Connective Tissue Disease and the Systemic Vasculitides

📋 Key Information Summary

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Connective tissue diseases (CTDs) — SLE, rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), and Sjögren syndrome — share autoimmune pathogenesis with overlapping clinical features and autoantibody profiles.
Systemic lupus erythematosus predominantly affects women of childbearing age (F:M ≈ 9:1); Australian prevalence is approximately 45 per 100 000, with significantly higher rates and severity in Aboriginal and Torres Strait Islander peoples.
Rheumatoid arthritis affects 0.5–1.0% of Australians; early referral within 3 months of symptom onset to rheumatology is critical to prevent irreversible joint destruction (treat-to-target strategy).
Systemic sclerosis (scleroderma) carries the highest mortality among CTDs; pulmonary arterial hypertension and interstitial lung disease are the leading causes of death.
Mixed connective tissue disease presents with overlapping features of SLE, SSc, polymyositis, and RA, characterised by high-titre anti-U1 RNP antibodies.
Sjögren syndrome increases the risk of B-cell non-Hodgkin lymphoma (5–10% lifetime); monitor for persistent parotid gland enlargement.
Raynaud phenomenon is present in >95% of SSc patients and may be the earliest manifestation; secondary features (digital ulcers, pitting) warrant urgent rheumatology assessment.
Giant cell arteritis (GCA) is a medical emergency — risk of irreversible blindness if not treated urgently with high-dose corticosteroids within hours of clinical suspicion.
Polymyalgia rheumatica (PMR) responds dramatically to low-dose corticosteroids (12.5–15 mg prednisolone); lack of response within 1 week should prompt reconsideration of diagnosis.
Polyarteritis nodosa (PAN) is a medium-vessel vasculitis diagnosed by angiography showing microaneurysms or tissue biopsy; treat with cyclophosphamide plus corticosteroids.
Autoantibody panels (ANA, anti-dsDNA, anti-CCP, RF, ANCA, anti-centromere, anti-Scl-70, anti-Ro/La) are essential for diagnosis and risk stratification but must be interpreted in clinical context.
Hydroxychloroquine is a cornerstone therapy for SLE, RA, and Sjögren syndrome — all patients should have baseline and annual ophthalmological screening for retinal toxicity.
Immunosuppressed CTD patients require infection screening (hepatitis B/C, TB, HIV) prior to starting biologic or immunosuppressive therapy, and should receive annual influenza and pneumococcal vaccination.
Pregnancy in women with SLE or antiphospholipid syndrome requires multidisciplinary care; hydroxychloroquine should be continued throughout pregnancy.

Introduction & Australian Epidemiology

Connective tissue diseases (CTDs) are a heterogeneous group of systemic autoimmune disorders characterised by immune-mediated inflammation of the musculoskeletal system, blood vessels, and internal organs. The major CTDs — systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren syndrome, and the inflammatory myopathies — share overlapping pathogenic mechanisms involving loss of self-tolerance, autoantibody production, immune complex deposition, and complement activation.

The systemic vasculitides represent a related but distinct group of disorders classified by the size of the predominantly affected blood vessels (large, medium, or small). In Australian general practice, the most clinically important vasculitides are giant cell arteritis (GCA), polymyalgia rheumatica (PMR), and polyarteritis nodosa (PAN). These conditions often present first to primary care physicians, and early recognition is essential to prevent organ damage or irreversible complications such as blindness (GCA) or renal failure (small-vessel vasculitis).

In Australia, CTDs collectively affect over 200 000 people and represent a significant burden of disease, particularly among women, Aboriginal and Torres Strait Islander peoples, and those in rural and remote areas with limited specialist access. The Australian Institute of Health and Welfare (AIHW) reports that musculoskeletal conditions are the fourth-largest contributor to total disease burden, with autoimmune inflammatory arthritis and lupus contributing substantially to years lived with disability (YLD).

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Key clinical principle: Many CTDs share overlapping features at presentation. A positive antinuclear antibody (ANA) alone does not diagnose any CTD — it must be interpreted in the clinical context. Referral to rheumatology should be considered early when multi-system autoimmune disease is suspected.

This guideline provides a comprehensive overview of the major connective tissue diseases and systemic vasculitides encountered in Australian primary and secondary care, with emphasis on diagnosis, risk stratification, pharmacological management aligned with current Australian Therapeutic Guidelines and PBS listings, monitoring strategies, and specific considerations for Aboriginal and Torres Strait Islander communities.

Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus is a chronic multisystem autoimmune disease with highly variable clinical manifestations ranging from mild mucocutaneous and joint involvement to life-threatening renal, neurological, and haematological complications. SLE predominantly affects women of childbearing age (female-to-male ratio approximately 9:1), though it can occur at any age, including childhood and in the elderly.

Australian Epidemiology

The prevalence of SLE in Australia is estimated at 40–50 per 100 000 in the general population. However, prevalence is significantly higher in Aboriginal and Torres Strait Islander peoples, with some studies reporting rates 2–3 times greater and with more severe organ involvement, particularly lupus nephritis. The disease is also more common and more severe in people of Asian, African, and Indigenous Australian descent compared to those of European ancestry.

Clinical Presentation

SLE is a clinical chameleon — presenting features may include:

Constitutional: Fatigue (present in >90%), fever, weight loss
Musculoskeletal: Symmetric polyarthralgia or non-erosive polyarthritis (most common presenting feature)
Cutaneous: Acute malar (butterfly) rash, discoid lupus, photosensitivity, oral ulcers (often painless), alopecia, Raynaud phenomenon
Renal: Lupus nephritis — ranges from mild proteinuria to rapidly progressive glomerulonephritis; renal biopsy classification (ISN/RPS 2003) guides therapy
Haematological: Autoimmune haemolytic anaemia, thrombocytopaenia, leucopaenia, lymphopaenia
Serositis: Pleurisy, pericarditis (most common cardiac manifestation)
Neuropsychiatric: Seizures, psychosis, cognitive dysfunction, cerebrovascular events, transverse myelitis
Cardiovascular: Accelerated atherosclerosis (leading cause of death in long-standing SLE), Libman-Sacks endocarditis

Classification Criteria

The 2019 EULAR/ACR classification criteria require a positive ANA (≥1:80 on HEp-2 cells) as an entry criterion, followed by weighted scoring across clinical and immunological domains (≥10 points = classified as SLE). These criteria have a sensitivity of 96% and specificity of 93%.

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Lupus nephritis: Any patient with SLE who develops new proteinuria, rising creatinine, active urinary sediment, or declining complement levels should be evaluated urgently for lupus nephritis. Renal biopsy is indicated for classification and treatment guidance. Referral to nephrology and rheumatology is essential.

Rheumatoid Arthritis (RA)

Rheumatoid arthritis is a chronic systemic autoimmune inflammatory arthritis characterised by symmetric peripheral polyarthritis, synovial hyperplasia, and progressive joint destruction if untreated. RA affects approximately 0.5–1.0% of the Australian population, with a female-to-male ratio of approximately 3:1.

Australian Epidemiology

An estimated 450 000–500 000 Australians live with RA. Aboriginal and Torres Strait Islander Australians have a higher prevalence and more severe disease with greater functional impairment. RA contributes significantly to work disability and healthcare utilisation in Australia, with total annual costs estimated at over .5 billion (ARATA, 2020).

Clinical Presentation

Joint involvement: Symmetric polyarthritis affecting small joints of the hands (MCPs, PIPs), wrists, and feet (MTPs) preferentially; morning stiffness lasting >30 minutes (often >1 hour)
Extra-articular manifestations: Rheumatoid nodules, interstitial lung disease, scleritis/episcleritis, Felty syndrome (splenomegaly + neutropaenia), vasculitis (rare but serious)
Systemic features: Fatigue, malaise, weight loss, low-grade fever

Early Referral — The Window of Opportunity

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Treat-to-target: The Australian Rheumatology Association (ARA) recommends referral to a rheumatologist within 6 weeks (and no later than 12 weeks) of symptom onset. The "window of opportunity" in early RA (first 3–6 months) offers the greatest chance of achieving remission and preventing irreversible joint damage. DMARD therapy should be initiated as soon as the diagnosis is made.

Classification Criteria

The 2010 ACR/EULAR classification criteria score ≥6/10 based on joint involvement (number and size), serology (RF and/or anti-CCP), acute phase reactants (CRP, ESR), and symptom duration (≥6 weeks). Anti-CCP antibodies have a specificity of approximately 95% for RA and are predictive of erosive disease.

Systemic Sclerosis (Scleroderma)

Systemic sclerosis (SSc) is a rare but serious CTD characterised by immune dysregulation, vasculopathy, and progressive fibrosis of the skin and internal organs. SSc has the highest mortality among all CTDs, with 10-year survival rates of approximately 65–80% depending on subtype and organ involvement.

Classification

Feature	Limited Cutaneous SSc (lcSSc)	Diffuse Cutaneous SSc (dcSSc)
Skin involvement	Distal to elbows/knees; face	Proximal limbs, trunk
Antibody	Anti-centromere (70–80%)	Anti-Scl-70 / anti-topoisomerase I (30–40%)
CREST syndrome	Yes (Calcinosis, Raynaud, oEsophageal dysmotility, Sclerodactyly, Telangiectasia)	Less common
Major risk	Pulmonary arterial hypertension (PAH)	Interstitial lung disease (ILD), scleroderma renal crisis
Prognosis	Better overall	Worse; rapid progression

Australian Epidemiology

SSc affects approximately 25–30 per 100 000 Australians, with a female predominance (F:M ≈ 4:1). Australia has one of the highest reported prevalences of SSc globally. The Australian Scleroderma Interest Group (ASIG) maintains a national registry and provides management recommendations for PAH and ILD screening.

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Scleroderma renal crisis: This medical emergency presents with acute-onset hypertension, oliguria, microangiopathic haemolytic anaemia (MAHA), and rapidly progressive renal failure. It occurs most commonly in dcSSc and is associated with anti-RNA polymerase III antibodies. Treatment is urgent initiation of ACE inhibitors (e.g., ramipril), even if creatinine is rising. Corticosteroids may precipitate renal crisis and should be used with extreme caution in SSc.

Mixed Connective Tissue Disease (MCTD)

Mixed connective tissue disease (MCTD) is an overlapping syndrome characterised by clinical features of SLE, systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis, with persistently high-titre anti-U1 ribonucleoprotein (anti-U1 RNP) antibodies. MCTD was first described by Sharp and colleagues in 1972.

Clinical Features

Raynaud phenomenon (present in nearly all patients, often the earliest symptom)
"Sausage-like" digital oedema (puffy hands)
Polyarthralgia or non-erosive arthritis
Sclerodactyly and oesophageal dysmotility
Myositis (proximal muscle weakness, elevated CK)
Pulmonary involvement — PAH is the most serious complication and the leading cause of death
SLE-like features — serositis, rash, lymphadenopathy, cytopenias

Diagnosis

No single classification criterion set is universally accepted. The Kasukawa or Alarcón-Segovia criteria are commonly used. The hallmark laboratory finding is high-titre anti-U1 RNP antibodies (detected by immunodiffusion or ELISA). ANA is positive with a speckled pattern. Anti-dsDNA and anti-Smith antibodies are typically negative (helping distinguish from SLE).

Prognosis

MCTD generally has a better prognosis than SLE or diffuse SSc, though a proportion of patients evolve over time into a more defined CTD. PAH remains the most significant cause of morbidity and mortality. Regular screening with echocardiography and pulmonary function tests is recommended.

Sjögren Syndrome & Raynaud Phenomenon

Sjögren Syndrome

Sjögren syndrome (SjS) is a chronic autoimmune exocrinopathy characterised by lymphocytic infiltration of the lacrimal and salivary glands, leading to keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth). It may occur as a primary disorder (pSjS) or secondary to another CTD, most commonly RA or SLE.

Australian epidemiology: Primary Sjögren syndrome affects approximately 0.1–0.6% of the Australian population, with a female-to-male ratio of approximately 9:1. Prevalence increases with age, with peak onset in the 4th–6th decades.

Classification Criteria (ACR/EULAR 2016)

A score of ≥4 from the following items (in patients with suggestive symptoms and positive anti-Ro/SSA or labial biopsy showing focal lymphocytic sialadenitis with focus score ≥1):

Labial salivary gland biopsy with focal lymphocytic sialadenitis (focus score ≥1): 3 points
Anti-Ro/SSA antibody positive: 3 points
Ocular staining score ≥5 (or van Bijsterveld score ≥4): 1 point
Schirmer test ≤5 mm in 5 minutes: 1 point
Unstimulated salivary flow rate ≤0.1 mL/min: 1 point

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Lymphoma risk: Patients with primary Sjögren syndrome have a 5–10% lifetime risk of B-cell non-Hodgkin lymphoma, particularly mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland. Persistent parotid gland enlargement, unexplained lymphadenopathy, or rapidly rising immunoglobulin levels should prompt urgent investigation.

Extra-glandular Manifestations

Interstitial lung disease
Renal tubular acidosis (type 1 distal RTA)
Peripheral and cranial neuropathy
Vasculitis (cutaneous or systemic)
Cryoglobulinaemia
Autoimmune thyroiditis

Raynaud Phenomenon

Raynaud phenomenon (RP) is characterised by episodic, reversible vasospasm of the digits triggered by cold exposure or emotional stress, causing sequential colour changes: white (ischaemia) → blue (cyanosis) → red (reperfusion hyperaemia). RP may be primary (idiopathic) or secondary to an underlying CTD, most importantly systemic sclerosis.

Distinguishing Primary from Secondary Raynaud

Feature	Primary Raynaud	Secondary Raynaud
Age of onset	Adolescence–young adulthood	Usually >30 years
Symmetry	Bilateral, symmetric	Often asymmetric
Digital ulceration	Absent	May be present
Nailfold capillaroscopy	Normal	Abnormal (dilated capillary loops, dropouts)
ANA	Negative	May be positive
Associations	Family history common	SSc, SLE, MCTD, DM/PM, occupational vibration

Management of Raynaud Phenomenon

Non-pharmacological: Cold avoidance, warm clothing, smoking cessation (critical)
First-line pharmacological: Calcium channel blockers — nifedipine slow-release 30–60 mg daily (PBS listed for Raynaud)
Second-line: Phosphodiesterase-5 inhibitors (sildenafil 25–50 mg BD for severe secondary RP with digital ulcers — specialist initiation), topical glyceryl trinitrate (Rectogesic® or transdermal GTN patch applied to affected digits)
Severe/refractory: Prostanoid infusions (iloprost IV) — requires rheumatology or vascular medicine specialist care

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Nifedipine (Modified Release)

Adalat® · Procardia® · Calcium channel blocker

Adult dose 30 mg PO once daily, titrate to 60 mg daily (max 90 mg daily)

Paediatric dose 0.25–0.5 mg/kg/day PO BD–TDS (immediate release); limited data in Raynaud

Route Oral

Renal adjustment None required

Hepatic adjustment Reduce dose; use with caution in severe hepatic impairment

PBS status ✔ PBS General Benefit

Systemic Vasculitides

The systemic vasculitides are a heterogeneous group of disorders characterised by inflammation of blood vessel walls, leading to tissue ischaemia, necrosis, and organ damage. They are classified by the predominant size of the affected vessels (Chapel Hill Consensus Conference, 2012 revised). This section focuses on the three most clinically relevant vasculitides in Australian primary care: polyarteritis nodosa (PAN), giant cell arteritis (GCA), and polymyalgia rheumatica (PMR).

Vasculitis Classification by Vessel Size

Vessel Size	Vasculitis	Key Features
Large vessel	Giant cell arteritis (GCA), Takayasu arteritis	Aorta and major branches; headache, jaw claudication, visual loss (GCA)
Medium vessel	Polyarteritis nodosa (PAN), Kawasaki disease	Visceral arteries; microaneurysms, mononeuritis multiplex, renal impairment, mesenteric ischaemia
Small vessel	ANCA-associated vasculitis (GPA, MPA, EGPA), IgA vasculitis, cryoglobulinaemic vasculitis	Glomerulonephritis, purpura, pulmonary haemorrhage, peripheral neuropathy

Giant Cell Arteritis (GCA) & Polymyalgia Rheumatica (PMR)

Giant Cell Arteritis (GCA)

GCA is the most common systemic vasculitis, affecting adults over 50 years (peak incidence 70–80 years). It involves granulomatous inflammation of medium-to-large arteries, particularly the cranial branches of the aortic arch. The superficial temporal artery, ophthalmic artery, and vertebral arteries are commonly affected. GCA and PMR frequently overlap — approximately 50% of GCA patients have PMR features, and 15–20% of PMR patients develop GCA.

Australian epidemiology: GCA incidence in Australia is approximately 15–25 per 100 000 person-years in those aged ≥50 years, with higher rates in populations of Northern European descent. It is rare in Aboriginal and Torres Strait Islander peoples and those of Asian descent.

Clinical Features

Headache: New-onset, temporal or generalised; the most common symptom (present in 70–80%)
Scalp tenderness: Particularly over the temporal arteries; difficulty combing hair or resting head on pillow
Jaw claudication: Pain with chewing (specificity ~90% for GCA)
Visual symptoms: Amaurosis fugax, sudden painless vision loss, diplopia — OPHTHALMIC EMERGENCY
Systemic features: Fever (may be high and PUO-like), weight loss, night sweats, malaise
Polymyalgia symptoms: Shoulder and hip girdle pain/stiffness in ~50%
Large-vessel GCA: Aortitis, limb claudication, aortic aneurysm/dissection — increasingly recognised

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Sight-threatening emergency: If GCA is suspected clinically, start high-dose prednisolone (40–60 mg PO daily or methylprednisolone 500 mg–1 g IV daily for 3 days if visual symptoms) IMMEDIATELY — do NOT delay treatment while awaiting temporal artery biopsy or blood results. Every hour of delay increases the risk of irreversible anterior ischaemic optic neuropathy and contralateral eye involvement. Arrange urgent temporal artery biopsy within 2 weeks of starting corticosteroids.

Investigations

Essential ESR and CRP ESR typically >50 mm/h (often >80); CRP elevated. Normal ESR does not exclude GCA but makes it unlikely.
Essential Full blood count Normochromic normocytic anaemia; thrombocytosis (reactive)
Essential Temporal artery biopsy Gold standard; ≥1 cm segment; sensitivity 70–90% (may remain positive for 2–4 weeks after starting steroids). Perform within 2 weeks of treatment initiation.
Available Temporal artery ultrasound "Halo sign" (hypoechoic vessel wall oedema) — operator dependent; sensitivity 55–100%. Used in some Australian centres as first-line imaging.
Referral PET-CT (FDG) For suspected large-vessel GCA; identifies aortitis and large-artery involvement. Limited availability — tertiary centres.
Specialist MRI of cranial arteries Emerging role; vessel wall enhancement. Not widely available for this indication in Australia.

Treatment of GCA

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Prednisolone

Panafcortelone® · Solone® · Corticosteroid

Induction (no visual loss) 40–50 mg PO daily for 2–4 weeks, then taper over 12–24 months guided by symptoms and CRP

Induction (visual symptoms) Methylprednisolone 500 mg–1 g IV daily for 3 days, then prednisolone 40–60 mg PO daily

Steroid-sparing agent Tocilizumab 162 mg SC weekly or fortnightly — PBS Authority Required (first-line steroid-sparing for GCA relapse or steroid-dependent disease)

Osteoporosis prophylaxis Calcium + vitamin D supplementation; consider bisphosphonate (alendronate 70 mg weekly) if ≥3 months prednisolone ≥7.5 mg daily

PJP prophylaxis Not routinely required at standard GCA doses (consider if high-dose prolonged steroids + additional immunosuppression)

PBS status (prednisolone) ✔ PBS General Benefit

Polymyalgia Rheumatica (PMR)

PMR is an inflammatory condition of the elderly characterised by aching and morning stiffness affecting the shoulder girdle, hip girdle, and neck. It is the most common inflammatory rheumatic condition in people over 70 years of age. PMR responds dramatically to low-dose corticosteroids, which is both diagnostic and therapeutic.

Australian epidemiology: PMR incidence in Australians aged ≥50 years is approximately 50–100 per 100 000 person-years. It is more common in people of Northern European descent and uncommon in Aboriginal and Torres Strait Islander peoples.

2012 EULAR/ACR Provisional Classification Criteria

Mandatory inclusion criteria: age ≥50 years, bilateral shoulder/hip girdle aching, abnormal CRP and/or ESR, and duration ≥2 weeks. Exclusion criteria: alternative diagnoses (RA, malignancy, infection, other CTD). Score ≥4 (without ultrasound) or ≥5 (with ultrasound) on the scoring algorithm.

Treatment of PMR

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Prednisolone

Panafcortelone® · Solone® · Corticosteroid

Initial dose 12.5–15 mg PO once daily (rapid response expected within 1–2 weeks)

Tapering Reduce by 1 mg every 2–4 weeks; aim to discontinue within 12–24 months. Many patients relapse and require prolonged low-dose therapy (2.5–5 mg daily)

Steroid-sparing Methotrexate 7.5–10 mg PO weekly — consider early if relapsing, steroid side-effects, or risk factors for relapse (high CRP at diagnosis, peripheral arthritis, female sex)

Osteoporosis prophylaxis Calcium + vitamin D; consider bisphosphonate for those on prolonged corticosteroids

PBS status ✔ PBS General Benefit

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Diagnostic red flag: If symptoms do not improve within 1 week of starting 15 mg prednisolone, reconsider the diagnosis — consider RA, malignancy, hypothyroidism, or other inflammatory conditions. Do not escalate steroid doses empirically without rheumatology review.

Polyarteritis Nodosa (PAN)

Polyarteritis nodosa is a necrotising medium-vessel vasculitis affecting muscular arteries, leading to aneurysm formation, vessel occlusion, and tissue infarction. PAN is distinguished from ANCA-associated vasculitis by its predilection for medium-sized muscular arteries and the absence of glomerulonephritis (renal involvement in PAN is via renovascular hypertension rather than primary glomerular disease).

Epidemiology

PAN is rare in Australia, with an estimated annual incidence of 4–10 per million. There is no clear sex predilection and onset is typically in the 5th–6th decades. A strong association with hepatitis B virus (HBV) infection exists — HBV accounts for approximately 30% of PAN cases globally. HBV-associated PAN is more common in endemic regions and in certain Aboriginal and Torres Strait Islander communities with higher HBV prevalence.

Clinical Features

Systemic: Fever, weight loss, malaise, myalgia, arthralgia
Renal: Renovascular hypertension, renal infarction (no glomerulonephritis)
Neurological: Mononeuritis multiplex (the most characteristic neurological feature), peripheral neuropathy
Gastrointestinal: Mesenteric ischaemia (postprandial pain, "intestinal angina"), bowel perforation, haemorrhage
Cutaneous: Livedo reticularis, nodules, purpura, digital gangrene, ulcers
Cardiac: Coronary arteritis, cardiomyopathy (leading cause of death)
Testicular: Pain, swelling (testicular artery involvement)

Diagnosis

Diagnosis requires either tissue biopsy (showing necrotising vasculitis of medium-sized arteries) or characteristic angiographic findings (microaneurysms, stenoses, or occlusions of medium-sized arteries, particularly in the renal, mesenteric, and hepatic circulations). The American College of Rheumatology 1990 criteria (≥3 of 10 features) have a sensitivity of 82% and specificity of 87%.

Treatment

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HBV screening is mandatory: All patients with suspected PAN must be tested for hepatitis B (HBsAg, anti-HBc, HBV DNA). HBV-associated PAN requires antiviral therapy (entecavir or tenofovir) in addition to immunosuppression. Immunosuppression without antiviral cover risks viral reactivation.

Scenario	Induction	Maintenance
Non-HBV PAN (severe/life-threatening)	Cyclophosphamide 2 mg/kg/day PO (or IV pulse 15 mg/kg q2–3 weeks) + corticosteroids (methylprednisolone 500 mg–1 g IV × 3 days then prednisolone 1 mg/kg/day PO, taper over 6–12 months)	Switch to azathioprine 2 mg/kg/day PO after 3–6 months remission; continue for ≥18–24 months
HBV-associated PAN	Antiviral therapy (entecavir 0.5 mg daily or tenofovir 300 daily) + short-course corticosteroids + plasma exchange (5–7 sessions)	Continue antiviral therapy; avoid long-term immunosuppression

Autoantibodies in Connective Tissue Disease

Autoantibody testing is a cornerstone of CTD diagnosis, classification, and prognostication. However, autoantibodies must always be interpreted in the clinical context — a positive result in the absence of compatible clinical features may be an incidental finding or represent early/latent autoimmunity. Conversely, seronegative CTD is a well-recognised entity.

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ANA interpretation: A positive ANA (at any titre) is found in up to 15–20% of healthy individuals, particularly elderly women. ANA is a screening test only — it is not diagnostic of any specific CTD. The 2019 EULAR/ACR SLE criteria require an ANA titre ≥1:80 on HEp-2 cells as an entry criterion. Avoid ordering ANA panels without clinical suspicion of autoimmune disease.

Key Autoantibodies — Clinical Significance

Antibody	Primary Association	Clinical Significance
Anti-dsDNA	SLE (highly specific)	Titres correlate with disease activity, particularly lupus nephritis; useful for monitoring
Anti-Smith (Sm)	SLE (highly specific, ~30% sensitive)	Highly specific for SLE; less useful for monitoring activity
Anti-Ro/SSA	Sjögren syndrome, SLE, neonatal lupus	Associated with cutaneous lupus, congenital heart block risk in neonates; present in ~70% of pSjS
Anti-La/SSB	Sjögren syndrome	Almost always found with anti-Ro; increases specificity for SjS
Anti-centromere	Limited cutaneous SSc (CREST syndrome)	Favourable prognosis vs diffuse SSc; associated with PAH risk; less commonly ILD
Anti-Scl-70 (anti-topoisomerase I)	Diffuse cutaneous SSc	Associated with ILD and more severe skin disease; worse prognosis
Anti-RNA polymerase III	Diffuse cutaneous SSc	Strongly associated with scleroderma renal crisis; rapid skin progression
Anti-U1 RNP	MCTD (high titre); SLE	High-titre anti-U1 RNP defines MCTD; also seen in SLE at lower titres
Anti-CCP (ACPA)	Rheumatoid arthritis	Specificity ~95%; predicts erosive disease; present years before clinical onset; more prognostic than RF
Rheumatoid factor (RF)	RA, Sjögren syndrome	Sensitivity ~70% for RA but less specific (also positive in infections, other CTDs, healthy elderly)
c-ANCA / PR3-ANCA	Granulomatosis with polyangiitis (GPA)	Positive in 75–90% of generalised GPA; correlates with disease activity
p-ANCA / MPO-ANCA	Microscopic polyangiitis (MPA), EGPA	Also seen in drug-induced vasculitis (e.g., hydralazine, propylthiouracil); less specific than PR3
Antiphospholipid antibodies (aPL)	Antiphospholipid syndrome (APS)	Lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein I; risk of arterial/venous thrombosis and pregnancy morbidity

Autoantibody Testing in Australian Practice

Most autoantibody tests are available through major Australian pathology providers (e.g., Sullivan Nicolaides Pathology, Douglass Hanly Moir, Clinical Labs) and are covered by Medicare under appropriate MBS item numbers when requested with clinical justification. ANCA testing is best performed by IIF (immunofluorescence) with antigen-specific ELISA confirmation (PR3, MPO) — the "fixed" ANCA ELISA approach alone has lower sensitivity. Rheumatoid factor and anti-CCP are widely available. More specialised antibodies (anti-RNA polymerase III, anti-U1 RNP by immunodiffusion) may require referral to specialist immunopathology laboratories.

Pharmacological Management of CTDs

Treatment of CTDs requires a combination of symptom control, suppression of autoimmune inflammation, prevention of organ damage, and management of treatment-related adverse effects. The treat-to-target approach is well established for RA and increasingly applied to SLE and vasculitides.

Disease-Modifying Antirheumatic Drugs (DMARDs)

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Hydroxychloroquine

Plaquenil® · Quinoric® · Antimalarial DMARD

Adult dose 200–400 mg PO daily (≤5 mg/kg actual body weight/day)

Indications SLE (first-line for all patients), RA (combination with MTX), Sjögren syndrome (mild systemic features), MCTD

Key monitoring Baseline ophthalmological exam + annual screening after 5 years (or sooner if risk factors: dose >5 mg/kg/day, renal impairment, concomitant tamoxifen, pre-existing retinal disease)

Renal adjustment Reduce dose if eGFR <30 mL/min; use ideal body weight for dosing calculation

PBS status ✔ PBS General Benefit

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Methotrexate

Methoblastin® · RA DMARD

Adult dose 7.5–25 mg PO/SC once weekly (start 7.5–10 mg, titrate up); folic acid 5 mg weekly (not on methotrexate day)

Indications First-line DMARD for RA; steroid-sparing agent in PMR, GCA, vasculitis, and SLE

Key monitoring FBC, LFTs, renal function every 2–4 weeks initially, then every 8–12 weeks once stable; chest X-ray at baseline

Renal adjustment Reduce dose if eGFR <60 mL/min; avoid if eGFR <15 mL/min

PBS status ✔ PBS General Benefit

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Azathioprine

Imuran® · Thioprine® · Immunosuppressant

Adult dose 1–3 mg/kg/day PO (typically 100–200 mg daily for maintenance in SLE/vasculitis)

Indications Maintenance therapy for SLE (lupus nephritis), vasculitis (post-induction), myositis, corticosteroid-sparing

Key monitoring TPMT/NUDT15 genotype or activity prior to initiation (risk of severe myelosuppression in poor metabolisers); FBC every 1–2 weeks initially, then every 8–12 weeks

PBS status ✔ PBS General Benefit

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Mycophenolate Mofetil

CellCept® · Myfortic® · Immunosuppressant

Adult dose 500 mg–1.5 g PO BD (induction for lupus nephritis: up to 3 g/day; maintenance: 1–2 g/day)

Indications Lupus nephritis (first-line alternative to cyclophosphamide for induction, particularly Class III/IV), SSc-ILD, myositis

Key monitoring FBC (neutropaenia risk), LFTs (hepatotoxicity); pregnancy must be excluded (teratogenic — Category D)

PBS status ⚠ PBS Authority Required

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Cyclophosphamide

Endoxan® · Alkylating immunosuppressant

Adult dose Oral: 2 mg/kg/day PO; IV pulse: 15 mg/kg IV every 2–4 weeks (Euro-Lupus regimen: 500 mg IV q2 weeks × 6 doses for non-severe lupus nephritis)

Indications Induction therapy for severe lupus nephritis (Class III/IV), severe vasculitis (PAN, ANCA-associated vasculitis), severe SLE (cerebritis, alveolar haemorrhage)

Key monitoring FBC 7–10 days post-dose (nadir), urinalysis (haemorrhagic cystitis — co-administer MESNA for IV doses), fertility counselling (consider GnRH agonist or sperm cryopreservation)

PBS status ⚠ PBS Authority Required

Biologic and Targeted Synthetic DMARDs

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Rituximab

MabThera® · Riximyo® · Anti-CD20 monoclonal antibody

Adult dose 1 g IV × 2 doses (days 1 and 15); repeat cycle every 6 months as needed

Indications RA (inadequate response to ≥1 DMARD), refractory SLE, ANCA-associated vasculitis (induction + relapsing disease)

PBS status ⚠ PBS Authority Required

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Belimumab

Benlysta® · Anti-BLyS (BAFF) monoclonal antibody

Adult dose 200 mg SC weekly (or 10 mg/kg IV every 4 weeks after loading)

Indications Active SLE despite standard therapy (hydroxychloroquine + corticosteroids ± immunosuppressants); also PBS-listed for lupus nephritis in combination with standard therapy

PBS status 🔴 PBS Authority Required (Specialist)

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Tocilizumab

RoActemra® · Anti-IL-6 receptor monoclonal antibody

Adult dose RA: 162 mg SC every 2 weeks or 8 mg/kg IV every 4 weeks; GCA: 162 mg SC weekly or fortnightly

Indications RA (moderate–severe, inadequate response to DMARDs), GCA (steroid-sparing), GCA (relapsing or steroid-dependent)

PBS status 🔴 PBS Authority Required (Specialist)

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Anifrolumab

Saphnelo® · Anti-type I interferon receptor monoclonal antibody

Adult dose 300 mg IV every 4 weeks

Indications Moderate-to-severe SLE despite standard therapy; TGA approved and PBS-listed (Authority Required)

PBS status 🔴 PBS Authority Required (Specialist)

Corticosteroids — General Principles

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Key principles of corticosteroid use in CTDs: Use the lowest effective dose for the shortest possible duration. All patients on prolonged prednisolone (≥7.5 mg/day for ≥3 months) should receive osteoporosis prophylaxis (calcium 600 mg + vitamin D 800 IU daily; consider bisphosphonate). Monitor for diabetes, hypertension, cataracts, adrenal suppression, and infection risk. Provide a steroid card and sick-day management advice. Always taper gradually — abrupt cessation risks adrenal crisis and disease flare.

Monitoring

Regular monitoring is essential for all patients with CTDs, encompassing disease activity assessment, organ damage surveillance, treatment-related adverse effect monitoring, and screening for comorbidities.

Disease Activity Monitoring

CTD	Disease Activity Markers	Organ Damage Monitoring
SLE	Anti-dsDNA titres, complement (C3/C4), ESR/CRP, urine protein/creatinine ratio, renal function, FBC	Annual: echocardiography (if APS or cardiac involvement), DXA (if on corticosteroids), ophthalmology (if on HCQ), BP, lipids, glucose
RA	DAS28-ESR or DAS28-CRP, ESR/CRP, patient-reported outcomes (HAQ), joint counts	Annual: hand/feet X-rays (or when flare suspected), FBC/LFTs/renal for DMARD monitoring, CXR (baseline for MTX), infection screening
SSc	Modified Rodnan skin score (mRSS)	Annual: echocardiography (PAH screening — ASIG recommends annually or if symptomatic), PFTs (DLCO + FVC for ILD), HRCT chest (baseline + if symptomatic), renal function, nailfold capillaroscopy
GCA	ESR/CRP (with each visit during taper), clinical symptoms	Steroid side-effects: BP, glucose, lipids, DXA; monitor for large-vessel complications (aortic aneurysm screening if indicated)
Vasculitis	ANCA titres (for MPA/GPA), ESR/CRP, BVAS score	Renal function, urinalysis, PFTs (GPA), imaging as indicated; infection screening (especially if on rituximab)

DMARD Monitoring Schedule

Drug	Baseline	Ongoing Monitoring
Methotrexate	FBC, LFTs, renal, hepatitis B/C serology, CXR, pregnancy test	FBC + LFTs every 2–4 weeks initially, then every 8–12 weeks
Azathioprine	TPMT/NUDT15 genotype, FBC, LFTs, hepatitis B/C	FBC every 1–2 weeks × 8 weeks, then every 8–12 weeks; LFTs periodically
Hydroxychloroquine	Baseline ophthalmological exam, renal function	Annual ophthalmology review after 5 years (sooner if risk factors)
Mycophenolate	FBC, LFTs, hepatitis B/C, pregnancy test	FBC + LFTs monthly × 3 months, then every 3 months
Cyclophosphamide	FBC, LFTs, renal, urinalysis, hepatitis B/C, pregnancy test, fertility counselling	FBC 7–10 days post-dose (nadir); urinalysis; renal function each cycle
Rituximab	Hepatitis B/C, HIV, immunoglobulin levels, FBC, TB screening	Immunoglobulin levels (IgG) before each cycle; FBC; hepatitis B reactivation monitoring

Pre-Treatment Infection Screening

Prior to initiating biologic therapy, high-dose immunosuppression, or cyclophosphamide:

Hepatitis B (HBsAg, anti-HBs, anti-HBc) — risk of reactivation with rituximab and corticosteroids
Hepatitis C antibody + RNA if positive
HIV serology
Tuberculosis screening (TST or IGRA) — particularly before biologic therapy
Varicella zoster — check immunity; vaccinate if non-immune (prior to immunosuppression, using live vaccine or Shingrix if already immunosuppressed)
Update vaccinations prior to immunosuppression where possible (influenza annually, pneumococcal (Prevenar 13 + Pneumovax 23), COVID-19, shingles [Shingrix])

Special Populations

🤰 Pregnancy

SLE in pregnancy: Multidisciplinary care (obstetrics, rheumatology, neonatology). Increased risk of flare (especially 2nd/3rd trimester and postpartum), pre-eclampsia, preterm delivery, fetal growth restriction, and neonatal lupus.

Safe medications in pregnancy:

Hydroxychloroquine — continue throughout pregnancy (Category D in previous classification but current evidence strongly supports safety and SLE flare prevention)

Azathioprine — generally considered safe; continue if required for disease control

Low-dose prednisolone/prednisone — generally safe; avoid high doses if possible

Low-dose aspirin (100–150 mg daily from 12 weeks gestation) — recommended for all SLE pregnancies to reduce pre-eclampsia risk

Contraindicated in pregnancy:

Methotrexate — teratogenic (Category X); stop ≥3 months before conception (ideally 6 months)

Mycophenolate mofetil — teratogenic (Category D); stop ≥6 weeks before conception

Cyclophosphamide — teratogenic, especially 1st trimester

Antiphospholipid syndrome (APS): Requires LMWH (enoxaparin 40 mg SC daily) + low-dose aspirin 100 mg daily throughout pregnancy and 6 weeks postpartum for thromboprophylaxis.

Anti-Ro/SSA and anti-La/SSB positive mothers: Risk of neonatal lupus and congenital heart block. Fetal echocardiography recommended from 16 weeks gestation every 1–2 weeks until 28 weeks.

All women with CTDs should have preconception counselling and pregnancy planning with their rheumatologist.

👶 Paediatrics

Childhood-onset SLE (cSLE): Accounts for 15–20% of SLE cases; more severe than adult-onset SLE with higher rates of renal, neurological, and haematological involvement. Requires paediatric rheumatology management.

Paediatric RA (JIA): Distinct entity from adult RA; classified by the International League of Associations for Rheumatology (ILAR) criteria. Methotrexate is first-line DMARD; biologics (etanercept, adalimumab, tocilizumab) for refractory disease.

Kawasaki disease: Most common childhood vasculitis; coronary artery aneurysms are the major concern. Treat with IV immunoglobulin (IVIG) 2 g/kg as single infusion + aspirin (high-dose then low-dose) within 10 days of fever onset.

Vaccination schedules must be reviewed — live vaccines are contraindicated during immunosuppression. Ensure all live vaccines are given ≥4 weeks before starting immunosuppression.

👴 Elderly

RA in the elderly (elderly-onset RA, EORA): Often presents with more systemic features, acute-onset polymyalgic presentation, higher ESR/CRP; may be more challenging to distinguish from PMR. Anti-CCP testing helps distinguish EORA from PMR.

GCA and PMR: Almost exclusively diseases of the elderly (≥50 years). Higher corticosteroid-related morbidity in this age group — osteoporosis, diabetes, cataracts, infections. Consider early steroid-sparing agents.

Polypharmacy and drug interactions: Elderly patients with CTDs are often on multiple medications. Monitor for drug interactions (e.g., methotrexate with trimethoprim; NSAIDs with corticosteroids increasing GI bleeding risk).

Fall risk assessment is essential in elderly patients on corticosteroids, particularly those with proximal myopathy.

🫘 Renal Impairment

Lupus nephritis: Renal biopsy classification (ISN/RPS) guides treatment. Class I/II: observation ± HCQ. Class III/IV: induction with cyclophosphamide or mycophenolate + corticosteroids; maintenance with mycophenolate or azathioprine. Class V: mycophenolate or cyclophosphamide for nephrotic-range proteinuria.

DMARD dose adjustment in CKD:

Methotrexate: reduce dose if eGFR <60; avoid if eGFR <15

Hydroxychloroquine: reduce dose if eGFR <30 (retinal toxicity risk increases)

Azathioprine: no specific adjustment but monitor more frequently

Mycophenolate: no dose adjustment but consider enteric-coated formulation (Myfortic®) for GI tolerance

Scleroderma renal crisis requires urgent ACE inhibitor therapy regardless of creatinine level.

🫁 Hepatic Impairment

Methotrexate: Avoid in significant hepatic impairment (Child-Pugh B/C). Contraindicated with pre-existing liver disease, active hepatitis, or excessive alcohol intake. Baseline LFTs and hepatitis B/C serology required.

Azathioprine: Hepatotoxicity is a known adverse effect. Monitor LFTs regularly. Use with caution in hepatic impairment.

Cyclophosphamide: No specific hepatic adjustment required but monitor LFTs.

Autoimmune hepatitis may overlap with CTDs — consider in patients with unexplained LFT abnormalities in the context of SLE or Sjögren syndrome.

🛡️ Immunocompromised

Infection risk: All CTD patients on immunosuppression are at increased risk of infection, including opportunistic infections (PJP, CMV, fungal). Risk correlates with degree of immunosuppression and corticosteroid dose.

PJP prophylaxis: Consider trimethoprim-sulfamethoxazole (one single-strength tablet daily or one double-strength tablet 3 times/week) when on high-dose corticosteroids (prednisolone ≥20 mg/day for ≥1 month) in combination with cyclophosphamide or rituximab.

Vaccination strategy: All non-live vaccines can and should be administered to immunosuppressed patients. Live vaccines (MMR, varicella, zoster [Zostavax], BCG, oral polio, oral typhoid, yellow fever) are generally contraindicated. Use Shingrix (non-live recombinant) rather than Zostavax for shingles prevention.

Ensure patients have access to a steroid emergency card and understand sick-day rules for corticosteroid management during acute illness.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Connective tissue diseases and vasculitides affect Aboriginal and Torres Strait Islander Australians disproportionately, with higher prevalence, earlier onset, more severe organ involvement, and worse outcomes compared to the non-Indigenous Australian population. Culturally safe healthcare, addressing the social determinants of health, and community-based approaches are essential to improving outcomes.

Higher Disease Burden

SLE prevalence is estimated to be 2–3 times higher in Aboriginal and Torres Strait Islander peoples, with significantly more lupus nephritis, neuropsychiatric involvement, and end-stage renal disease (ESRD). RA is more prevalent and associated with greater functional disability and work loss. Systemic sclerosis, though rare, appears to have a more severe phenotype in Indigenous Australians.

Hepatitis B and Vasculitis

Hepatitis B prevalence is significantly higher in some Aboriginal and Torres Strait Islander communities, particularly in the Northern Territory and remote Western Australia/Queensland. HBV-associated polyarteritis nodosa (PAN) should be considered in the differential diagnosis of multi-system vasculitis. HBV vaccination and screening programs are critical public health measures.

Remote Access to Specialist Care

Many Aboriginal and Torres Strait Islander people live in rural and remote areas with limited access to rheumatology, nephrology, and ophthalmology services. Telehealth has expanded significantly since COVID-19 and should be leveraged for specialist consultations. Point-of-care testing and store-and-forward dermatology/imaging can support primary care clinicians managing CTDs in remote settings.

Medication Adherence and Monitoring

Long-term medication adherence can be challenging in remote settings due to pharmacy access, cost, and competing health priorities. Community-controlled health services (e.g., Aboriginal Community Controlled Health Organisations — ACCHOs) play a vital role in supporting medication adherence, monitoring DMARD toxicity, and coordinating specialist visits. Long-acting depot corticosteroids should generally be avoided in preference for oral therapy with regular monitoring.

Cultural Safety and Communication

Healthcare for Aboriginal and Torres Strait Islander patients must be delivered in a culturally safe and respectful manner, acknowledging the impact of intergenerational trauma, systemic racism, and distrust of healthcare systems. Use of Aboriginal and Torres Strait Islander health workers and liaison officers, patient-centred communication, and shared decision-making are essential. Written health information should be available in plain English and relevant Indigenous languages where possible.

Comorbidity Management

CTDs frequently coexist with high rates of cardiovascular disease, diabetes, chronic kidney disease, and infections (including hepatitis B, rheumatic heart disease) in Aboriginal and Torres Strait Islander communities. An integrated, whole-person approach to chronic disease management is essential, supported by Indigenous-specific MBS items (e.g., MBS 715 health assessments) and Closing the Gap PBS co-payment measures for eligible patients.

Eye Health and GCA

While GCA is uncommon in Aboriginal and Torres Strait Islander populations, ophthalmological screening for hydroxychloroquine retinal toxicity remains essential. Access to ophthalmology services in remote communities is limited — coordination with visiting specialist services and organisations like the Royal Flying Doctor Service (RFDS) is important. Teleophthalmology and retinal photography programs can assist with screening.

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Closing the Gap PBS co-payment: Aboriginal and Torres Strait Islander Australians with, or at risk of, chronic disease are eligible for PBS medicines at a reduced or zero co-payment under the Closing the Gap PBS Co-payment Program. Ensure eligible patients are registered with this program through their community pharmacy to minimise medication access barriers. MBS item 715 (annual Aboriginal and Torres Strait Islander health assessment) should be offered to all Indigenous patients with CTDs.

📚 References

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