritis), need to be considered and are often later thought to be the actual diagnosis.

Inflammatory markers such as CRP and ESR are often useful adjuncts and can be repeated to assess the response to therapy. An FBC can be useful to look at the haemoglobin (anaemia of chronic disease) and white cell count (inflammation/infection), and LFTs and U&Es to get a baseline (as these are required prior to and for ongoing monitoring of most DMARDs). X-rays (joint erosion and fusion; see Figure 5) and ultrasound (synovitis and effusions) are useful in assessing painful joints, and bone density scanning (DEXA, dual-energy X-ray absorptiometry) to assess bone mineral health (particularly in the context of repeated corticosteroid courses).

Left: Image source: Wikimedia Commons (2017). Rheumatoid arthritis with unaffected carpal bones 2009, Licensed under a Creative Commons licence. Available for free at:  https://commons.wikimedia.org/wiki/File:Rheumatoid_arthritis_with_unaffected_carpal_bones_2009.jpg (Accessed: 17 January 2024).

Right: Image source: Wikimedia Commons (2017). Rheumatoid arthritis with carpal ankylosis 2017, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Rheumatoid_arthritis_with_carpal_ankylosis_2017.jpg (Accessed: 17 January 2024).

Alongside clinical judgement, the ACR/EULAR (American College of Rheumatology/European League Against Rheumatism) Classification Criteria (2010) can be used to identify those with early RA who are likely to develop chronic RA. It cannot be used to exclude RA, and indeed, over time, the score may change as the condition evolves. In those who have clinical synovitis in one joint or more, which is not better explained by another pathology, a score of six or more is suggestive of definite RA (points scored for joint involvement, serology, acute phase reactants and duration of symptoms).

Management of RA

The key treatment aim in RA is to intensively pursue remission to prevent deformity and disability. Tools such as the Disease Activity Score 28 Joints (DAS-28) are used to assess the treatment response over time in a patient-centred way.

The initial step of the treatment ladder usually consists of a DMARD and a corticosteroid (whilst the DMARD takes effect). Typically, methotrexate is used first-line. If a clinical response is not seen within 3-6 months, or if it is not tolerated, then it will be substituted for one of either hydroxychloroquine, sulfasalazine or leflunomide. The following table details the monitoring required and the potential side effects of each of these agents:

Table 2 DMARDs used in RA with their monitoring requirements and side effects (not an exhaustive list)

The next step, if remission is not induced at the maximum tolerated doses of two different DMARDs combined (one of which is usually methotrexate), is the addition of a biologic agent to the DMARD (ideally methotrexate). The first-line anti-TNF-ɑ drugs are adalimumab, etanercept and infliximab. If remission is still not achieved, then an alternative biologic is tried, such as anti-CD-20 drug (rituximab) or anti-IL-6 drug (tocilizumab).

Again, these drugs require careful monitoring and, because they are powerful immunosuppressants, require certain investigations prior to their initiation. This normally includes excluding tuberculosis (risk stratifying, chest X-ray and IgRA, interferon-gamma release assay), hepatitis, HIV and ANA positivity (can cause an SLE-like syndrome when started on anti-TNF-ɑ drugs). Additionally, demyelinating disorders, congestive cardiac failure, interstitial lung disease and uveitis require caution when considering initiation, as all of these conditions can be exacerbated by anti-TNF-ɑ drugs. Interestingly, anti-TNF-ɑ therapies have also been associated with the recurrence of previous malignancies and de novo skin cancers (but not solid tumours). The decision to initiate should be made on an individual risk/benefit basis.

Once remission has been induced, the corticosteroid is gradually weaned. Patients on these medications should be carefully counselled about seeking medical help when feeling unwell as they are prone to infections with opportunistic or rare organisms such as herpes zoster (for which immunoglobulin should be given) or fungi. In the context of suspected sepsis, they require aggressive broad-spectrum antimicrobial therapy and require their DMARDs and biologics to be held and their corticosteroids (if they are on them) to be up-titrated during their illness, as they are at risk of adrenal insufficiency in times of physiological stress.

Effective analgesia usually includes paracetamol and ibuprofen (often with gastroprotection).

References

• Clunie, G, Wilkinson N, Nikiphorou E, Jadon D. Oxford Handbook of Rheumatology. Fourth Edition. Oxford: Oxford University Press; 2018
• Yazici Y. Rheumatoid Arthritis [Internet]. BMJ Best Practice. BMJ Publishing Group; 2023 [Cited 2023 August 17]. Available from: https://bestpractice.bmj.com/topics/en-gb/105

Crystal arthropathies

Gout

Overview of gout

Gout is a common, chronic condition characterised by acute, severe flares of joint pain, classically affecting the first metatarsophalangeal (MTP) joints (known as podagra). If risk factors are not managed over time, it may cause a destructive and deforming arthropathy. It manifests due to deposition of urate crystals in the joint space, typically due to raised plasma urate levels.

Risk factors for gout include male gender, advancing age, obesity, hypertension (partly due to the medications used to treat), diabetes mellitus, CKD (due to impaired urate excretion), trauma and any condition causing rapid cell turnover (such as tumour lysis syndrome classically, or indeed any condition causing haemolysis). Historically, it is associated with a diet rich in meat, fish and alcohol. There are a host of drugs associated with gout; these include: salicylates, diuretics (particularly furosemide but also bendroflumethiazide), ciclosporin, levodopa and the tuberculosis drugs pyrazinamide and ethambutol.

The acute management typically involves anti-inflammatory drugs such as NSAIDs, colchicine or corticosteroids, while the chronic management focuses on urate-lowering therapies such as allopurinol, a xanthine oxidase inhibitor (as well as managing any underlying cause).

Signs and symptoms of gout

The typical presentation for an attack of gout is a sudden-onset (over hours), severely painful, erythematous, swollen joint (typically a single joint) and, in cases of podagra (see Figure 6), exquisite difficulty in weight bearing. It typically affects joints in the lower limbs rather than the upper limbs (and almost never the spinal column). Over time, it becomes more likely that attacks are polyarticular rather than the usual monoarticular presentation. Urate crystals eventually become deposited in the soft tissues (such as the ear pinna and Achilles tendon), forming subcutaneous tophi (see Figure 7), which are a marker of chronically raised urate levels and can diagnostically be helpful.

Image source: Wikimedia Commons (2019). Gout2010, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Gout2010.JPG (Accessed: 19 January 2024).

Image source: Wikimedia Commons (2010). Case 30-top, Licensed under a Creative Commons licence. Available for free at: https://en.m.wikipedia.org/wiki/File:Case_30-top.jpg (Accessed: 19 January 2024).

Investigation of gout

The diagnosis is typically suspected based on a previous history, having identifiable risk factors (especially if there is a recent temporal relationship) and clinical examination.

Gout can be confirmed by needle aspiration of synovial fluid during a flare, showing negatively birefringent needle-shaped crystals on microscopy (though their absence does not exclude the diagnosis). X-rays may highlight punched-out erosions and sclerotic margins, as well as soft tissue swelling and joint effusion (see Figure 8), and ultrasound may show tophaceous deposits.

Other differential diagnoses to consider include pseudogout, OA, RA, psoriatic arthritis, as well as both reactive arthritis and, crucially, septic arthritis in the immunosuppressed. There is no role for measuring urate levels in the acute phase to confirm or refute the diagnosis; it should only be used to confirm chronically elevated levels and the response to therapy. Note, however, that a raised serum urate may be detected in an asymptomatic patient without any previous episodes of gout and does not necessarily predict future episodes of gout; treatment in this circumstance remains controversial.

Image source: Wikimedia Commons (2010). Gichtfuss im Roentgenbild 002, Licensed under a Creative Commons licence. Available for free at:  https://commons.wikimedia.org/wiki/File:Gichtfuss_im_Roentgenbild_002.png (Accessed: 19 January 2024).

Management of gout

The management can be divided into acute and chronic.

Acute treatment relies on supportive measures such as rest, ice and elevation combined with a short course of NSAIDs, colchicine (0.5 mg, 2-4 times a day) or corticosteroids, either oral (if multiple joints affected) or intra-articular (if a single joint is affected). In this circumstance, urate-lowering drugs such as allopurinol should be continued, although if this is the first presentation, their initiation should be delayed until the flare resolves. The anti-IL-1𝛃 drugs, such as anakinra, can be initiated in repeated and/or refractory gout or where other medications are contraindicated.

The chronic management involves urate-lowering drugs, such as allopurinol, aiming for a reduction in serum urate levels <360 µmol/L. Febuxostat is an alternative from the same family of drugs, used if allopurinol does not achieve the recommended urate levels, and Rasburicase can be used in frequent, severe gout not controlled by the previous medications mentioned. Care should be used in the initiation of uricosuric drugs such as probenecid in patients who suffer with nephrolithiasis. The modification of lifestyle factors is of vital importance; weight loss and dietary modification should be encouraged. The management of other conditions triggering attacks should also be optimised, and medications such as diuretics should be continued at the lowest effective dose.

Calcium pyrophosphate dihydrate deposition (CPPD) disease

Overview of CPPD disease

Previously known as pseudogout, as the historic name suggests, calcium pyrophosphate deposition disease is similar to gout in its pathophysiology, clinical presentation and management. The deposition of calcium pyrophosphate (CPP) crystals may be asymptomatic and inconsequential. If symptoms occur, they can vary from an acute, self-limiting synovitis in an unwell hospitalised patient, to a chronic process causing inflammation and chondrocalcification in locations such as the spinal column causing arthropathy. The varying severity of symptoms related to crystal deposition is very similar to hydroxyapatite deposition disease, though this predominantly affects the tendons, characteristically of the shoulder.

The incidence rises with advancing age, and if it occurs in those less than 50 years of age, then an underlying metabolic cause should be explored. It is associated with hyperparathyroidism, haemochromatosis and Wilson’s disease, as well as hypomagnesaemia and hypophosphataemia. An isolated flare can be triggered by acute illness, the post-surgery state (especially post-parathyroidectomy), in trauma and upon initiation of levothyroxine.

Signs and symptoms of CPPD disease

The signs and symptoms are as per that of gout; they are clinically impossible to differentiate without needle aspiration of the affected joint. That being said, as a general rule, the joints affected in CPPD disease are typically larger joints, such as the knees, whilst gout typically involves the smaller joints, such as the toes and fingers.

Investigation of CPPD disease

The diagnosis is typically suspected based on the history and examination. Much like gout, the diagnosis can usually be confirmed by needle aspiration of synovial fluid during a flare, showing positively birefringent rhomboid-shaped crystals on microscopy. X-rays and ultrasound may identify calcium deposits. As with gout, other differential diagnoses should be excluded.

Management of CPPD disease

Management of acute CPPD disease is similar in rationale to gout. Supportive measures can help, and the mainstay is with anti-inflammatory agents. Colchicine is also used as prophylaxis in chronic CPPD disease. The optimal management of any underlying metabolic conditions is vital. The anti-IL-1𝛃 drugs such as anakinra can be used in refractory acute flares, and DMARDs such as methotrexate and hydroxychloroquine in chronic resistant disease.

References

• Clunie, G, Wilkinson N, Nikiphorou E, Jadon D. Oxford Handbook of Rheumatology. Fourth Edition. Oxford: Oxford University Press; 2018
• Badlissi F. Gout [Internet]. BMJ Best Practice. BMJ Publishing Group; 2022 [Cited 2023 August 17]. Available from: https://bestpractice.bmj.com/topics/en-gb/13
• Rosenthal A. Calcium Pyrophosphate Deposition [Internet]. BMJ Best Practice. BMJ Publishing Group; 2019 [Cited 2023 August 17]. Available from: https://bestpractice.bmj.com/topics/en-gb/370

Juvenile idiopathic arthritis (JIA)

Overview of JIA

JIA describes a collection of inflammatory arthritides that occur in children of any age below 16 years old (but typically less than six years old), with an incidence of approximately 1:1000. There are a number of subsets described including oligo-JIA, poly-JIA and systemic-JIA. The pathophysiology is thought to be similar in mechanism to that of RA.

Historically, the diagnosis of JIA was delayed, in part due to the wide differential list. A high index of suspicion is required for what is a clinical diagnosis, and in suspected cases, treatment should begin prior to being seen by a Paediatric Rheumatologist. Primarily, this is to provide timely pain relief but also to rapidly limit the degree of joint damage, which can lead to subsequent growth restriction and later deformity.

Management typically involves intra-articular or systemic corticosteroid, whilst DMARDs take effect. On occasion, biologic therapies are required. Interestingly, 10-20% of JIA cases are associated with uveitis and so prompt referral to Ophthalmology is prudent. Otherwise, holistic management is best achieved via a multidisciplinary team approach, including psychological support. Approximately 25% of those with JIA experience ongoing inflammatory arthritis in adulthood.

Signs and symptoms of JIA

The typical features are swollen, erythematous, stiff, painful joints and entheses, associated with a reduced range of movement. In order to reach the diagnostic threshold, one or more joints must be involved for more than six weeks. Sometimes, there are systemic features such as fever and rash.

Clearly, there is overlap with other differential diagnoses, including reactive and septic arthritis, psoriatic arthritis, osteomyelitis, Kawasaki disease, Lyme disease, tuberculosis, SLE and even haematological malignancies such as leukaemia, lymphoma or sarcoma, which need appropriate work up. Red flags would include systemic upset, significant weight loss, headaches, unremitting pain of a non-mechanical nature, pain at night, significant gait disturbance, neurological signs or symptoms and overlying skin changes, including petechiae.

Investigation of JIA

JIA is a clinical diagnosis, though laboratory investigations in a suspected case would typically include blood tests for FBC (anaemia of chronic disease, inflammation/ infection), CRP and ESR (though, unlike RA, in children these markers do not tend to correlate with disease activity and grossly raised counts should make you consider malignancy) and auto-antibodies including ANA, RF, anti-CCP and ferritin levels. X-rays and ultrasound can qualify joint inflammation and erosion.

Management of JIA

The recurring theme, regardless of JIA-subtype is early administration of NSAIDs. For oligo-JIA (less than or equal to four joints), intra-articular corticosteroid is given as a bridge for disease-modifying therapy to take effect, which is typically methotrexate. For poly-JIA (more than or equal to five joints), oral corticosteroid is substituted. If methotrexate is poorly tolerated or disease is refractory, then either the DMARD is substituted like in RA, or usually biologic therapy is initiated (similar agents as used in RA). Systemic-JIA (around 5% of cases, previously known as Still’s disease) usually has grossly elevated WCC, CRP and ESR counts on laboratory investigations and is managed similarly to other subtypes of JIA, but with a lower threshold for biologics.

A recognised complication is secondary haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), where haemopoietic stem cells in the bone marrow are destroyed by macrophages as part of the ‘cytokine storm’ in response to an infective trigger. This has non-specific features, but the child is invariably unwell with severe systemic upset and often multi-organ failure. It is diagnosed in the setting of cytopenias, falling inflammatory markers, platelets and fibrinogen and elevated ferritin and triglycerides. As well as providing organ support, treatment involves aggressive broad-spectrum antimicrobial therapy to cover for sepsis and specifically pulsed methylprednisolone, IVIG and then biologics (in that order of escalation). The all-cause mortality in secondary HLH is 8-22%. 

Overall, multidisciplinary team involvement is vital for a good outcome in JIA, and indeed, with modern treatments, outcomes are improving. Reassuringly, the incidence of joint replacement in later life is falling as long-term remission of JIA is now more possible. However, vision loss due to uveitis occurs in approximately 25% of cases with minimal symptoms to suggest deteriorating vision, reiterating the importance of screening programmes. The same concern needs to be had for patients with JIA as with all immunocompromised patients, particularly in regards to opportunistic infections. Vaccinations, including live ones, are still recommended even if immunosuppressed, as their benefits far outweigh the risks.

References

• Clunie, G, Wilkinson N, Nikiphorou E, Jadon D. Oxford Handbook of Rheumatology. Fourth Edition. Oxford: Oxford University Press; 2018
• Clinch J & Smallwood N. Juvenile Idiopathic Arthritis [Internet]. BMJ Best Practice. BMJ Publishing Group; 2023 [Cited 2023 August 17]. Available from: https://bestpractice.bmj.com/topics/en-gb/806

Adult-onset Still’s disease (AOSD)

Overview of AOSD

AOSD can be thought of as being on the same continuum as systemic-JIA. It is a rare, muti-system inflammatory disorder, affecting males and females equally, with a bimodal incidence in the late teens/early 20s and the late 40s/early 50s. The cause is unknown, though there is thought to be a genetic preponderance in patients with certain HLA subtypes. It can be triggered by pregnancy, and the index presentation may occur in the postpartum period. Various infections have also been identified as triggers, including viral (CMV, EBV, Coxsackie) and bacterial (Mycoplasma pneumoniae and Chlamydia pneumonia) infections.

The pathophysiology of the response seen in AOSD is similar to that in RA, being mediated by lymphocytes and a ‘cytokine storm’ thought to involve IFN-ɣ, TNF-ɑ and IL-6, among other markers. The principles of treatment and, indeed, the agents used are similar to those used in RA and systemic-JIA, including in the case of secondary HLH, usually guided by a Rheumatologist. There are three patterns of AOSD, with an approximately equal split: monophasic (a single episode with remission within one year); polycyclic systemic (recurrent flares with periods of remission, typically separated by years); and chronic articular (mainly affecting the joints causing a severe, destructive and disabling arthritis).

Signs and symptoms of AOSD

The clinical features are varied and often non-specific, making the diagnosis a challenge and so requiring a low index of suspicion:

• Fever – sudden-onset daily fevers up to 40℃, typically in the late afternoon/early evening, which settle without antipyretics in a majority of cases. Fever is the most common first symptom.
• Rash – typically a salmon-pink macular or maculopapular rash of the trunk and limbs, appearing whilst febrile and then disappearing. This occurs in around 70% of cases.
• Arthritis – classically mild, oligoarticular and transient but may evolve into a severe, symmetrical polyarthropathy. The wrists, knees and ankles are mainly affected, but the shoulders, elbows, hands and hips may also be involved.
• Pharyngitis – occurs in approximately 70% of cases, particularly if an infective trigger is thought likely.
• Hepatomegaly, splenomegaly and/or lymphadenopathy – occurs in approximately 50% of cases.
• Serositis – in approximately one-third of cases, pleuritis and pericarditis occur, their signs and symptoms adding to the confusing constellations of clinical features possible at presentation.

AOSD has considerable overlap with many other conditions, some of which also have multi-system manifestations, and so, in a similar manner to JIA, AOSD is a diagnosis of exclusion.

Investigation of AOSD

There is no specific diagnostic test for AOSD. Inflammatory markers such as CRP and ESR are often elevated, and there is typically leucocytosis with thrombocytosis and normocytic anaemia. Key to the diagnosis is a grossly elevated ferritin (>1000 ng/ml with a glycosylated fraction <20% giving a 90% specificity). An elevation in bilirubin, transaminases, and lactate dehydrogenase is also common. In cases of secondary HLH (approximately 40% of cases), pancytopaenia and DIC can occur (associated with a drop in ESR, low fibrinogen, high triglycerides and a markedly raised ferritin). This condition has a significant morbidity and mortality and so timely diagnosis is crucial. Gold standard is identifying haemophagocytosis in bone marrow aspirates, but features may also be evident on a blood film.

The Yamaguchi criteria were created from retrospective data and have a 93.5% sensitivity for AOSD. These include signs, symptoms and laboratory investigations. Diagnosis requires five or more criteria (two of which should be major criteria) without any of the exclusion criteria:

Table 3 Yamaguchi criteria for AOSD

X-rays in AOSD show non-specific joint space narrowing without erosions (and ankylosis over time), and so may help diagnostically but will not be as key to making the diagnosis as having a low index of suspicion clinically and requesting the appropriate laboratory investigations (particularly to exclude other conditions and screen for multi-system involvement).

Management of AOSD

NSAIDs are used as antipyretics and as analgesics for arthritic pain. The mainstay of treatment is immunosuppression, first-line being oral corticosteroids and then intravenous methylprednisolone in severe cases. If AOSD is refractory, then DMARDs are initiated, inducing remission in around 70% of cases. Methotrexate, azathioprine, hydroxychloroquine, ciclosporin and tacrolimus are used as corticosteroid-sparing agents. There is evidence for the use of IVIG in refractory cases, during pregnancy and in life-threatening secondary HLH. Biologics such as anakinra (an anti-IL-1𝛃 drug) and tocilizumab (an anti-IL-6 drug) can also be used, though anti-TNF-ɑ drugs such as adalimumab and etanercept have reportedly led to secondary HLH and paradoxical AOSD flares in case reports. The choice of initial agent and, indeed, the decision to escalate agents will depend on disease severity and the degree of organ involvement at that time.

References

• Clunie, G, Wilkinson N, Nikiphorou E, Jadon D. Oxford Handbook of Rheumatology. Fourth Edition. Oxford: Oxford University Press; 2018
• Savic S & Al-Hakim A. Adult-Onset Still’s Disease [Internet]. BMJ Best Practice. BMJ Publishing Group; 2023 [Cited 2023 December 3]. Available from: https://bestpractice.bmj.com/topics/en-gb/3000317