Vasculitis, Polymyalgia, and Other Inflammatory Diseases

TL;DR. Vasculitis is inflammation of blood vessel walls, and everything about it follows from one question: which size of vessel is affected. Inflame the large arteries and you get headache, jaw pain, and sudden blindness. Inflame the medium ones and you get organ infarction. Inflame the smallest and you get a purple rash, kidney failure, and lungs filling with blood. The single most time-critical condition in this chapter is giant cell arteritis, where a few hours of delay can cost an eye permanently, and where the correct action is to start steroids immediately and confirm the diagnosis afterwards. This chapter also covers three other immune-mediated diseases that had nowhere else to go: sarcoidosis, which imitates everything, myasthenia gravis, where antibodies block the signal from nerve to muscle, and IgG4-related disease, which was only recognised as a single entity in this century.

Key takeaways

• Giant cell arteritis is a medical emergency. New headache in someone over 50 with raised inflammatory markers means high-dose steroids now, before the biopsy, because vision loss is sudden, painless, and permanent.
• Polymyalgia rheumatica and giant cell arteritis are the same disease spectrum. Roughly 15 to 20 percent of polymyalgia patients develop arteritis, and about 40 to 50 percent of arteritis patients have polymyalgia symptoms.
• Vasculitis is classified by vessel size, and that classification predicts the symptoms, the investigations, and the treatment.
• ANCA-associated vasculitis was almost uniformly fatal within a year before cyclophosphamide; treated, most patients now survive long term.
• Sarcoidosis resolves spontaneously in most people and can be fatal when it affects the heart, which is why cardiac assessment matters even in mild-looking disease.
• Myasthenia gravis causes weakness that worsens with use, which is a distinctive and easily tested feature.

How vasculitis is organised

In short: By vessel size, because the size of the vessel determines the symptoms.

The Chapel Hill consensus classification sorts vasculitis by the calibre of vessel predominantly affected. It is not a technicality; it is the most useful clinical framework in the field.

Two features run through nearly all of them: systemic inflammation (fever, weight loss, fatigue, raised CRP) and evidence of tissue ischaemia in whatever the affected vessels supply.

Giant cell arteritis

In short: Inflammation of the large arteries of the head in people over 50, and the most time-critical diagnosis in rheumatology.

What it is

Giant cell arteritis (GCA), also called temporal arteritis, is granulomatous inflammation of large and medium arteries, particularly the branches of the external carotid artery and the ophthalmic artery. It essentially never occurs before 50, and incidence rises steeply with age. It is most common in populations of Northern European descent, with the highest rates recorded in Scandinavia, and is roughly two to three times more common in women.

What it does

The complication that defines management: sudden, painless, permanent vision loss in one eye, from occlusion of the artery supplying the optic nerve. It occurs in a proportion of untreated patients, it can happen without warning, and once it has happened it does not reverse. If the second eye follows, the person is blind.

The rule

Don't be confused: in giant cell arteritis you treat first and confirm afterwards. This reverses the usual order in medicine, and it is correct. A new headache in someone over 50 with a raised ESR or CRP warrants high-dose corticosteroids immediately, on the same day, before any biopsy or scan. The biopsy remains informative for up to about two weeks after starting steroids, so nothing is lost by treating, and an eye is potentially lost by waiting. If visual symptoms are present, the steroids are intravenous and the urgency is measured in hours.

Diagnosis and treatment

Diagnosis: raised ESR and CRP (occasionally normal, which does not exclude it), temporal artery ultrasound looking for a non-compressible "halo" of vessel wall oedema, and temporal artery biopsy, which is specific but can miss the diagnosis because the inflammation is patchy ("skip lesions"). PET-CT identifies large vessel involvement.

Treatment: high-dose prednisolone, tapered slowly over 12 to 24 months. Relapse on tapering is common, and cumulative steroid toxicity is substantial in this elderly population. Tocilizumab (blocking IL-6) is now established as a steroid-sparing agent, allowing faster tapering and reducing relapse; note that it suppresses CRP, so that marker can no longer be used to monitor disease. Low-dose aspirin is often added. Bone protection and glucose monitoring are standard, because the steroid dose and the patient's age together make osteoporosis and diabetes predictable.

Polymyalgia rheumatica

In short: Shoulder and hip girdle pain and stiffness in the over-50s, with a response to low-dose steroids so rapid it is almost diagnostic.

Polymyalgia rheumatica (PMR) is one of the commonest inflammatory rheumatic diseases in older adults. It causes:

• Aching and severe morning stiffness in the shoulders, neck, and hips, usually bilateral, lasting well over 45 minutes.
• Difficulty rising from a chair, raising arms above the head, or turning over in bed.
• Systemic features: fatigue, low-grade fever, weight loss, low mood.
• Raised ESR and CRP, usually markedly.
• No true muscle weakness on testing, despite the pain making movement difficult, and normal muscle enzymes. This distinguishes it from myositis (Chapter 51).

The steroid response is characteristic. Low-dose prednisolone typically produces dramatic improvement within 24 to 72 hours, and failure to respond that quickly should prompt reconsidering the diagnosis. That said, treating an undiagnosed condition with steroids because they help is a recognised trap: several cancers, infections, and other inflammatory diseases improve temporarily on steroids too.

PMR and GCA overlap substantially, and every PMR patient should be told the symptoms of arteritis and instructed to seek same-day help if they develop a new headache, jaw pain on chewing, or any visual change.

Treatment is prednisolone tapered over one to two years, with methotrexate or tocilizumab as steroid-sparing options in relapsing disease, plus bone protection.

ANCA-associated vasculitis

In short: Small-vessel vasculitis attacking kidneys and lungs, once almost uniformly fatal, now usually survivable.

ANCA stands for anti-neutrophil cytoplasmic antibody. These antibodies target enzymes inside neutrophils, and when they bind, they activate the neutrophil while it is inside a small vessel, causing it to degranulate and destroy the vessel wall. It is one of the more directly demonstrated autoantibody mechanisms in medicine.

Three conditions:

The two emergencies:

• Rapidly progressive glomerulonephritis: kidney function falling over days to weeks, with blood and protein in the urine. Untreated it destroys the kidneys permanently within weeks.
• Pulmonary haemorrhage: bleeding into the alveoli, causing breathlessness, falling oxygen, and sometimes coughing blood, which can be absent even in severe bleeding.

Any patient with unexplained kidney impairment plus a systemic illness needs a urine dipstick. Blood and protein in the urine in that setting is the finding that opens this diagnosis, and it takes seconds.

Treatment transformed the prognosis. Untreated GPA had a mean survival of around five months and a one-year mortality above 80 percent. Cyclophosphamide changed that in the 1970s, and rituximab has since been shown to be at least as effective for induction with less infertility and bladder toxicity. Plasma exchange is used in selected severe cases. Maintenance uses rituximab or azathioprine, and avacopan, which blocks the complement C5a receptor, reduces steroid requirements.

The other vasculitides

In short: Four more worth recognising, two of which mainly affect children.

Polyarteritis nodosa affects medium arteries, causing organ infarction, aneurysms visible on angiography, skin nodules and ulcers, and mononeuritis multiplex (individual named nerves failing one after another, producing for example a sudden foot drop). Classically associated with hepatitis B infection, though that link has become rarer with vaccination. It notably spares the lungs and does not cause glomerulonephritis, which distinguishes it from the small-vessel group.

Kawasaki disease is a medium-vessel vasculitis of young children and the leading cause of acquired heart disease in children in high-income countries. It causes prolonged fever with rash, red eyes, red cracked lips and strawberry tongue, swollen hands and feet with later peeling, and cervical lymph node enlargement. Its danger is coronary artery aneurysms, which develop in up to a quarter of untreated cases and which can cause myocardial infarction in childhood. Intravenous immunoglobulin within ten days reduces that risk to a few percent, which makes prompt recognition of prolonged fever in a young child genuinely important.

IgA vasculitis (Henoch-Schönlein purpura) is the commonest vasculitis of childhood, typically following an upper respiratory infection. It produces a palpable purpuric rash on the buttocks and lower limbs, joint pain, abdominal pain (occasionally with intussusception), and glomerulonephritis. Most children recover fully; the kidney involvement determines outcome and requires urine monitoring for months afterwards. In adults it is less common and more likely to affect the kidneys seriously.

Behçet's disease causes recurrent painful oral ulcers, genital ulcers, uveitis, skin lesions, and, distinctively among vasculitides, it can affect vessels of any size including veins, causing thrombosis. It is most common along the historic Silk Road, from Turkey through the Middle East to East Asia, and is associated with HLA-B51. Eye involvement can destroy vision, and neurological and large-vessel involvement carry the worst prognosis.

Sarcoidosis

In short: Granulomas forming anywhere, most often the lungs, in a disease that resolves by itself in most people and kills a few through the heart.

What it is

Sarcoidosis is a multisystem inflammatory disease characterised by non-caseating granulomas: organised clumps of immune cells that, unlike tuberculosis granulomas, do not have a necrotic cheesy centre. The cause is unknown, and the leading model is an exaggerated immune response to an unidentified environmental antigen in a genetically susceptible person.

Where it appears

Löfgren syndrome is an acute presentation with fever, erythema nodosum, bilateral hilar lymphadenopathy, and arthritis in the ankles. It matters because it carries an excellent prognosis: the large majority resolve spontaneously within two years.

Course and treatment

Most sarcoidosis resolves without treatment, particularly acute presentations. A minority becomes chronic and progressive. Treatment is therefore reserved for organ-threatening or symptomatic disease rather than given automatically.

When treatment is needed: corticosteroids first, then methotrexate, azathioprine, or mycophenolate as steroid-sparing agents, then anti-TNF (infliximab) for refractory disease.

Cardiac sarcoidosis deserves specific mention because it is the main way sarcoidosis kills, it can be the first manifestation, and it is under-diagnosed. Any unexplained heart block or ventricular arrhythmia in a younger adult should prompt consideration of it, and imaging with cardiac MRI or PET is how it is found.

Myasthenia gravis

In short: Antibodies blocking the signal from nerve to muscle, producing weakness that gets worse the more you use the muscle.

What it is

At every junction between a nerve and a muscle, the nerve releases acetylcholine, which binds receptors on the muscle and triggers contraction (Chapter 6). In myasthenia gravis, antibodies against the acetylcholine receptor (in about 85 percent) or against a related protein MuSK block or destroy that connection.

What it does

Fatigable weakness is the defining feature, and it is unusual enough to be diagnostic when looked for: the muscle works at first and progressively fails with repeated use, recovering with rest. Symptoms are typically worse in the evening.

Myasthenic crisis is respiratory muscle failure requiring ventilation, and it can be precipitated by infection, surgery, pregnancy, or certain drugs. Many common medicines worsen myasthenia, including aminoglycoside and fluoroquinolone antibiotics, magnesium, beta blockers, and some anaesthetic agents, which is why every patient should carry a list.

The thymus is involved. Around 10 to 15 percent of patients have a thymoma, a thymus tumour, and many others have thymic hyperplasia. Chest imaging is mandatory at diagnosis, and thymectomy improves outcomes in generalised disease in patients under about 65, including in those without a thymoma, which was demonstrated in a randomised trial.

Treatment: pyridostigmine, which blocks the breakdown of acetylcholine and so increases the amount available at the junction, for symptoms; immunosuppression (steroids, azathioprine, mycophenolate) for the underlying autoimmunity; thymectomy where indicated; and, for crisis or severe disease, intravenous immunoglobulin or plasma exchange. Newer targeted agents, complement inhibitors and FcRn blockers which accelerate the clearance of circulating antibodies, have substantially expanded options for refractory disease.

IgG4-related disease

In short: A condition recognised only this century, which explains a scattered set of conditions previously thought unrelated.

IgG4-related disease is a fibro-inflammatory condition producing tumour-like swellings in almost any organ, infiltrated by IgG4-positive plasma cells, with characteristic storiform (whorled) fibrosis.

Its recognition around 2003 unified conditions that had been described separately for a century: autoimmune pancreatitis, Mikulicz disease (salivary and lacrimal gland swelling), Riedel's thyroiditis, retroperitoneal fibrosis, and some cases of orbital pseudotumour.

It is important because it imitates cancer. A mass in the pancreas, the bile ducts, the orbit, or the retroperitoneum that turns out to be IgG4-related disease can be treated with steroids rather than resected, and patients have historically had major surgery for what was a treatable inflammatory condition. It responds well to corticosteroids and to rituximab, and it relapses frequently.

Is any of this contagious?

In short: No, with one causal link worth knowing.

None of the conditions in this chapter is transmissible.

Two genuine infection connections: polyarteritis nodosa is classically associated with hepatitis B infection, and cryoglobulinaemic vasculitis is strongly associated with hepatitis C (Chapter 32). In both, treating the virus treats the vasculitis, which makes them the closest thing here to a curable vasculitis, and it is why hepatitis serology is checked in new vasculitis.

Kawasaki disease is suspected to follow an infectious trigger and does not spread between children, and IgA vasculitis commonly follows a respiratory infection that is itself contagious.

What the person can do

In short: Know the four emergency presentations in this chapter, because all four are time-critical.

• New headache over 50 with scalp tenderness, jaw pain on chewing, or any visual change: same-day medical assessment. Do not wait for a routine appointment. If you already have polymyalgia rheumatica, treat this as your standing instruction.
• Any sudden visual loss: emergency.
• Prolonged fever in a young child with rash, red eyes, and red lips: seek assessment, because Kawasaki disease treated within ten days protects the coronary arteries.
• Coughing blood, breathlessness, or falling kidney function with a systemic illness: urgent assessment for small-vessel vasculitis.
• Take steroid tapering seriously, and never stop long-term steroids abruptly (Chapter 59). Carry a steroid card.
• Ask for bone protection whenever a long steroid course is started, because osteoporosis in this group is predictable and preventable.
• In myasthenia, carry a list of drugs to avoid, and tell every clinician, anaesthetist, and dentist about the diagnosis.
• In sarcoidosis, ask whether your heart has been assessed, particularly if you have palpitations, blackouts, or breathlessness.

Sources and notes

Chapel Hill Consensus Conference nomenclature: Jennette et al., Arthritis & Rheumatism, 2013. Giant cell arteritis epidemiology and management: BSR and EULAR guidelines; tocilizumab in GCA: GiACTA trial, NEJM, 2017. Temporal artery ultrasound halo sign: TABUL study, 2016. PMR and GCA overlap frequencies: standard rheumatology references. Untreated GPA survival: Walton, BMJ, 1958. Rituximab versus cyclophosphamide: RAVE, NEJM, 2010, and RITUXVAS. Avacopan: ADVOCATE, NEJM, 2021. Plasma exchange: PEXIVAS, NEJM, 2020. Kawasaki disease and IVIG: Newburger et al., NEJM, 1986, and AHA statements. Behçet's and HLA-B51: de Menthon et al., meta-analysis. Sarcoidosis epidemiology and course: ATS/ERS statements; Löfgren syndrome prognosis: Swedish cohort data. Cardiac sarcoidosis under-diagnosis: HRS expert consensus. Myasthenia gravis thymectomy trial: Wolfe et al., NEJM, 2016 (MGTX). FcRn blockade: ADAPT trial, Lancet Neurology, 2021. IgG4-related disease unification: Kamisawa et al., 2003, and Stone, Zen, and Deshpande, NEJM, 2012.

Open questions. The trigger for sarcoidosis is unknown after a century of investigation. Why giant cell arteritis is confined to older adults and to specific arterial territories is unexplained. Whether ANCA antibodies are directly pathogenic in all cases, or markers in some, is debated.

Next: the conditions where the pain and exhaustion are real, the tests are normal, and patients have spent decades being disbelieved. 👉