Overlap syndromes

The overlap syndromes are autoimmune conditions of unknown aetiology, and causative factors are not well defined. It is possible that an as yet unidentified environmental exposure may trigger the disease in a genetically predisposed host.

Mixed connective tissue disease is associated with HLA-DR4 and HLA-DR2 antigens. The prevalence of certain HLA antigen subtypes is increased in other autoimmune diseases, including systemic lupus erythematosus (HLA-DR2 and HLA-DR3) and scleroderma (HLA-DR2, DQA1*0501, and DQB1*0301).

Widespread proliferative vascular changes contribute to many of the clinical manifestations of mixed connective tissue disease (MCTD). Obliterative vascular changes are common in both large and small vessels; intimal proliferation with abnormal collagen deposition is seen, along with medial hypertrophy in large arteries. This may explain the finding of Raynaud's phenomenon and pulmonary hypertension in these patients. In addition, the vascular compromise may lead to organ dysfunction or haemorrhage. In the kidneys, membranous and membranoproliferative glomerulonephritis are seen. Muscle biopsies demonstrate both infiltrating lymphocytes and immunoglobulin deposition, contributing to the muscle atrophy seen commonly. Auto-antigen released from necrotic or apoptotic cells is taken up by antigen-presenting cells, modified, and then presented non-covalently bound in the antigen-binding cleft of HLA molecules to auto-reactive T cells. These could subsequently perpetuate the autoimmune response by producing cytokines that would serve to expand the clone of auto-reactive T and B cells, both of which seem necessary to the final disease pathway. MCTD is characterised by high-titre antibodies to a specific ribonucleoprotein (anti-U1 RNP).[10] Disease manifestations may be mediated by auto-antibody or effector T cells, or both.

Immune complexes may also play a role in mediating some of the manifestations of antisynthetase syndrome, particularly interstitial lung disease. Antisynthetase syndrome is characterised by specific antibodies (anti-Jo-1, an antibody directed against histidyl-tRNA synthetase) to enzymes that are used by various viruses during replication. It is possible that during replication, a virus-enzyme complex is exposed to the immune system, becomes immunogenic, and results in anti-Jo-1 production.

Clinical classification

Overlap syndromes are characterised by specific clinical features, auto-antibody profiles, and immunogenetics.

Mixed connective tissue disease (MCTD) is a distinct clinical entity characterised by overlapping features of systemic lupus erythematosus, scleroderma, myositis, and rheumatoid arthritis in the setting of a high titre of auto-antibodies to a defined nuclear antigen, known as U1 ribonucleoprotein (U1 RNP, also called RNP or nRNP).[1][2] Clinical features of MCTD are highly variable, involving prominently arthritis, Raynaud's phenomenon, sclerodermatous skin changes, and myositis. Severe central nervous system and renal diseases are rare manifestations.
Antisynthetase syndromes form a distinct group characterised by the presence of antibodies directed against various aminoacyl-tRNA synthetase enzymes (anti-Jo-1, an antibody directed against histidyl-tRNA synthetase, and several others), with overlapping clinical features of myositis, arthritis, and interstitial lung disease.[3]
Polymyositis/scleroderma (PM/Scl) syndrome is characterised by overlapping features of scleroderma and polymyositis, and PM/Scl antibody, and by the presence of Raynaud's phenomenon, tendon inflammation, and interstitial lung disease.[2][4] Sclerodactyly may occur, but the truncal sclerodermatous skin changes characteristic of systemic sclerosis are absent.

Pathophysiology

Classification

Clinical classification