Connective Tissue Diseases

A broad category of systemic autoimmune disorders characterised by immune mediated inflammation and damage to connective tissue components across multiple organs, comprising systemic lupus erythematosus, systemic sclerosis, Sjögren syndrome, the idiopathic inflammatory myopathies, mixed connective tissue disease, and overlap syndromes in which features of more than one condition coexist in the same patient.

Pathophysiology

Loss of self tolerance drives production of autoantibodies directed against nuclear, cytoplasmic and cell surface antigens.

Immune complex deposition, complement activation and T cell mediated tissue injury converge on vascular endothelium, serosal surfaces, skin, joints and, in individual diseases, specific target organs.

Genetic susceptibility (HLA associations, complement deficiencies), environmental triggers (ultraviolet light, infection, certain drugs) and hormonal factors (strong female predominance in most subtypes) interact to produce disease.

Undifferentiated connective tissue disease

A recognised entity in which patients have clinical and serological features suggestive of a connective tissue disease without fulfilling classification criteria for any single named condition. A proportion evolve into a defined disease over years, while many remain stable or resolve, requiring longitudinal follow up rather than premature labelling.

Overlap syndromes

Patients meeting criteria for two or more connective tissue diseases simultaneously, most commonly lupus with Sjögren syndrome, or scleroderma with myositis, requiring management directed at each component.

Constitutional symptoms (fatigue, low grade fever, weight loss) are near universal across this group and are frequently the presenting complaint before organ specific features emerge.

Cutaneous features vary by disease but commonly include photosensitivity, malar or other characteristic rashes, Raynaud phenomenon, digital ulceration and sclerodactyly.

Musculoskeletal involvement with arthralgia, non erosive inflammatory arthritis and myalgia is common across the group, with true myositis in the inflammatory myopathies specifically.

Serositis (pleuritis, pericarditis), sicca symptoms (dry eyes and dry mouth), Raynaud phenomenon with or without digital vasculopathy, and organ specific manifestations (interstitial lung disease, renal involvement, gastrointestinal dysmotility, neurological and cardiac disease) occur with a pattern and frequency specific to each named condition.

The overlapping nature of symptoms across the group is precisely why classification and specific serology matter, since management diverges substantially once a specific diagnosis or dominant clinical pattern is established.

Antinuclear antibody testing is the appropriate screening test for this group, positive in the great majority of patients with an established connective tissue disease, though a positive result alone is non specific and occurs in a meaningful proportion of the healthy population, particularly at low titre.

Specific autoantibody panels refine the diagnosis once antinuclear antibody positivity or a compatible clinical picture is present: anti double stranded DNA and anti Smith for lupus, anti Ro and anti La for Sjögren syndrome and neonatal lupus risk, anti centromere and anti Scl 70 for systemic sclerosis subtypes, anti U1 RNP at high titre for mixed connective tissue disease, and the myositis specific and myositis associated antibody panel for inflammatory myopathy.

Complement levels (C3, C4), inflammatory markers, full blood count, renal function and urinalysis are checked in every patient to screen for organ involvement.

Organ specific investigation is directed by the clinical picture: high resolution computed tomography of the chest for suspected interstitial lung disease, echocardiography for pulmonary hypertension or pericardial disease, nailfold capillaroscopy for Raynaud phenomenon and suspected scleroderma spectrum disease, and renal biopsy where glomerulonephritis is suspected.

Classification criteria for the individual named diseases are applied once the clinical and serological picture is assembled, recognising these were developed for research classification rather than as strict diagnostic rules, and clinical judgement takes precedence in an individual patient.

Management is directed at the specific diagnosis once established, detailed under each individual condition, with general principles applying across the group.

Hydroxychloroquine is used broadly across the connective tissue disease spectrum for its favourable safety profile and modest disease modifying effect on skin, joint and constitutional symptoms, with baseline and annual ophthalmological screening for retinal toxicity with prolonged use.

Corticosteroids are used for disease flares and organ threatening manifestations, at the lowest effective dose and duration given cumulative toxicity, with steroid sparing immunosuppression (methotrexate, azathioprine, mycophenolate) introduced early where ongoing disease activity is anticipated.

Biologic and targeted therapy (rituximab, belimumab, Janus kinase inhibitors) is increasingly used for refractory or organ threatening disease within specific conditions, under specialist rheumatology direction.

Sun protection, cardiovascular risk factor management, vaccination (avoiding live vaccines during significant immunosuppression), bone protection with long term steroid use, and pregnancy planning (given teratogenicity of several agents and disease specific pregnancy risks, particularly anti Ro positive pregnancies and neonatal lupus) are addressed proactively.

Multidisciplinary care involving rheumatology, dermatology, nephrology, respiratory medicine and cardiology as organ involvement dictates, with long term surveillance given the chronic relapsing remitting course typical of this disease group.