Etiology
The overlap syndromes are autoimmune conditions of unknown etiology, 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).
Pathophysiology
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 phenomenon and pulmonary hypertension in these patients. In addition, the vascular compromise may lead to organ dysfunction or hemorrhage. 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. Autoantigen released from necrotic or apoptotic cells is taken up by antigen-presenting cells, modified, and then presented noncovalently bound in the antigen-binding cleft of HLA molecules to autoreactive T cells. These could subsequently perpetuate the autoimmune response by producing cytokines that would serve to expand the clone of autoreactive T and B cells, both of which seem necessary to the final disease pathway. MCTD is characterized by high-titer antibodies to a specific ribonucleoprotein (anti-U1 RNP).[10] Disease manifestations may be mediated by autoantibody 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 characterized 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.
Classification
Clinical classification
Overlap syndromes are characterized by specific clinical features, autoantibody profiles, and immunogenetics.
Mixed connective tissue disease (MCTD) is a distinct clinical entity characterized by overlapping features of systemic lupus erythematosus, scleroderma, myositis, and rheumatoid arthritis in the setting of a high titer of autoantibodies 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 phenomenon, sclerodermatous skin changes, and myositis. Severe central nervous system and renal diseases are rare manifestations.
Antisynthetase syndromes form a distinct group characterized 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 characterized by overlapping features of scleroderma and polymyositis, and PM/Scl antibody, and by the presence of Raynaud phenomenon, tendon inflammation, and interstitial lung disease.[2][4] Sclerodactyly may occur, but the truncal sclerodermatous skin changes characteristic of systemic sclerosis are absent.
Use of this content is subject to our disclaimer