Medicine – Common Autoantibodies in Connective Tissue Diseases

Autoantibodies are antibodies produced by the immune system that react against the body’s own cellular components. They are important laboratory markers in connective tissue and autoimmune diseases and can help support a diagnosis, distinguish between related conditions, and, in selected diseases, provide information about disease activity or likely organ involvement. However, autoantibody results should always be interpreted together with the patient’s clinical presentation because many antibodies can occur in more than one condition.

1. Anti-dsDNA Antibodies

Anti-double-stranded DNA (anti-dsDNA) antibodies are strongly associated with systemic lupus erythematosus (SLE). They are relatively specific for SLE and therefore provide useful support for the diagnosis when the appropriate clinical features are present. Anti-dsDNA levels may also correlate with disease activity in some patients, particularly in lupus nephritis, where rising titres can accompany active renal disease.

2. Anti-Smith (Anti-Sm) Antibodies

Anti-Smith (anti-Sm) antibodies are another important marker of SLE. Although they are present in only a proportion of patients, they are highly specific for SLE, making them particularly useful diagnostically. Unlike anti-dsDNA antibodies, anti-Sm levels generally do not closely reflect changes in disease activity.

3. Anti-Ro Antibodies

Anti-Ro antibodies, also known as anti-SSA antibodies, are particularly associated with Sjögren’s syndrome and SLE. In Sjögren’s syndrome, they may occur in patients with prominent dryness of the eyes and mouth resulting from autoimmune involvement of the exocrine glands. In SLE, anti-Ro antibodies are associated with certain manifestations, particularly photosensitive skin disease. They are also clinically important during pregnancy because maternal antibodies can cross the placenta and are associated with neonatal lupus and congenital heart block.

4. Anti-La Antibodies

Anti-La antibodies, also called anti-SSB antibodies, are associated mainly with Sjögren’s syndrome and SLE. They frequently occur together with anti-Ro antibodies and can provide additional evidence of an underlying autoimmune connective tissue disease. Like anti-Ro, maternal anti-La antibodies may also be relevant when assessing the risk of neonatal autoimmune manifestations during pregnancy.

5. Anti-RNP Antibodies

Anti-ribonucleoprotein (anti-RNP) antibodies, particularly antibodies against U1-RNP, are strongly associated with mixed connective tissue disease (MCTD). This disorder combines clinical characteristics of several connective tissue diseases, including features resembling SLE, systemic sclerosis, and inflammatory myositis. Anti-RNP antibodies may also occur in SLE, but high titres in the appropriate clinical setting are particularly characteristic of mixed connective tissue disease.

6. Anti-Jo-1 Antibodies

Anti-Jo-1 antibodies are associated with inflammatory myositis, particularly polymyositis and the antisynthetase syndrome. Patients may develop proximal muscle weakness, and the presence of anti-Jo-1 is particularly associated with interstitial lung disease. Other features of the antisynthetase syndrome can include inflammatory arthritis, Raynaud phenomenon, fever, and characteristic roughened skin over the fingers known as mechanic’s hands.

7. Anti-Scl-70 Antibodies

Anti-Scl-70 antibodies, also known as anti-topoisomerase I antibodies, are particularly associated with diffuse cutaneous systemic sclerosis. This form of systemic sclerosis can produce widespread skin thickening together with internal organ involvement. Anti-Scl-70 positivity is especially associated with an increased risk of interstitial lung disease and pulmonary fibrosis.

8. Anti-Centromere Antibodies

Anti-centromere antibodies are strongly associated with limited cutaneous systemic sclerosis, historically referred to as the CREST syndrome. In this form of systemic sclerosis, skin involvement is generally more restricted than in diffuse disease. The CREST features include calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia. Anti-centromere antibodies are also associated with an increased risk of developing pulmonary arterial hypertension during the course of the disease.

9. Anti-Cardiolipin Antibodies

Anti-cardiolipin antibodies belong to the group of antiphospholipid antibodies and are associated with antiphospholipid syndrome (APS). They may also occur in patients with SLE, either with or without clinical antiphospholipid syndrome. Persistent antiphospholipid antibodies can be associated with an increased tendency toward arterial or venous thrombosis and pregnancy-related complications, such as recurrent pregnancy loss. Diagnosis of antiphospholipid syndrome requires appropriate clinical findings together with persistent laboratory evidence of antiphospholipid antibodies.

10. Anti-Histone Antibodies

Anti-histone antibodies are classically associated with drug-induced lupus. Drug-induced lupus is a lupus-like autoimmune syndrome that can develop after exposure to certain medications. Patients commonly develop constitutional symptoms, arthralgia, and other lupus-like manifestations. Anti-histone antibodies are frequently detected, although they are not completely specific because they may also occur in idiopathic SLE and other autoimmune conditions.

Important Associations to Remember

The most useful associations for revision are anti-dsDNA and anti-Sm with SLE; anti-Ro and anti-La with Sjögren’s syndrome and SLE; anti-RNP with mixed connective tissue disease; anti-Jo-1 with inflammatory myositis; anti-Scl-70 with diffuse systemic sclerosis; anti-centromere with limited systemic sclerosis; anti-cardiolipin with antiphospholipid syndrome; and anti-histone antibodies with drug-induced lupus.

Medicine – Juvenile Chronic Arthritis

Juvenile chronic arthritis, now more commonly referred to as juvenile idiopathic arthritis (JIA), is a group of chronic inflammatory joint disorders that begin during childhood. The diagnosis is based on persistent arthritis, onset before adulthood, and exclusion of other identifiable causes of joint inflammation. The condition may affect a single joint or several joints and can vary considerably in severity and systemic involvement.

1. Persistent Arthritis

A key diagnostic feature is the presence of arthritis affecting at least one joint for more than three months. Arthritis is characterised by joint swelling or by a combination of pain, stiffness, warmth, and limitation of movement. The persistent nature of the inflammation helps distinguish juvenile chronic arthritis from short-lived joint symptoms caused by transient infections or minor injuries.

2. Onset Before 16 Years of Age

The disease begins before the age of 16 years. Symptoms may develop gradually or more abruptly, depending on the subtype. Children may present with joint pain, morning stiffness, swelling, reduced movement, or difficulty using the affected limb. In younger children, the first sign may simply be limping or reluctance to participate in normal activities.

3. Exclusion of Other Causes

Juvenile chronic arthritis is a diagnosis of exclusion, meaning that other disorders capable of producing arthritis must first be considered and ruled out. These include infections, connective tissue diseases, malignancy, trauma, and other inflammatory or metabolic conditions. Clinical assessment, laboratory investigations, and imaging are used as needed to exclude alternative explanations for the joint disease.

Still’s Disease

Still’s disease represents the systemic form of juvenile chronic arthritis and accounts for approximately 10% of cases in older classifications. Unlike other forms that mainly affect the joints, systemic juvenile arthritis may involve the entire body and can produce prominent constitutional and inflammatory symptoms.

1. Fever

A characteristic feature is high spiking fever, often occurring once or twice daily and returning toward normal between episodes. The fever may precede the development of obvious arthritis and is usually accompanied by other systemic inflammatory features.

2. Evanescent Salmon-Pink Rash

Patients may develop an evanescent, macular, erythematous rash that is classically described as salmon pink. The rash tends to appear during febrile episodes and may fade when the temperature falls. It commonly affects the trunk and proximal limbs and is usually non-pruritic.

3. Arthritis

Arthritis is an essential feature, but the systemic manifestations may appear before the joint inflammation becomes obvious. Over time, multiple joints may become involved, and persistent inflammatory arthritis can lead to pain, stiffness, restricted movement, and functional impairment. In Still’s disease, therefore, fever and rash may precede the onset of arthritis, which can initially make the diagnosis less straightforward.

Medicine – Revised Jones Criteria for the Diagnosis of Acute Rheumatic Fever

The Jones criteria are used to support the diagnosis of acute rheumatic fever (ARF), an immune-mediated inflammatory complication that may occur following infection with group A β-haemolytic Streptococcus (GAS). The manifestations are traditionally divided into major and minor criteria. In most initial episodes, diagnosis requires an appropriate combination of these manifestations together with evidence of a preceding group A streptococcal infection.

Major Criteria

1. Carditis

Carditis is one of the most important manifestations of acute rheumatic fever because it can result in permanent valvular heart disease. Inflammation may involve the endocardium, myocardium, and pericardium, although valvulitis is particularly significant. The mitral valve is most commonly affected, with the aortic valve sometimes involved as well. Patients may develop a new cardiac murmur, tachycardia, cardiomegaly, heart failure, or pericardial inflammation. Modern criteria also recognise subclinical carditis detected by echocardiography.

2. Polyarthritis

Acute rheumatic fever classically causes an acute migratory polyarthritis, predominantly involving the large joints. The knees, ankles, elbows, and wrists are commonly affected. Inflammation may improve in one joint while appearing in another, producing the characteristic migratory pattern. The affected joints are usually painful, swollen, warm, and restricted in movement, but permanent joint destruction is uncommon.

3. Chorea

Sydenham chorea is a neurological manifestation characterised by involuntary, rapid, irregular, and purposeless movements. Patients may also develop emotional instability, behavioural changes, poor coordination, and deterioration in handwriting. Chorea can appear several months after the original streptococcal infection and may occasionally occur when other manifestations of acute rheumatic fever have already disappeared.

4. Erythema Marginatum

Erythema marginatum is a characteristic but relatively uncommon skin manifestation. It consists of a non-pruritic, erythematous rash with serpiginous or ring-shaped margins and central clearing. The rash generally occurs on the trunk and proximal parts of the limbs and usually spares the face. Individual lesions may appear and disappear rapidly.

5. Subcutaneous Nodules

Subcutaneous nodules are small, firm, painless nodules that usually develop over bony prominences, extensor surfaces, tendons, or the spine. They are uncommon but are strongly associated with rheumatic carditis when present. The nodules usually persist for a limited period and resolve as the underlying inflammatory process improves.

Minor Criteria

1. Fever

Fever is a common systemic manifestation of acute rheumatic fever and reflects the underlying inflammatory response. The precise temperature threshold used as a minor criterion varies according to whether the patient belongs to a population considered at low or moderate-to-high risk for acute rheumatic fever.

2. Arthralgia

Arthralgia refers to joint pain without the objective inflammatory changes required to diagnose arthritis. The pattern of arthralgia considered a minor manifestation also varies according to the patient’s underlying population risk. Importantly, the same joint manifestation should not normally be counted simultaneously as both a major and a minor criterion.

3. Other Minor Criteria

Current Jones criteria also include laboratory and electrocardiographic findings among the minor manifestations. These include elevated inflammatory markers, such as ESR or C-reactive protein (CRP), and prolongation of the PR interval on ECG, provided carditis is not already being counted as a major manifestation.

A previous history of rheumatic fever or established rheumatic heart disease was included as a minor feature in older versions of the Jones criteria, but it is not listed as a minor criterion in the current revised criteria. Instead, previous rheumatic fever or rheumatic heart disease affects the criteria used to diagnose a recurrent attack.

Evidence of Recent Streptococcal Infection

In addition to the clinical criteria, there should usually be evidence of a preceding group A streptococcal infection. This may be demonstrated by an elevated or rising antistreptolysin-O (ASO) titre, other elevated streptococcal antibody titres, a positive throat culture for group A Streptococcus, or a positive rapid antigen test.

An important distinction is that ASO/ASOT is a blood antibody test, whereas a throat culture directly detects group A streptococci. They are therefore separate forms of evidence for preceding streptococcal infection.

Diagnostic Combination

For a first episode of acute rheumatic fever, the usual diagnostic requirement is:

Two major criteria, or one major plus two minor criteria, together with evidence of a preceding group A streptococcal infection.

The current revised Jones criteria also distinguish between low-risk and moderate-/high-risk populations, with slightly different definitions for some joint manifestations, fever, and inflammatory-marker thresholds. In addition, there are specific criteria for diagnosing recurrent acute rheumatic fever in patients with a previous history of rheumatic fever or rheumatic heart disease.

Medicine – Essential Features of Vasculitis

Vasculitis refers to a group of disorders characterised by inflammation and damage of blood vessel walls. The resulting vascular injury may cause narrowing, occlusion, thrombosis, haemorrhage, or aneurysm formation, leading to tissue ischaemia and organ damage. Vasculitides are commonly classified according to the predominant size of the affected vessels into large-vessel, medium-vessel, and small-vessel vasculitis.

Large-Vessel Vasculitis

1. Takayasu’s Arteritis

Takayasu’s arteritis is a chronic, progressive inflammatory disease affecting the aorta and its major branches. Inflammation of the arterial walls can cause progressive thickening, stenosis, and eventual occlusion of affected vessels. It occurs predominantly in young women, particularly those younger than 40 years of age.

Vascular involvement may result in ischaemia or aneurysm formation within the aorta or its major branches. A characteristic presentation is arm claudication, in which patients develop pain or fatigue in the upper limbs during activity because of reduced arterial blood flow. Peripheral pulses may become weak or absent, giving rise to the description “pulseless disease.” Differences in blood pressure between the arms and vascular bruits may also occur.

Diagnosis is based primarily on vascular imaging, traditionally angiography, which demonstrates stenosis, occlusion, dilatation, or aneurysmal changes in the affected arteries. Treatment aims to control vascular inflammation and prevent further arterial damage. Corticosteroids and other immunosuppressive drugs are commonly used, while surgical or endovascular intervention may be necessary when severe vascular obstruction or aneurysm formation develops.

2. Giant Cell Arteritis

Giant cell arteritis is a large-vessel granulomatous vasculitis that commonly affects branches of the carotid artery, particularly the temporal arteries, although larger vessels may also be involved. Arterial inflammation causes narrowing of the lumen and reduced blood supply to affected tissues. It is especially important because it is a treatable cause of irreversible visual loss in older adults.

Patients usually have a markedly elevated erythrocyte sedimentation rate (ESR) and other evidence of systemic inflammation. Diagnosis is supported by temporal artery biopsy, although a negative biopsy does not completely exclude the condition because inflammation may occur in discontinuous segments of the artery.

The typical clinical presentation includes a new unilateral throbbing headache, often associated with scalp tenderness. Jaw claudication, in which pain develops during chewing, is particularly suggestive of the disease. Visual manifestations include amaurosis fugax, diplopia, and permanent visual loss resulting from ocular ischaemia. Approximately half of affected patients may also experience symptoms of polymyalgia rheumatica, such as prominent shoulder and hip girdle pain and morning stiffness.

Giant cell arteritis responds well to high-dose corticosteroid therapy. When the condition is strongly suspected, treatment should be started promptly rather than delayed while awaiting biopsy because early corticosteroid treatment can help prevent permanent blindness.

Medium-Vessel Vasculitis

1. Polyarteritis Nodosa (PAN)

Polyarteritis nodosa is a systemic necrotising vasculitis that predominantly affects medium-sized arteries. The inflammatory process can cause arterial narrowing, thrombosis, tissue ischaemia, and the development of small aneurysms. An important association is hepatitis B virus infection, although many cases occur without an identifiable infectious trigger.

Clinical manifestations vary according to the organs affected. Constitutional symptoms such as fever, malaise, and significant weight loss may occur. Skin involvement can produce livedo reticularis, while vascular inflammation involving the testes may cause testicular pain or tenderness. Musculoskeletal manifestations include myalgia and leg tenderness, and peripheral nerve involvement may produce mononeuropathy or polyneuropathy.

Features used in classification criteria include weight loss greater than 4 kg, livedo reticularis, testicular pain, myalgia or leg tenderness, mono- or polyneuropathy, evidence of hepatitis B infection, characteristic arteriographic abnormalities, and compatible biopsy findings. Angiography may reveal abnormalities such as aneurysms or arterial occlusions, while biopsy of affected tissue can demonstrate vasculitis.

2. Kawasaki Disease

Kawasaki disease is an acute systemic vasculitis that primarily affects young children, particularly those under five years of age. It predominantly involves medium-sized arteries and is especially important because of its potential effects on the coronary circulation.

One of the most serious complications is the development of coronary artery aneurysms or other coronary lesions. Severe coronary involvement can result in thrombosis, myocardial ischaemia, myocardial infarction, sudden cardiac death, or papillary muscle dysfunction. The risk of coronary complications makes early recognition and treatment particularly important.

Standard treatment consists of intravenous immunoglobulin (IVIG) together with aspirin. IVIG significantly reduces the likelihood of coronary artery abnormalities, while aspirin is used for its anti-inflammatory and antiplatelet effects depending on the phase of illness.

Small-Vessel Vasculitis

1. Churg–Strauss Syndrome

Churg–Strauss syndrome, now known as eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic small-vessel vasculitis strongly associated with asthma and eosinophilia. Patients typically have a history of asthma or allergic disease before developing systemic manifestations of vasculitis.

The combination of asthma, marked peripheral blood eosinophilia, and systemic vasculitis is highly characteristic. Multiple organs may become involved, including the lungs, skin, peripheral nerves, gastrointestinal tract, and heart. Corticosteroids are an important component of treatment, with additional immunosuppressive or targeted therapy used in more severe disease.

2. Wegener’s Granulomatosis

Wegener’s granulomatosis, now called granulomatosis with polyangiitis (GPA), is a necrotising granulomatous systemic vasculitis that mainly affects small and medium-sized vessels. It characteristically involves the upper respiratory tract, lungs, and kidneys.

The disease is strongly associated with cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA), particularly antibodies directed against proteinase 3 (PR3). However, ANCA testing supports the diagnosis and should be interpreted together with the clinical findings rather than being used alone.

Upper respiratory tract involvement is very common and may present with recurrent epistaxis, purulent or bloody nasal discharge, and chronic sinusitis. Lower respiratory tract disease may produce pulmonary infiltrates, nodules, cough, breathlessness, or pulmonary haemorrhage, with haemoptysis occurring in severe cases.

Renal involvement is another major feature and can cause proteinuria and haematuria. More aggressive renal disease may progress to rapidly progressive glomerulonephritis and renal failure. Other systemic manifestations include polyarthralgia and a vasculitic skin rash.

3. Henoch–Schönlein Purpura

Henoch–Schönlein purpura, currently known as IgA vasculitis, is an IgA-mediated small-vessel leukocytoclastic vasculitis. It is one of the most common systemic vasculitides occurring in children. The disease is characterised by the deposition of IgA-containing immune complexes, particularly within small vessels of the skin and kidneys.

The illness frequently develops following an upper respiratory tract infection. Its most characteristic manifestation is a palpable purpuric rash, particularly over dependent areas such as the lower limbs and buttocks. The purpura occurs without thrombocytopenia and reflects inflammation of small dermal vessels.

Other important manifestations include arthralgia or arthritis, particularly involving the lower-limb joints. Renal involvement may cause haematuria, proteinuria, or glomerulonephritis. Gastrointestinal vasculitis can result in colicky abdominal pain and gastrointestinal bleeding. In children, bowel involvement may occasionally lead to intussusception, which is an important acute complication.

Treatment of Vasculitis

Treatment depends on the type of vasculitis, severity of disease, and organs involved. Severe systemic vasculitis, particularly when there is major renal, pulmonary, neurological, or other organ-threatening disease, may require aggressive immunosuppression.

Induction of Remission

The initial objective in severe vasculitis is to achieve rapid control of active vascular inflammation and induce remission. High-dose corticosteroids are commonly used, and severe disease may require intravenous pulsed methylprednisolone. Additional immunosuppressive therapy, such as cyclophosphamide, may be required for life-threatening or organ-threatening disease.

Maintenance of Remission

Once remission has been achieved, treatment is usually changed to a less intensive maintenance regimen to reduce the risk of relapse while limiting the adverse effects of prolonged powerful immunosuppression. Depending on the specific type of vasculitis, maintenance therapy may include corticosteroids together with drugs such as azathioprine or other steroid-sparing immunosuppressive agents.

Plasma Exchange

Plasma exchange has historically been used in selected patients with particularly severe vasculitis. Its role depends on the specific disease and clinical situation and is more limited in current practice than older treatment schemes suggest. It may still be considered in selected severe presentations where removal of circulating pathogenic antibodies or immune components is clinically indicated.

Medicine – Essential Features of Polymyalgia Rheumatica

Polymyalgia rheumatica is an inflammatory disorder that mainly affects older adults, particularly those between 60 and 70 years of age. It is characterised by pain and marked stiffness around the shoulder and hip girdles, especially in the morning. The condition is closely associated with giant cell arteritis and typically produces a strong inflammatory response, reflected by elevated inflammatory markers such as the erythrocyte sedimentation rate.

1. Age Group

Polymyalgia rheumatica occurs almost exclusively in older people and is most commonly seen in patients aged around 60–70 years. The likelihood of the condition increases with advancing age, and it is uncommon in younger adults.

2. Association with Giant Cell Arteritis

There is a strong relationship between polymyalgia rheumatica and giant cell arteritis. Around 25% of patients may have associated giant cell arteritis. Because of this connection, patients should be assessed for symptoms such as new headache, scalp tenderness, jaw claudication, or visual disturbance, as untreated giant cell arteritis can threaten vision.

3. Raised ESR and Alkaline Phosphatase

Laboratory investigations usually demonstrate evidence of systemic inflammation. The erythrocyte sedimentation rate is typically raised, and some patients also have an increase in alkaline phosphatase, reported in about 30% of cases. These abnormalities support the diagnosis but should always be interpreted together with the clinical picture.

4. Rapid Response to Steroids

A characteristic feature of polymyalgia rheumatica is the rapid improvement of both symptoms and inflammatory markers after corticosteroid treatment. Patients often experience a striking reduction in pain and stiffness within a short period after starting therapy. The ESR also tends to fall as the inflammatory process comes under control, and this response can provide useful support for the diagnosis.

Clinical Features

1. Sudden Onset of Proximal Symptoms

The illness often begins suddenly, with prominent symptoms affecting the proximal muscles and girdle regions. Patients commonly report difficulty moving the shoulders or hips, particularly after periods of rest. The discomfort is usually most severe in the morning and can make activities such as getting out of bed, dressing, or raising the arms difficult. Although patients may describe weakness, the main problem is usually pain and stiffness rather than true loss of muscle power.

2. Weight Loss

Some patients develop unintentional weight loss as part of the systemic inflammatory illness. This may occur together with constitutional symptoms such as malaise, reduced appetite, or low-grade fever.

3. Joint Pain

Joint pain may accompany the more typical shoulder and hip girdle symptoms. The pain can contribute to reduced mobility and functional limitation, although marked destructive arthritis is not a typical feature of polymyalgia rheumatica.

4. Symptoms of Giant Cell Arteritis

Patients may also present with manifestations of giant cell arteritis, including headache, scalp tenderness, jaw pain during chewing, or visual symptoms. These features are clinically important because giant cell arteritis requires urgent treatment to reduce the risk of serious complications such as permanent visual loss.

Medicine – Essential Features of Fibromyalgia

Fibromyalgia is a chronic pain syndrome characterised by widespread musculoskeletal pain, increased sensitivity to pressure, fatigue, sleep disturbance, and a variety of associated somatic symptoms. Despite the severity of the patient’s symptoms, routine physical examination and investigations usually do not demonstrate inflammatory, neurological, or structural abnormalities. The condition may therefore produce a noticeable difference between the degree of symptoms and disability reported by the patient and the objective clinical findings.

1. Pain

Pain is the most prominent feature of fibromyalgia. It commonly affects the neck and back, although many patients describe widespread or generalized pain involving several areas of the body. The discomfort may be persistent, aching, or burning in character and can fluctuate considerably in severity. Symptoms are often aggravated by psychological stress, exposure to cold weather, and physical activity, although the pattern varies between individuals.

2. Generalised Morning Stiffness

Patients frequently experience generalised stiffness on waking in the morning. Rather than being confined to a single joint, the stiffness may involve several regions of the body and can contribute to difficulty beginning normal daily activities. Unlike inflammatory arthropathies, however, the stiffness of fibromyalgia is not accompanied by objective evidence of joint inflammation or synovitis.

3. Paraesthesiae

Paraesthesiae of the hands and feet are commonly reported. Patients may describe tingling, numbness, prickling, or abnormal sensations in the extremities. These symptoms can resemble those produced by peripheral neurological disorders, but neurological examination is usually normal and there is typically no objective sensory or motor deficit.

4. Fatigue

Persistent fatigability is another major feature of fibromyalgia. Patients may feel tired even after relatively minor physical or mental activity and may experience a persistent lack of energy throughout the day. Fatigue can significantly interfere with work, exercise, concentration, and other normal activities and is often closely related to disturbed sleep.

5. Non-restorative Sleep

Sleep disturbance is particularly characteristic of fibromyalgia. Although patients may sleep for an apparently adequate number of hours, the sleep is often non-restorative, meaning that they wake feeling tired and unrefreshed. Poor-quality sleep can worsen pain sensitivity, daytime fatigue, cognitive difficulties, and overall functioning.

6. Headache

Recurrent headaches are frequently associated with fibromyalgia. These may occur as tension-type headaches or sometimes have migraine-like features. Headache symptoms often coexist with neck and shoulder discomfort and may become more prominent during periods of stress, fatigue, or poor sleep.

7. Gastrointestinal Symptoms

Some patients experience diffuse abdominal pain accompanied by changes in bowel habit. Bowel symptoms may include episodes of constipation, diarrhoea, or alternating patterns of both. These gastrointestinal manifestations often overlap with symptoms commonly associated with functional bowel disorders such as irritable bowel syndrome.

8. Urinary Frequency

Increased urinary frequency may occur despite the absence of a urinary tract infection or other obvious structural abnormality. Patients may feel the need to pass urine more frequently than usual, and these urinary symptoms may accompany the other functional or somatic complaints associated with fibromyalgia.

9. Dysmenorrhoea

Women with fibromyalgia may experience dysmenorrhoea, or painful menstruation. Menstrual discomfort may be more pronounced in some patients because of the increased sensitivity to pain that characterises the disorder.

Clinical Signs

1. Discordance Between Symptoms and Objective Findings

A characteristic clinical feature is the disproportion between the severity of reported symptoms and the limited objective abnormalities found on examination. Patients may experience substantial pain and functional limitation even though joints, muscles, neurological examination, and routine investigations show no corresponding structural or inflammatory abnormality.

2. Absence of Objective Weakness, Synovitis, or Neurological Abnormality

Despite complaints of pain, fatigue, numbness, or weakness, examination typically demonstrates no true muscle weakness, synovitis, or focal neurological abnormality. Muscle power and neurological function are generally preserved. This absence of objective inflammatory or neurological findings can help distinguish fibromyalgia from inflammatory arthritis, myopathy, and neurological disease.

3. Multiple Hyperalgesic Sites

Patients may have multiple areas of hyperalgesia, meaning that stimuli that would normally cause only mild discomfort are perceived as unusually painful. This increased pain sensitivity reflects altered processing of painful stimuli and is an important clinical characteristic of fibromyalgia.

4. Tenderness on Rolling the Mid-Trapezius Skin Fold

Marked tenderness may be produced by rolling or pinching the skin fold over the mid-trapezius region. The degree of discomfort can be substantially greater than would normally be expected from such light mechanical stimulation, reflecting the increased sensitivity to pressure and touch seen in fibromyalgia.

5. Cutaneous Hyperaemia After Palpation

Palpation of tender areas may sometimes produce local cutaneous hyperaemia, with visible redness of the skin occurring after pressure has been applied. This response can accompany the pronounced tenderness and increased sensitivity found at symptomatic sites.

6. Negative Control Sites

When examining a patient for tenderness, control sites may remain relatively non-tender compared with symptomatic areas. This finding helps demonstrate that the pain response is not necessarily uniform throughout the body and can assist in assessing the distribution of tenderness during clinical examination.

Medicine – Primary Malignant Bone Tumours

1. Osteosarcoma

Osteosarcoma is a primary malignant bone tumour that occurs predominantly in young adults. It most commonly involves the long bones, particularly around the knee, with the distal femur and proximal tibia being characteristic sites. The tumour usually demonstrates rapid and aggressive growth, and patients commonly present with progressively worsening bone pain and local swelling. Osteosarcoma has a tendency to spread through the bloodstream, particularly to the lungs, resulting in pulmonary metastases. Treatment generally consists of a combination of surgery and chemotherapy. The table gives an approximate cure rate of 40%.

2. Chondrosarcoma

Chondrosarcoma is a malignant tumour of cartilage-producing cells that is most frequently seen in adults between 35 and 60 years of age. Common sites include the pelvis, ribs, spine, and long bones. In contrast to osteosarcoma, chondrosarcoma generally shows slow and progressive enlargement. As the tumour advances, it may eventually invade nearby blood vessels and surrounding structures. Surgical removal is the principal form of treatment, as conventional chemotherapy is generally less effective for most chondrosarcomas. According to the table, the approximate cure rate is 75%.

3. Fibrosarcoma and Malignant Fibrous Histiocytoma

Fibrosarcoma and malignant fibrous histiocytoma can occur at almost any age, although their incidence peaks at approximately 30–40 years. These tumours commonly affect bones such as the femur, tibia, humerus, and pelvis. Their behaviour is characterised mainly by progressive local growth and invasion of blood vessels, allowing the tumour to extend into surrounding tissues and potentially spread to distant sites. The main treatment is surgical excision, with the aim of completely removing the malignant tissue. The table indicates an approximate cure rate of 40%.

4. Ewing’s Sarcoma

Ewing’s sarcoma is an aggressive malignant bone tumour that occurs mainly in children and teenagers. It commonly affects the long bones, pelvis, and ribs. Unlike some more slowly growing bone tumours, Ewing’s sarcoma is highly aggressive and has a significant tendency to develop widespread metastases. Because of its systemic nature and responsiveness to cytotoxic drugs, chemotherapy forms an important part of treatment, usually as part of multimodal therapy. The table lists an approximate cure rate of 10%.

Medicine – Causes of a Very High ESR (>100 mm/hr)

A very high erythrocyte sedimentation rate (ESR) of more than 100 mm/hr usually indicates the presence of a significant underlying inflammatory, infectious, malignant, or haematological disorder. Although ESR is a nonspecific marker and does not identify the exact cause of disease, such a marked elevation should prompt further investigation to determine the underlying condition.

1. Multiple Myeloma

Multiple myeloma is an important haematological cause of a markedly elevated ESR. It is a plasma cell malignancy characterised by excessive production of monoclonal immunoglobulins or their components. The increased concentration of abnormal proteins in the blood promotes aggregation of red blood cells into rouleaux, causing them to sediment more rapidly and resulting in a very high ESR. Patients may also present with features such as bone pain, anaemia, renal impairment, hypercalcaemia, and recurrent infections.

2. Giant Cell Arteritis and Polymyalgia Rheumatica

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory disorders that commonly produce a substantial rise in ESR. Giant cell arteritis is a large-vessel vasculitis that typically affects older adults and may present with new-onset headache, scalp tenderness, jaw claudication, and visual disturbances. Polymyalgia rheumatica is closely associated with GCA and usually causes pain and morning stiffness involving the shoulders, neck, and hips. The marked inflammatory response in these conditions can result in an ESR exceeding 100 mm/hr.

3. Sepsis

Sepsis and other severe infections can cause a very high ESR because of the intense systemic inflammatory response triggered by infection. Inflammatory cytokines stimulate the liver to produce acute-phase proteins, particularly fibrinogen, which promotes red blood cell aggregation and increases the sedimentation rate. Depending on the source and severity of infection, patients may develop fever, tachycardia, hypotension, altered mental status, and evidence of organ dysfunction.

4. Occult Malignancy

An occult malignancy refers to a cancer that is present but has not yet been clinically identified. Certain malignancies can produce a markedly elevated ESR as a consequence of systemic inflammation, tissue damage, increased circulating proteins, or associated anaemia. A persistently unexplained ESR greater than 100 mm/hr, particularly when accompanied by features such as unintentional weight loss, persistent fatigue, night sweats, anaemia, or lymphadenopathy, may warrant investigation for an underlying malignancy.

5. Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease capable of producing widespread inflammation involving multiple organs. Increased immunoglobulin levels and inflammatory proteins promote red blood cell aggregation, which can substantially increase the ESR. Patients may have a variety of manifestations, including joint pain, skin rashes, photosensitivity, oral ulcers, haematological abnormalities, and renal involvement. ESR may rise considerably during active disease and can therefore provide supportive information when assessing inflammatory activity.

Medicine – Antirheumatoid Drugs

1. Hydroxychloroquine

Hydroxychloroquine is a disease-modifying antirheumatic drug that helps reduce inflammation by altering immune activity. One of its actions is to interfere with complement-dependent antigen–antibody reactions, which decreases the inflammatory response involved in rheumatoid arthritis. Although it is generally considered less immunosuppressive than some other antirheumatic agents, long-term treatment requires careful monitoring. Important adverse effects include increased skin pigmentation, retinal maculopathy, and leukopenia. Retinal toxicity is particularly important because prolonged exposure may damage the macula and impair vision, so regular ophthalmological assessment is recommended during long-term therapy.

2. Gold

Gold compounds were previously used as disease-modifying drugs in rheumatoid arthritis, although they are now used much less frequently. Their antirheumatic effect is mainly related to the inhibition of macrophage activity, which reduces the release of inflammatory mediators and suppresses immune-mediated tissue damage. However, treatment with gold is associated with several significant adverse effects. The most common is dermatitis, which may occur in approximately 30% of patients. Renal complications such as proteinuria and glomerulonephritis can also develop. In addition, gold therapy may suppress bone marrow function and lead to thrombocytopenia, leukopenia, or, in severe cases, aplastic anaemia.

3. Penicillamine

Penicillamine is another older disease-modifying antirheumatic drug that works by altering immune responses. It can reduce circulating IgM rheumatoid factor and suppress T-cell activity, thereby decreasing some of the autoimmune processes involved in rheumatoid arthritis. Despite its therapeutic effects, penicillamine has a relatively wide range of adverse reactions. Patients may develop a maculopapular skin rash or loss of taste, particularly during treatment. Renal involvement may occur in the form of proteinuria or nephrotic syndrome. Penicillamine can also trigger autoimmune complications such as drug-induced lupus and myasthenia gravis. Haematological toxicity is another important concern, with possible thrombocytopenia and pancytopenia.

4. Sulfasalazine

Sulfasalazine is commonly used as a conventional disease-modifying antirheumatic drug. Its active systemic component, sulfapyridine, contributes to the suppression of inflammatory reactions and reduces the production of inflammatory mediators, including prostaglandins. Through these actions, the drug helps control joint inflammation and may slow disease progression. Gastrointestinal adverse effects such as nausea are relatively common, while skin rashes and hepatitis may also occur. Less common but important complications include pulmonary eosinophilia, haemolytic anaemia, and pancytopenia. In men, sulfasalazine may also cause a reversible reduction in sperm count, which usually improves after the medication is discontinued.

5. Methotrexate

Methotrexate is one of the most important disease-modifying antirheumatic drugs and is widely used in the management of rheumatoid arthritis. It acts as a folic acid antagonist and interferes with enzymes involved in folate metabolism, thereby reducing nucleotide synthesis and limiting DNA synthesis and cellular replication. At the lower doses used in rheumatoid arthritis, its major therapeutic effect is related to suppression of inflammatory and immune activity. Methotrexate can cause significant toxicity if not monitored properly. Important adverse effects include hepatotoxicity, which may progress to hepatic fibrosis with prolonged use, as well as bone marrow suppression and blood dyscrasias. Regular monitoring of liver function and blood cell counts is therefore important during treatment.

6. Cyclophosphamide

Cyclophosphamide is a powerful immunosuppressive and cytotoxic drug that may be used in severe autoimmune disease when stronger suppression of the immune system is required. It reduces both antibody-mediated and cell-mediated immune responses, thereby decreasing the activity of immune cells that contribute to inflammation and tissue injury. Because of its potency, the drug is associated with serious adverse effects. One characteristic complication is haemorrhagic cystitis, which results from toxic metabolites irritating the urinary bladder. Cyclophosphamide can also cause marked bone marrow suppression, leading to pancytopenia and an increased risk of infection, bleeding, and anaemia.

7. Azathioprine

Azathioprine is an immunosuppressive drug that acts mainly by inhibiting purine and nucleic acid synthesis. This action limits the proliferation of rapidly dividing immune cells, particularly lymphocytes, resulting in suppression of cell-mediated hypersensitivity and alteration of antibody production. By reducing immune-system activity, azathioprine can help control inflammatory and autoimmune disease. However, treatment may produce several important adverse effects. Bone marrow suppression can occur and may lead to reductions in white blood cells, red blood cells, and platelets. The drug may also cause cholestatic hepatitis, while gastrointestinal effects such as nausea and vomiting are relatively common. Another notable adverse effect is pancreatitis, which may require discontinuation of therapy.

Infectious Disease and Microbiology – Comamonas Species

Overview

Comamonas species are aerobic Gram-negative bacilli of generally low pathogenicity. They are common environmental organisms and only rarely cause human disease. Because they can also appear as incidental laboratory contaminants, a positive culture should always be interpreted in the context of the patient’s clinical presentation.

The clinically recognized species include Comamonas acidovorans, Comamonas terrigena, and Comamonas testosteroni, with C. testosteroni being the species most often associated with human infection.

Microbiologic Characteristics

Comamonas organisms are aerobic Gram-negative rods. They are primarily environmental bacteria and are not considered major components of normal human flora.

Their low intrinsic virulence means that infection usually occurs in patients with important predisposing factors, such as immunosuppression, intravenous drug use, or disruption of normal tissue barriers.

Epidemiology

These bacteria are widely distributed in the environment, including soil and water. Human infection is uncommon.

Because Comamonas may occasionally contaminate clinical specimens, the significance of an isolated positive culture depends on factors such as repeated recovery from sterile sites, compatible symptoms, and the absence of a more plausible pathogen.

Endocarditis

Comamonas species have rarely been associated with infective endocarditis, particularly in people who inject drugs.

Clinical features may include:

• Persistent fever

• Cardiac murmur

• Embolic phenomena

• Positive blood cultures

Repeated isolation from blood in a compatible clinical setting supports true infection rather than contamination.

Bacteremia

Bacteremia may occur, especially in immunocompromised patients.

Possible manifestations include:

• Fever

• Chills

• Hypotension

• Sepsis in severe cases

As with other unusual Gram-negative organisms, identification from multiple blood cultures makes a true bloodstream infection more likely.

Keratitis

C. acidovorans has rarely been reported as a cause of keratitis and corneal ulceration.

Patients may present with:

• Eye pain

• Redness

• Photophobia

• Corneal opacity or ulceration

• Reduced vision

Prompt ophthalmologic assessment is important because progressive corneal infection can threaten vision.

Diagnosis

Diagnosis is established by culture of the organism from an appropriate specimen.

Depending on the syndrome, specimens may include:

• Blood

• Cardiac-related samples

• Corneal scrapings

• Other infected tissue or fluid

Because contamination is possible, clinicians should correlate the microbiologic result with the overall clinical picture.

Interpreting a Positive Culture

A positive culture is more likely to represent true infection when:

• The organism is recovered repeatedly

• It is isolated from a normally sterile site

• The patient has compatible symptoms

• There are recognized risk factors

• No more likely pathogen is identified

A single positive culture without clinical evidence of infection may represent contamination.

Treatment

There are limited clinical data defining the optimal antimicrobial regimen for Comamonas infections.

Available experience suggests that antipseudomonal agents may be active against many isolates.

Potential choices may include selected:

• Antipseudomonal beta-lactams

• Fluoroquinolones

• Other active Gram-negative agents

Definitive therapy should be guided by antimicrobial susceptibility testing whenever possible.

Severe Infection

For endocarditis, bacteremia, or another invasive infection, management should include:

• Susceptibility-directed antimicrobial therapy

• Assessment for an infected catheter or other source

• Echocardiography if endocarditis is suspected

• Source control when necessary

High-Yield Clinical Pattern

Unusual Gram-negative bacillus in blood culture

• ●

Intravenous drug use or immunosuppression

• ●

Compatible bacteremia or endocarditis

→ Consider true Comamonas infection, while still evaluating carefully for contamination.

Exam Essentials

Genus: Comamonas

Important species: C. testosteroni, C. acidovorans, C. terrigena

Most common human species: C. testosteroni

Microbiology: Aerobic Gram-negative bacillus

Virulence: Generally low

Typical habitat: Environment

Major infections: Endocarditis, bacteremia, rare keratitis

Important risk groups: Intravenous drug users and immunocompromised patients

Diagnosis: Culture

Important interpretation issue: May represent contamination

Treatment: Limited evidence; antipseudomonal agents may be effective, ideally guided by susceptibility testing

Key clinical pearl: Comamonas is usually a low-virulence environmental organism, so the major challenge is deciding whether a positive culture represents true invasive infection or contamination.