overlap syndrome

Overlap syndromes Straight to the point of care Last updated: May 05, 2020 Table of Contents Overview 3 Summary 3 Definition 3 Theory 4 Epidemiology 4 Aetiology 4 Pathophysiology 4 Classification 4 Case history 5 Diagnosis 7 Approach 7 History and exam 10 Risk factors 12 Investigations 13 Differentials 18 Criteria 19 Management 20 Approach 20 Treatment algorithm overview 23 Treatment algorithm 25 Emerging 36 Secondary prevention 36 Patient discussions 36 Follow up 37 Monitoring 37 Complications 38 Prognosis 39 Guidelines 40 Treatment guidelines 40 References 41 Disclaimer 45 Overlap syndromes Overview Summary Refers to a group of conditions that have clinical features of, and meet classification criteria for, more than one well-characterised rheumatic disease. The spectrum of overlap syndromes includes mixed connective tissue disease (MCTD); antisynthetase syndrome; and polymyositis/scleroderma (PM/Scl) overlap syndrome. 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 U1 ribonucleoprotein. Antisynthetase syndromes form a distinct group characterised by antibodies directed against various aminoacyl-tRNA synthetase enzymes with overlapping clinical features of myositis, arthritis, and interstitial lung disease. PM/Scl syndrome is characterised by overlapping features of scleroderma and polymyositis, PM/Scl antibody, Raynaud's phenomenon (RP), tendon inflammation, and interstitial lung disease. Treatment of overlap syndromes is tailored to the active clinical manifestations and ranges from supportive therapy to cytotoxic immunosuppressive regimens. Definition Overlap syndromes' refers to a diverse group of conditions that have clinical features of, and meet classification criteria for, more than 1 well-characterised rheumatic disease. They usually present subacutely with clinical manifestations that can include different organ systems. The pattern of organ involvement reflects the characteristic features of the well-defined rheumatic diseases occurring together. O V E R VIE W This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 3 Overlap syndromes Theory T H E O R Y Epidemiology Rigorous epidemiological studies on the incidence and prevalence of overlap syndromes have not been done, and data are lacking. However, they are all rare conditions. The estimated prevalence of mixed connective tissue disease (MCTD) in a Japanese epidemiological series was 2.7 per 100,000.[1] At a tertiary US referral centre, it was found to be less common than systemic lupus erythematosus (SLE), as common as systemic sclerosis, and more common than polymyositis. Patients with MCTD generally present between the ages of 20 and 30 years, and it (similar to SLE) is far more common in women (female to male ratio of 10:1).[2] No familial clustering has been noted. Antisynthetase antibodies (including anti-Jo-1, an antibody directed against histidyl-tRNA synthetase) are found in 5% to 20% of patients with polymyositis or dermatomyositis. Aetiology 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). 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'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 autoreactive 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). 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. Classification 4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Theory 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). 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 histidyltRNA synthetase, and several others), with overlapping clinical features of myositis, arthritis, and interstitial lung disease. • 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. Sclerodactyly may occur, but the truncal sclerodermatous skin changes characteristic of systemic sclerosis are absent. Case history Case history #1 A 35-year-old woman presents with a 6-month history of painful colour changes of her fingers on exposure to cold. She describes initial pallor, followed by dusky discoloration that is then followed by painful erythema of her fingers. This has been associated with swelling of her fingers as well as arthralgias of the small joints of her hands. She has a history of reflux oesophagitis and moderate dyspnoea on exertion. Physical examination confirms skin thickening and oedema of her fingers, with mild synovitis of the interphalangeal joints, but is otherwise unremarkable. Serological testing reveals a positive test for antinuclear antibodies (ANAs) at a titre of 1:2560, with high titre positivity for anti-U1 ribonucleoprotein antibody. Case history #2 A 50-year-old man without any significant past medical history presents with a 6-month history of arthritis of the small joints of both hands. He notes morning stiffness of about 1 hour. This has been associated with a non-productive cough and progressive decrease in his ability to climb the 2 flights of stairs to his apartment due to dyspnoea and pain in his thigh muscles. Physical examination is remarkable for the presence of interphalangeal synovitis, with a scaly rash over the palmar surface of his hands and fingers, and proximal muscle weakness. Fine rales are heard in both lung bases, but the remainder of the cardiopulmonary examination is normal. Laboratory tests demonstrate an elevated creatine kinase, negative rheumatoid factor and ANA tests, but a positive anti-Jo-1 antibody, consistent with antisynthetase syndrome. T H E O R Y This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 5 Overlap syndromes Theory T H E O R Y Other presentations As the clinical manifestations of overlap syndromes, including mixed connective tissue disease, can affect almost any organ system, the presenting symptoms may be protean. In addition to the common presenting features described, other initial manifestations may be typical of other well-characterised connective tissue diseases, such as the malar rash, cytopenias, and serositis also seen in systemic lupus erythematosus; diffuse scleroderma skin changes typical of the systemic sclerosis spectrum of diseases; and xerostomia and xerophthalmia, seen in Sjogren's syndrome. 6 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Diagnosis Approach The overlap syndromes are a diverse group of conditions that usually present subacutely with clinical manifestations that can include different organ systems. The pattern of organ involvement reflects the characteristic features of the well-defined rheumatic diseases occurring together. History and examination For many patients, non-specific symptoms are often present for many months before a diagnosis is made. Any organ system can be involved, and the pattern of involvement is defined by the underlying rheumatic conditions occurring together. No one historical symptom defines any of the overlap syndromes; diagnostic suspicion should be raised when patients present with a constellation of findings affecting multiple organ systems with simultaneous features of more than one rheumatic disease. Apart from mixed connective tissue disease (MCTD), for most other overlap syndromes small numbers have limited the ability to define an evidence-based diagnostic approach, and these are best considered in the context of specific clinical features, auto-antibody profiles, and immunogenetics. • MCTD: The characteristic pattern of presentation is relatively well defined by diagnostic criteria and includes overlapping features of systemic lupus erythematosus (SLE), 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). Clinical features are highly variable, involving predominantly arthritis, Raynaud's phenomenon (RP), sclerodermatous skin changes, and myositis. Approximately 90% of patients with MCTD have RP on presentation. Severe central nervous system and renal diseases are rare manifestations. • Antisynthetase syndrome: This syndrome forms a distinct group characterised by the presence of antibodies directed against various aminoacyl-tRNA synthetase enzymes with anti-Jo-1 being the most common; overlapping clinical features of myositis, arthritis, and interstitial lung disease are seen. • Polymyositis/scleroderma (PM/Scl) overlap syndrome: This is characterised by overlapping features of scleroderma and polymyositis, and the PM/Scl antibody, and by the presence of RP, tendon inflammation, and interstitial lung disease. Sclerodactyly may occur, but the truncal sclerodermatous skin changes characteristic of systemic sclerosis are absent. Physical examination should focus on identifying patterns of organ system involvement, with particular attention to detecting classic findings of well-defined rheumatic diseases such as sclerodactyly, synovitis, myopathy, and rashes typical of SLE. Many patients show lymphadenopathy on presentation. • Musculoskeletal manifestations: Joint symptoms are present in almost all patients with MCTD and are a common presenting symptom. Frank arthritis develops in 50% to 60% of patients during follow-up. A small-joint polyarthritis is the most common pattern of involvement, but deformities are uncommon. Swollen hands are very common at presentation in MCTD and may progress to swelling of the entire hand. Sclerodactyly is also common but tends to occur as a later manifestation of disease. Myalgias occur in 25% to 50% of MCTD patients, but myositis is less common, usually without frank weakness on physical examination. However, myositis is a key component of patients with antisynthetase syndrome. In this instance they may present with weakness (usually in the proximal muscles). • Pulmonary manifestations: Evaluation for pulmonary disease is important, as this is the largest cause of death in patients with MCTD. Pulmonary involvement in MCTD occurs in 43% of patients on presentation but will eventually affect up to 66% of patients. Both pulmonary hypertension (in DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 7 Overlap syndromes Diagnosis DIA G N O SIS 20% to 25% of patients) and interstitial lung disease (in 50% of patients) may be seen. Among patients with antisynthetase syndrome, interstitial lung disease is even more common, occurring in 40% to 100% of patients. Physical examination may demonstrate signs of elevated right-sided heart pressures or bibasilar rales. Pleural effusions occur uncommonly. • Neurological manifestations: A full neurological examination should be performed. A predominantly sensory polyneuropathy may be seen and should be further evaluated with nerve conduction studies and electromyography (EMG). Trigeminal neuralgia may very rarely be the presenting feature of MCTD, presenting as neuropathic pain or anaesthesia over the distribution of 1 or more of the branches of the trigeminal nerve. Neuropsychiatric diseases including psychosis and seizures are rare manifestations of MCTD. Uncommonly in MCTD, headaches (due to aseptic meningitis) may be a presenting complaint. • Cutaneous manifestations: Skin lesions may be evident, present in 50% to 60% of patients. Approximately 90% of patients with MCTD have RP on presentation. Abnormal nail fold capillaroscopy (the pattern of blood vessels visible under low magnification) has been shown to have predictive value for an underlying rheumatic disease. Giant capillaries and loss of the normal architecture with dropout of vessels are patterns that may suggest underlying systemic sclerosis or polymyositis.[3] [4] In MCTD, malar rashes and discoid lesions similar to those characteristic of SLE may be seen occasionally. Acrosclerosis with telangiectasias and occasionally calcinosis may be seen, but truncal sclerodermatous skin changes are very rare. Skin changes typical of dermatomyositis, including Gottron's papules and a heliotrope rash, may occur in MCTD, but the nodules of rheumatoid arthritis are rarely seen. Alopecia may also be seen in MCTD. • Gastrointestinal manifestations: GORD is common in MCTD. Patients with MCTD may present with symptoms of oesophageal dysmotility, with reflux symptoms, dysphagia, or regurgitation. Initial laboratory investigations No single blood test, or combination of tests, is diagnostic. Initial blood tests include the following tests. • With FBC, urea, and serum creatinine, and inflammatory markers such as erythrocyte sedimentation rate (ESR) or CRP, non-specific findings such as anaemia, leukopenia, and hypergammaglobulinaemia may be seen. Inflammatory markers (ESR or CRP) may or may not be elevated. • For most patients, measurement of antinuclear antibodies (ANAs) is an appropriate initial test when the clinical evaluation reveals symptoms or signs suggestive of an underlying rheumatic disease. ANA titres are seen in almost all patients with MCTD but are also present in other conditions such as SLE and scleroderma, and so are not diagnostic for an overlap syndrome. • Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody levels should be measured. Both are markers of rheumatoid arthritis, and may be elevated in patients with overlap syndrome • Muscle enzymes may be elevated in patients who have MCTD, antisynthetase syndrome, or polymyositis as one of the rheumatic conditions. The most sensitive indicator enzyme is creatine kinase. • Significant proteinuria or haematuria on urinalysis is indicative of renal involvement. • High-titre anti-U1 ribonucleoprotein (U1 RNP) is a requirement for diagnosis of MCTD. Absence of anti-U1 RNP indicates an alternative overlap syndrome or separate autoimmune disease. • Antibodies to various aminoacyl-tRNA synthetase enzymes are the defining antibodies of antisynthetase syndrome, with the anti-Jo-1 antibody the most common. 8 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Diagnosis Additional auto-antibody serology When there is clinical suspicion of an autoimmune overlap syndrome, with or without the initial finding of a positive ANA, additional tests should be considered to evaluate for the presence of serological markers more specific for the rheumatic diseases. In the absence of anti-U1 RNP antibodies, serological tests provide additional evidence for an underlying variant of overlap syndrome or for an alternative autoimmune process. • Antibodies to double-stranded (ds) DNA or the Smith's antigen may suggest SLE; in MCTD Smith's antigen is negative, although a subset of patients with MCTD may be positive for anti-dsDNA. • Anti-Scl 70, anticentromere antibodies and anti-RNA polymerase III, anti-Ku, or anti-PM/Scl antibodies suggest scleroderma overlap syndrome. • Anti-Ro (SS-A) and anti-La (SS-B) antibodies are evaluated for co-existent Sjogren's syndrome. • Anti-Jo-1 antibodies are highly specific for antisynthetase syndromes and are sought in patients with myositis. • Other antisynthetase antibodies (including PL7, PL12, OJ, EJ, KS, Ha and others) may be present in antisynthetase syndromes, but are less common than anti-Jo1. The finding of these auto-antibodies is highly suggestive of their associated diseases, and further investigations then follow the protocols for those conditions. In the absence of any of the specific serological findings, some patients who do not meet criteria for any well-defined disease should remain classified as having undifferentiated connective tissue disease (UCTD). The diagnosis can only be further clarified with follow-up over time for the development of additional clinical or serological findings. One study estimated that, of patients initially classified as having UCTD, 64% retained that diagnosis at 1 year and 47% at 5 years of follow-up.[5] Another study among Hungarian patients suggested that one third of patients with UCTD progressed to another rheumatic diagnosis, and that this was most likely to happen within the first 2 years of follow-up.[6] Additional investigations Additional investigations are required to define the pattern and severity of organ involvement. • Complaints of dyspnoea, dry cough, or decreased exercise tolerance should prompt further evaluation for pulmonary or cardiac involvement by CXR, ECG, and echocardiogram. Complete pulmonary function tests (PFTs) with spirometry, lung volumes and diffusion capacity, and a CXR are also performed. A high-resolution CT scan of the lungs is more sensitive than CXR for early interstitial lung disease and should be considered in those with abnormal PFTs indicative of restrictive lung disease. High-resolution CT may also be performed if lung volume or functional status declines. If echocardiogram findings are suggestive of pulmonary hypertension (e.g., elevated right ventricular systolic pressure), referral for right-heart catheterisation and full evaluation should be considered. • A barium swallow can be helpful to look for features consistent with GORD, including dysmotility and reflux. It is also indicated when symptoms of heartburn worsen, or do not improve, with appropriate therapy. Symptoms and signs of dysphagia may require investigation with upper gastrointestinal endoscopy. • Patients with polyneuropathy should be further evaluated with nerve conduction studies and EMG. • In patients with symptoms of arthralgia or arthritis, plain x-rays of affected joint(s) may show evidence of inflammation, non-erosive arthritis, or bony erosions. DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 9 Overlap syndromes Diagnosis DIA G N O SIS • Tissue biopsy is not generally done as part of the diagnostic evaluation. Occasionally clinical suspicion of particular organ involvement may prompt tissue examination, such as muscle biopsy to confirm the autoimmune nature of myositis, lung biopsy to better characterise the nature of lung infiltrates, or kidney biopsy to evaluate for immune-mediated glomerular disease. History and exam Key diagnostic factors presence of risk factors (common) • Risk factors include female sex (female to male ratio approximately 10:1) and age between 20 and 40 years. digital pallor/pain (common) • Approximately 90% of patients with mixed connective tissue disease have Raynaud's phenomenon (RP) on presentation. • RP may also be an isolated condition, but abnormal nail fold capillaroscopy suggests eventual development of underlying rheumatic condition. Only infrequently is RP complicated by findings of digital ischaemia or infarcts in overlap syndromes. arthritis/arthralgia (common) • Joint symptoms are present in almost all patients with mixed connective tissue disease and are a common presenting symptom. Frank arthritis develops in 50% to 60% of patients during follow-up. Small-joint polyarthritis is the most common pattern of involvement, but deformities are uncommon. swollen hands (common) • Very common at presentation in mixed connective tissue disease, and may progress to entire hand swelling. sclerodactyly (common) • Common in mixed connective tissue disease, but tends to occur as a later manifestation of disease. nail fold vascular changes (common) • Abnormal nail fold capillaroscopy (pattern of blood vessels visible under low magnification in the nail bed) has predictive value for an underlying rheumatic disease in patients presenting with Raynaud's phenomenon. • Patterns of giant capillaries and loss of the normal architecture with dropout of vessels may suggest underlying mixed connective tissue disease, systemic sclerosis, or polymyositis.[3] [4] dyspnoea or cough (common) • Pulmonary involvement in mixed connective tissue disease occurs in 43% of patients on presentation, but will eventually affect up to 66% of patients. Both interstitial lung disease and pulmonary hypertension may be seen. • Among patients with antisynthetase syndrome, interstitial lung disease is even more common, occurring in 40% to 100% of patients. • Physical examination may demonstrate signs of elevated right-sided heart pressures or bibasilar rales. Pleural effusions occur uncommonly. 10 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Diagnosis GORD and heartburn (common) • On presentation, 47% of patients with mixed connective tissue disease already have symptoms of oesophageal dysmotility, with reflux symptoms, dysphagia, and regurgitation. Ultimately seen in 65% of patients during follow-up. Much less commonly, patients develop symptoms due to pancreatitis, mesenteric ischaemia, or malabsorption. myalgias or myositis (uncommon) • Myalgias occur in 25% to 50% of mixed connective tissue disease patients, but myositis is less common, usually without frank weakness on physical examination. • Myositis is a key component of antisynthetase syndrome. Other diagnostic factors haematuria (common) • Renal involvement in 25% of patients with mixed connective tissue disease (MCTD); rare in other overlap syndromes. In MCTD, focal proliferative glomerulonephritis is the most common cause. Rarely, membranous glomerulonephritis with nephrotic syndrome occurs. Renal biopsy is indicated in patients with significant abnormalities on urinalysis and in some cases of declining renal function. lymphadenopathy (common) • Reported to occur in 25% to 50% of patients with mixed connective tissue disease, often as a presenting sign that improves with time. alopecia (common) • Has been reported in 40% of mixed connective tissue disease patients. skin rashes (uncommon) • Many different types may occur in 50% to 60% of patients; in mixed connective tissue disease (MCTD), malar rashes and discoid lesions similar to those characteristic of systemic lupus erythematosus may be seen occasionally. • Acrosclerosis with telangiectasias and occasionally calcinosis may be seen, but truncal sclerodermatous skin changes are very rare. • Skin changes typical of dermatomyositis, including Gottron's papules and a heliotrope rash, may occur in MCTD, but the nodules of rheumatoid arthritis are rarely seen. proximal muscle weakness (uncommon) • Patients may develop an inflammatory myositis. Patients with these symptoms, or those with suspected muscular involvement, require serum muscle enzymes, possibly followed by an electromyogram/nerve conduction study and muscle biopsy. trigeminal neuralgia (uncommon) • Very rarely may be the presenting feature of mixed connective tissue disease, presenting as neuropathic pain or anaesthesia over the distribution of 1 or more of the branches of the trigeminal nerve. headaches (uncommon) • May be seen due to aseptic meningitis in mixed connective tissue disease. DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 11 Overlap syndromes Diagnosis DIA G N O SIS neuropsychiatric disease including psychosis and seizures (uncommon) • Rare manifestations of mixed connective tissue disease. peripheral neuropathy (uncommon) • Predominantly sensory polyneuropathy may be seen and should be further evaluated with nerve conduction studies and electromyography. fever (uncommon) • Low-grade fever due to mixed connective tissue disease is uncommon. A careful search for infection is therefore mandatory. Risk factors Strong female sex • Mixed connective tissue disease is far more common in women (female to male ratio of 10:1).[2] The sex distribution of the other overlap syndromes is less well defined. age 20 to 40 years • Although overlap syndromes can occur at any age, patients with mixed connective tissue disease generally present between 20 and 40 years of age; patients with antisynthetase syndrome typically present later in life. Weak presence of specific HLA genotypes • Genotypes HLA-DR4 and HLA-DR2 are associated with mixed connective tissue disease. • Prevalence of certain HLA 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). 12 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Diagnosis Investigations 1st test to order Test Result FBC • Leukopenia, thrombocytopenia, and anaemia of chronic disease seen in 50% to 75% of patients with mixed connective tissue disease (MCTD). • Not specific for MCTD; may be seen in other autoimmune conditions, including systemic lupus erythematosus, as well as in non-rheumatic diseases. variable; may show anaemia, leukopenia erythrocyte sedimentation rate • Non-specific marker; may be elevated due to an acute-phase response from any cause. elevated (non-specific) CRP • Non-specific marker; may be elevated due to an acute-phase response from any cause. elevated (non-specific) serum urea and creatinine • Renal insufficiency is a relatively uncommon manifestation of mixed connective tissue disease, but glomerulonephritis may occur, leading to renal dysfunction. • Rarely seen in other overlap syndromes. normal or elevated rheumatoid factor • If present, may indicate more classic rheumatoid arthritis. may be positive antinuclear antibodies • Appropriate initial test when the clinical evaluation reveals symptoms or signs suggesting underlying rheumatic disease. • Antinuclear antibody titres are seen in almost all patients with mixed connective tissue disease but are also present in other conditions such as systemic lupus erythematosus and scleroderma, and so are not diagnostic for an overlap syndrome. positive anti-cyclic citrullinated peptide (anti-CCP) antibody • May assist in the diagnosis of early rheumatoid arthritis, although can be elevated in overlap syndromes. may be positive urinalysis • Renal involvement in 25% of patients with mixed connective tissue disease (MCTD); rarely in other overlap syndromes. • In MCTD, focal proliferative glomerulonephritis is the most common cause. Rarely, membranous glomerulonephritis with nephrotic syndrome occurs. • Renal biopsy is indicated in patients with significant abnormalities on urinalysis and in some cases of declining renal function. variable; may show proteinuria, haematuria, occasional RBC casts anti-U1 ribonucleoprotein • Essential for the diagnosis of mixed connective tissue disease (MCTD). Anti-U1 ribonucleoprotein is typically present at positive or high titre positive levels in patients with classic MCTD, but may be borderline or negative in patients with undifferentiated connective tissue diease. may be positive DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 13 Overlap syndromes Diagnosis DIA G N O SIS Test Result anti-Jo-1 • Anti-Jo-1 antibody is negative in patients with mixed connective tissue disease. When present, it is highly specific for antisynthetase syndrome. However, not all patients with myositis and lung involvement are positive for anti-Jo-1. may be positive 14 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Diagnosis Other tests to consider Test Result creatine kinase • Indicates underlying myositis as part of overlap syndrome. variable; may be elevated anti-double-stranded DNA • If positive, should suggest an alternative diagnosis of systemic lupus erythematosus rather than mixed connective tissue disease (MCTD). A subset of patients with MCTD may be positive for anti-doublestranded DNA. usually negative Smith's antigen • If positive, should suggest alternative diagnosis of systemic lupus erythematosus rather than mixed connective tissue disease. negative anti-SS-A and anti-SS-B • If positive, should suggest an alternative diagnosis of primary Sjogren's syndrome rather than mixed connective tissue disease (MCTD). • A subset of patients with MCTD may be positive for anti-SS-A and anti-SS-B and have secondary Sjogren's syndrome. variable; usually negative pulmonary function tests (spirometry, lung volumes and diffusion capacity measurement) • Important to evaluate for restrictive lung disease and for pulmonary hypertension. • Should be done at onset followed by annual monitoring. If symptoms are progressing, should be done more frequently. • High-resolution CT scan of the chest should be done for declining lung volumes or functional status. • Referral to a respiratory physician and/or rheumatologist should be made if results are abnormal. interstitial lung disease: decrease in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) plus an overall restrictive pattern; pulmonary hypertension: disproportionate drop in DLCO compared with FVC CXR • Important to evaluate interstitial lung disease. • Should be done at onset if pulmonary function tests (PFTs) are abnormal and repeated if PFTs show a change. • High-resolution CT of the lungs is more sensitive than CXR for diagnosis of early interstitial lung disease and should therefore be performed if PFTs are abnormal or deteriorate. normal; evidence of interstitial lung disease demonstrated by bibasilar interstitial infiltrates; possibly cardiomegaly or signs of right-heart failure high-resolution CT scan of chest • Should be considered in those with abnormal pulmonary function tests indicative of restrictive lung disease. • May also be performed if lung volumes or functional status declines. • This is a more sensitive test for the diagnosis of early interstitial lung disease than CXR, although CXR is often done initially. normal or evidence of interstitial lung disease demonstrated by groundglass opacities (possible alveolitis), thickened interstitium (interstitial fibrosis); also traction bronchiectasis and honeycombing echocardiogram • Should be done at onset and yearly. • If symptoms are progressing, should be done more frequently. • Echo can estimate right ventricular systolic pressure (RVSP) based on tricuspid/pulmonic regurgitation jet. pulmonary hypertension: rise in right ventricular systolic pressure RVSP; pericardial effusion, right or left ventricular DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 15 Overlap syndromes Diagnosis DIA G N O SIS Test Result • Pleural effusions are generally small without haemodynamic compromise, but are a marker for poor prognosis. • Referral for right-heart catheterisation and full evaluation should be done if RVSP is raised, as echo findings may not indicate true pulmonary artery pressures. diastolic dysfunction may be present right-heart catheterisation • The definitive diagnostic for pulmonary haemodynamic measurement and required to confirm presence of pulmonary hypertension, to establish specific diagnosis and determine severity of pulmonary hypertension. normal or mean pulmonary arterial pressure >25 mmHg at rest or >30 mmHg with exercise, with pulmonary capillary wedge pressure <15 mmHg and pulmonary vascular resistance >3 Wood units barium swallow • Can be helpful to look for features consistent with scleroderma, including dysmotility and reflux. • Should also be done if symptoms of heartburn worsen or do not improve with appropriate therapy. diminished oesophageal peristalsis and gastroparesis; diminished muscle tone in lower oesophagus, with reflux of barium; strictures upper gastrointestinal endoscopy ± biopsy • Indicated with new onset of dysphagia, to evaluate for stricture. • Needs to be performed with care due to possibility of oesophageal stricture. oesophageal inflammation, ulceration, strictures, Barrett's metaplasia, adenocarcinoma may be present plain x-ray of affected joint(s) • Considered in patients with symptoms of arthralgia or arthritis. normal or may show inflammation, non-erosive arthritis; bony erosions electromyography • Indicated if weakness is present in the setting of elevated muscle enzymes and if diagnosis of inflammatory myositis is in question. • Identification of inflammatory myositis is important, as it requires treatment with immunosuppression. inflammatory myositis: abnormal with inflammatory features nerve conduction studies • Indicated if weakness is present in the setting of elevated muscle enzymes and if diagnosis of inflammatory myositis is in question. myopathic pattern muscle biopsy • Considered if inflammatory myositis is suspected. inflammatory myositis: abnormal with inflammatory features lung biopsy • Considered if interstitial lung disease is suspected. interstitial inflammation and fibrosis renal biopsy • Considered if immune-mediated glomerular disease is suspected. immune deposits, mesangial hypercellularity; focal, segmental, or global glomerulonephritis 16 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. 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Overlap syndromes Diagnosis Emerging tests Test Result anti-Ku antibodies • If positive, may suggest polymyositis/scleroderma (PM/Scl) overlap syndrome. variable; usually negative in mixed connective tissue disease antipolymyositis/scleroderma antibodies • If positive, may suggest polymyositis/scleroderma overlap syndrome. variable; usually negative in mixed connective tissue disease other antisynthetase antibodies (PL7, PL12, OJ, EJ, KS, Ha and others) • May be present in antisynthetase syndromes, but are less common than anti-Jo1. variable; usually negative in mixed connective tissue disease, but highly specific for antisynthetase syndrome DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 17 Overlap syndromes Diagnosis DIA G N O SIS Differentials Condition Differentiating signs / symptoms Differentiating tests Systemic lupus erythematosus (SLE) • No differentiating symptoms or signs. • Negative for anti-U1 ribonucleoprotein (U1 RNP). • High antibody titres to the Smith's antigen or to double-stranded DNA in the absence of antiU1 RNP suggest SLE as the underlying diagnosis, whereas high titres to antiU1 RNP suggest mixed connective tissue disease. Polymyositis • More pronounced muscle weakness than is typical of mixed connective tissue disease (MCTD); Raynaud's phenomenon uncommon. • Negative for anti-U1 ribonucleoprotein (U1 RNP). • High antibody titres to the Mi-2 antigen or signal recognition particle suggest dermatomyositis or polymyositis rather than overlap syndrome. • High-titre antibodies to U1 RNP suggest MCTD; antibodies to the tRNA synthetase enzymes suggest antisynthetase syndrome. Scleroderma • Digital ischaemia and infarcts more common than in mixed connective tissue disease (MCTD); truncal sclerodermatous skin changes may also be seen, unlike in MCTD. • Negative for anti-U1 ribonucleoprotein. • Antibody titres to anticentromere antibody suggest scleroderma spectrum disease rather than MCTD. • Anti-Ku and antipolymyositis/ scleroderma point to a scleroderma overlap. Idiopathic Raynaud's phenomenon • Nail fold capillaroscopy normal, digital infarcts and necrosis not seen; abnormalities suggest underlying connective tissue disease instead. • Negative for anti-U1 ribonucleoprotein. Vasculitis • Palpable purpura or livedo reticularis suggest small and medium vessel vasculitis that are only rarely seen in mixed connective tissue disease. • Negative for anti-U1 ribonucleoprotein. • Antineutrophil cytoplasmic antibodies may be seen in primary small-vessel vasculitides. 18 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Diagnosis Criteria Diagnostic criteria of Alarcon-Segovia and Villareal[7] Mixed connective tissue disease (MCTD) is defined by: • Serological criteria: positive anti-U1 ribonucleoprotein (U1 RNP) passive haemagglutination titre greater than or equal to 1:1600 and • Clinical criteria: three of the following clinical findings, at least one of which must be either synovitis or myositis: • Oedema of the hands • Synovitis • Myositis • Raynaud's phenomenon • Acrosclerosis. Diagnostic Criteria of Kasukawa et al[8] Definitive diagnosis of MCTD requires: • One or two common symptoms: Raynaud's phenomenon and/or swollen fingers of hands • Positive anti-U1 RNP • One or more findings in at least two of the following disease categories: • Systemic lupus erythematosus-like findings: polyarthritis, lymphadenopathy, facial erythema, pericarditis or pleuritis, leukopenia, or thrombocytopenia • Systemic sclerosis-like findings: sclerodactyly, pulmonary fibrosis (restrictive changes of the lung, or reduced diffusing capacity of the lung for carbon monoxide), hypomotility, or dilation of oesophagus • Polymyositis-like findings: muscle weakness, increased creatine kinase, myogenic pattern in an electromyogram. DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 19 Overlap syndromes Management M A N A G E M E N T Approach There is a paucity of data from controlled trials to support management strategies specifically in patients with mixed connective tissue disease (MCTD) (or any of the overlap syndromes), in whom the clinical features and need for treatment are highly variable. As such, the treatment of these patients is highly individualised, tailored to the organ systems involved and the severity of involvement. Treatment strategies and the evidence to support specific treatments are borrowed from standard therapies proven to be effective in other welldefined rheumatic conditions. The overall goal of therapy is symptom control, prevention of organ injury, and, where possible, arrest of the underlying autoimmune disease process. General management It is essential that all patients be referred to a rheumatologist with experience in managing these conditions. Any patient with evidence of lung disease should be referred to a consultant to evaluate for progressive lung disease. For many patients with overlap syndromes, symptomatic benefit is gained by use of non-steroidal antiinflammatory drugs (NSAIDs) and corticosteroids. The long-term side effects of corticosteroid therapy are well documented, and patients should be counselled regarding risk of hypertension, hyperglycaemia, and potential skin changes. Caution is advised regarding corticosteroid use in patients with upper gastrointestinal (GI) symptoms, especially if also taking NSAIDs. The lowest possible dose to control symptoms should be used for the shortest period of time. General lifestyle modifications should be recommended for all patients. These should include: • Education to encourage the patient to take responsibility for his/her disease management • Maintenance of an ideal body weight for their height • Reduction of salt intake in the presence of hypertension due to renal disease • Exercise guidelines to maintain optimum cardiovascular fitness, in patients with stable disease • Smoking cessation encouraged for patients who smoke. Arthralgias and arthritis The typical small-joint arthralgias of MCTD and the other overlap syndromes are managed with the use of NSAIDs (e.g., naproxen) at the lowest effective doses, with attention paid to monitoring for, and prevention of, cardiovascular, renal, and GI toxicities. If NSAIDs are found to be inadequate or ineffective, consider adding antimalarial medications, particularly hydroxychloroquine, which has been shown to be effective in systemic lupus erythematosus, and may be used in MCTD. If this is given, regular ophthalmological screening for retinopathy should be done. In patients who develop frank synovitis, short courses of low-dose corticosteroids are helpful. If the arthritis is resistant to corticosteroids, synovitis is not adequately controlled on low doses of corticosteroids, or the patient has deforming or erosive disease, the addition of methotrexate is useful. It should not be used in patients with renal failure, and should be used cautiously in those with interstitial lung disease. Folate supplementation should be given simultaneously, and close attention paid to advice on contraception and reproductive health. 20 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Management Raynaud's phenomenon Lifestyle modifications including avoidance of cold or sudden changes in temperature should be advised. Smoking cessation is essential. Treatment is important to prevent progression to digital ulceration. First-line pharmacological interventions include calcium-channel blockers such as nifedipine. These agents are useful at decreasing the frequency and severity of attacks.[9] [10] [11] In patients with Raynaud's phenomenon (RP) secondary to scleroderma, alpha-1-blocking agents (e.g., prazosin) have been found to be useful. For patients unable to tolerate or resistant to calcium-channel blockers, fluoxetine has been found to reduce the frequency and severity of attacks in patients with primary RP or RP related to systemic sclerosis.[12] Other second-line therapies include the phosphodiesterase-5 inhibitor sildenafil, which has been shown to be effective and may be considered in patients who fail to respond to calciumchannel blockers.[13] In more severe cases associated with systemic sclerosis, parenteral prostacyclin analogues have been tried with some success. The endothelin receptor antagonist bosentan has been shown to reduce the incidence of new ischaemic ulcers.[14] These agents should only be used under the supervision of physicians familiar with their use, as side effects are common. Puffy hands NSAIDs such as naproxen may improve symptoms. Low-dose prednisolone may be added if needed. Myositis Corticosteroid therapy is the mainstay of management of myositis in MCTD, as well as in antisynthetase syndrome and polymyositis/scleroderma overlap syndrome where an inflammatory myopathy is a prominent component.[15] Prednisolone is effective followed by slow tapering after 4 to 6 weeks if the disease has been controlled. For those patients who do not remit with corticosteroid therapy, or in those who continue to require unacceptably high doses for disease control, addition of methotrexate or azathioprine may provide a corticosteroid-sparing effect. High-dose intravenous immunoglobulin has been used in resistant cases, with reports of efficacy in polymyositis and dermatomyositis. GORD Treatment of GORD is important, both for patient comfort and to prevent complications (e.g., oesophageal stricture). Proton-pump inhibitors are the mainstay of management. Lifestyle measures are also recommended. Patients should be counselled to avoid eating food 2 to 3 hours before bedtime, and to avoid drinking caffeinated and carbonated beverages. Sicca symptoms Treatment is largely symptomatic. Close ophthalmic and dental follow-up are essential for prevention of complications related to decreased tear and saliva pools. Artificial tears are helpful as initial therapy. Parasympathomimetic agents such as pilocarpine and cevimeline may improve tear and saliva flow but may have numerous anticholinergic side effects. A retrospective, open-label study found benefit from hydroxychloroquine in patients with primary Sjogren's syndrome, and this may also be of benefit in patients with sicca symptoms as part of their overlap M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 21 Overlap syndromes Management M A N A G E M E N T syndrome.[16] If this is given, regular ophthalmological screening for retinopathy should be done. Immunosuppressive therapies, including TNF-alpha blockers, have been largely disappointing and cannot be routinely recommended for these patients. Neuropathy For sensory neuropathy, standard treatment with gabapentin or amitriptyline may be tried first. Transcutaneous electrical nerve stimulation has been found to be effective and may be added on to existing therapy or used alone. In more severe cases with motor neuropathy or transverse myelitis, immunosuppressive therapy with high-dose corticosteroids (and rarely cytotoxic agents) may be required. Of the cytotoxic drugs, cyclophosphamide has been the most frequently employed agent; the roles of less toxic regimens using mycophenolate are still under investigation. All drugs should only be used under the care of an experienced rheumatologist. Serositis Mild serositis may respond to NSAIDs, but corticosteroids are the mainstay of management for more severe disease. Depending on the severity of the serosal involvement, moderate or high-dose prednisolone may be required; the response is generally good.[17] Pulmonary hypertension All patients with MCTD should undergo regular screening for the development of pulmonary hypertension.[18] Treatment should be guided by the results of right-heart catheterisation, including documentation of vasomotor responsiveness to vasodilators. Acute vasodilator response is defined as a fall in mean pulmonary artery pressure of ≥10 mmHg to ≤40 mmHg, with an increased or unchanged cardiac output during acute challenge with inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine. If patients are responsive, they should be treated with optimally tolerated doses of calciumchannel blockers as first-line therapy. Non-responders to vasoreactivity testing and patients without sustained response to calcium-channel blockers should be started on another pulmonary arterial hypertension-specific therapy. Targeted treatment options include oral phosphodiesterase-5 inhibitors such as sildenafil; oral endothelin receptor antagonists such as bosentan; and parenteral and inhaled prostacyclin analogues, among others. • Sildenafil has been shown to improve symptoms, functional capacity, and haemodynamics when used in patients with primary pulmonary hypertension and in pulmonary hypertension secondary to rheumatic diseases.[19] • Bosentan has also been shown to improve symptoms and functional capacity, but its long-term use and effects on pulmonary haemodynamics are less certain.[20] [21] It should be used only by physicians experienced in its use, as very close monitoring for side effects, including hepatotoxicity, is needed. • Epoprostenol, inhaled iloprost, and treprostinil have been tried, singly and in combination regimens.[22] [23] [24] Close follow up with a respiratory physician with experience in the treatment of pulmonary arterial hypertension is mandatory. Immunosuppressive agents, alone or in combination with vasodilators, may be used in refractory cases.[25] [26] Combination therapy with corticosteroids and cyclophosphamide is somtimes effective.[25] 22 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Management Interstitial lung disease There are no randomised controlled trials addressing the optimum timing or regimen for the treatment of interstitial lung disease (ILD) in overlap syndromes, so therapy is based on those agents known to be effective for scleroderma or myositis-associated ILD. High-dose corticosteroid therapy with prednisolone is started, with the subsequent introduction of mycophenolate, which has been shown to be better tolerated and with less toxicity than the alternative, cyclophosphamide.[27] [28] Among patients with antisynthetase syndrome and interstitial lung disease, prednisolone is the most frequently used therapy, although additional immunsuppressive agents are increasingly being used. Treatment algorithm overview Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 23 Overlap syndromes Management M A N A G E M E N T Ongoing ( summary ) all patients 1st supportive care + lifestyle changes with arthralgias and arthritis plus non-steroidal anti-inflammatory drug adjunct hydroxychloroquine adjunct oral corticosteroid adjunct methotrexate + folic acid with Raynaud's phenomenon plus avoidance of trigger factors plus pharmacotherapy with puffy hands plus non-steroidal anti-inflammatory drug adjunct oral corticosteroid with myositis plus oral corticosteroid adjunct alternative immunosuppressant with GORD plus proton-pump inhibitor plus dietary modification with sicca symptoms plus artificial tears/saliva plus cholinergic drug adjunct hydroxychloroquine with neuropathy plus gabapentin or amitriptyline adjunct immunosuppressant adjunct transcutaneous electrical nerve stimulation with serositis plus non-steroidal anti-inflammatory drug or oral corticosteroid with pulmonary hypertension plus pulmonary vasodilator adjunct immunosuppressant with interstitial lung disease plus immunosuppressant 24 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Management Treatment algorithm Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 25 Overlap syndromes Management M A N A G E M E N T Ongoing all patients all patients 1st supportive care + lifestyle changes » It is essential that all patients be referred to a rheumatologist with experience in managing these conditions. Any patient with evidence of lung disease should be referred to a consultant to evaluate for progressive lung disease. » Patients should be counselled regarding lifestyle changes. These may include patient education to encourage the patient to take responsibility for his/her disease management; advice regarding how to maintain an ideal body weight for their height; reduction of salt intake in the presence of hypertension due to renal disease; and exercise guidelines to maintain optimum cardiovascular fitness. » Patients who smoke should be encouraged to stop. with arthralgias and arthritis plus non-steroidal anti-inflammatory drug Treatment recommended for ALL patients in selected patient group Primary options » naproxen: 500 mg orally twice daily when required, maximum 1500 mg/day OR » ibuprofen: 300-400 mg orally every 6-8 hours when required, maximum 2400 mg/day » Typical small-joint arthralgias of mixed connective tissue disease and other overlap syndromes are managed with the use of nonsteroidal anti-inflammatory drugs at the lowest effective doses, with attention paid to monitoring for, and prevention of, cardiovascular, renal, and gastrointestinal toxicities. adjunct hydroxychloroquine Treatment recommended for SOME patients in selected patient group Primary options » hydroxychloroquine: 6.5 mg/kg/day orally given in 1-2 divided doses Dose refers to hydroxychloroquine sulfate salt. » If non-steroidal anti-inflammatory drugs are found to be inadequate or ineffective, consider 26 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Management Ongoing adding antimalarial medications, particularly hydroxychloroquine, which has been shown to be effective in systemic lupus erythematosus and may be used in mixed connective tissue disease. » Patients require regular ophthalmological screening for retinopathy. adjunct oral corticosteroid Treatment recommended for SOME patients in selected patient group Primary options » prednisolone: 5-10 mg orally once daily » In patients who develop frank synovitis, short courses of corticosteroids are helpful. adjunct methotrexate + folic acid Treatment recommended for SOME patients in selected patient group Primary options » methotrexate: 7.5 mg orally once weekly on the same day of each week, increase by 2.5 mg/week increments every 2 weeks according to response, maximum 25 mg/ week -and- » folic acid: 1 mg orally once daily » If arthritis is resistant to corticosteroids, synovitis is not adequately controlled on low doses of corticosteroids, or patient has deforming or erosive disease, addition of methotrexate is useful. » Should not be used in patients with renal failure, and should be used cautiously in those with interstitial lung disease. » Folate supplementation should be given simultaneously, and close attention paid to advice on contraception and reproductive health. Monitoring of FBC, renal function, and liver enzymes is recommended. with Raynaud's phenomenon plus avoidance of trigger factors Treatment recommended for ALL patients in selected patient group » Lifestyle modifications including avoidance of cold or sudden changes in temperature should be advised. » Smoking cessation is essential. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 27 Overlap syndromes Management M A N A G E M E N T Ongoing plus pharmacotherapy Treatment recommended for ALL patients in selected patient group Primary options » nifedipine: 30 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 90 mg/day OR » prazosin: 1 mg orally twice daily Secondary options » fluoxetine: 20 mg orally once daily OR » sildenafil: 50 mg orally twice daily Tertiary options » bosentan: 62.5 mg orally twice daily for 4 weeks, followed by 125 mg orally twice daily » Treatment is important to prevent progression to digital ulceration. » First-line pharmacological interventions include calcium-channel blockers such as nifedipine. These agents are useful at decreasing the frequency and severity of attacks.[9] [10] In patients with Raynaud's phenomenon secondary to scleroderma, alpha-1-blocking agents (e.g., prazosin) have been found to be useful. » Second-line therapies include fluoxetine and the phosphodiesterase-5 inhibitor sildenafil, which has been shown to be effective and may be considered in patients who fail to respond to calcium-channel blockers.[13] » In more severe cases associated with systemic sclerosis, parenteral prostacyclin analogues have been tried with some success. The endothelin receptor antagonist bosentan has been shown to reduce the incidence of new ischaemic ulcers.[14] These agents should only be used under the supervision of physicians familiar with their use, as side effects are common. with puffy hands plus non-steroidal anti-inflammatory drug Treatment recommended for ALL patients in selected patient group 28 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Management Ongoing Primary options » naproxen: 500 mg orally twice daily when required, maximum 1500 mg/day OR » ibuprofen: 300-400 mg orally every 6-8 hours when required, maximum 2400 mg/day » Non-steroidal anti-inflammatory drugs may improve symptoms. These should be used at the lowest effective doses, with attention paid to monitoring for, and prevention of, cardiovascular, renal and gastrointestinal toxicities. adjunct oral corticosteroid Treatment recommended for SOME patients in selected patient group Primary options » prednisolone: 5-10 mg orally once daily » In patients unresponsive to non-steroidal antiinflammatory drugs, low-dose corticosteroids may improve symptoms. with myositis plus oral corticosteroid Treatment recommended for ALL patients in selected patient group Primary options » prednisolone: 0.5 to 1 mg/kg/day orally for 4-6 weeks, then taper dose gradually according to response » Corticosteroid therapy is the mainstay of management of myositis in mixed connective tissue disease and those overlap syndromes in which inflammatory myopathy is a prominent component.[15] » Prednisolone, with slow tapering after 4-6 weeks if disease is controlled, is the drug of choice. adjunct alternative immunosuppressant Treatment recommended for SOME patients in selected patient group Primary options » methotrexate: 7.5 mg orally once weekly on the same day of each week initially, increase by 5 mg/week increments every 2 weeks M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 29 Overlap syndromes Management M A N A G E M E N T Ongoing according to response, maximum 25 mg/ week -and- » folic acid: 1 mg orally daily OR » azathioprine: 50 mg orally once daily initially, increase according to response every 4-6 weeks, maximum 2.5 mg/kg/day Secondary options » normal immunoglobulin human: 400 mg/kg/ day intravenously for 5 days each month » For those patients who do not remit with corticosteroid therapy, or in those who continue to require unacceptably high doses for disease control, addition of methotrexate or azathioprine may provide a corticosteroid-sparing effect. » If methotrexate is used, folate supplementation should be given simultaneously, and close attention paid to advice on contraception and reproductive health. Monitoring of FBC, renal function, and liver enzymes is recommended. » Patients with low thiopurine methyltransferase (TPMT) activity are at increased risk of myelosuppression with conventional doses of azathioprine; patients may be tested for TPMT deficiency prior to initiation. » High-dose intravenous immunoglobulin has been used in resistant cases, with reports of efficacy in polymyositis and dermatomyositis. with GORD plus proton-pump inhibitor Treatment recommended for ALL patients in selected patient group Primary options » esomeprazole: 20 mg orally once or twice daily OR » omeprazole: 20 mg orally once or twice daily OR » lansoprazole: 30 mg orally once or twice daily 30 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Management Ongoing » Proton-pump inhibitors are the mainstay of management. Treatment is usually lifelong. plus dietary modification Treatment recommended for ALL patients in selected patient group » Dietary lifestyle measures are recommended. » Patients should be counselled to avoid eating food 2-3 hours before bedtime, and to avoid drinking caffeinated and carbonated beverages. with sicca symptoms plus artificial tears/saliva Treatment recommended for ALL patients in selected patient group » Artificial tears are helpful as initial therapy. Artificial saliva preparations may be required for those with dry mouth. » Close ophthalmological and dental followup are essential to prevention of complications related to decreased tear and saliva pools. plus cholinergic drug Treatment recommended for ALL patients in selected patient group Primary options » pilocarpine: 5 mg orally four times daily OR » cevimeline: 30 mg orally three times daily » Parasympathomimetic agents such as pilocarpine and cevimeline may improve tear and saliva flow. adjunct hydroxychloroquine Treatment recommended for SOME patients in selected patient group Primary options » hydroxychloroquine: 6.5 mg/kg/day orally given in 1-2 divided doses Dose refers to hydroxychloroquine sulfate salt. » A retrospective, open-label study found benefit from hydroxychloroquine in patients with primary Sjogren's syndrome, and this may also be of benefit in patients with sicca symptoms as part of their overlap syndrome.[16] M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 31 Overlap syndromes Management M A N A G E M E N T Ongoing » If given, regular ophthalmological screening for retinopathy should be done. with neuropathy plus gabapentin or amitriptyline Treatment recommended for ALL patients in selected patient group Primary options » gabapentin: 300-1800 mg/day orally daily given in 3 divided doses OR » amitriptyline: 25-50 mg orally once daily at night » For sensory neuropathy, standard treatment with gabapentin or amitriptyline may be used as first-line therapy. adjunct immunosuppressant Treatment recommended for SOME patients in selected patient group Primary options » prednisolone: 0.5 to 1 mg/kg/day orally for 4-6 weeks, then taper dose gradually according to response Secondary options » cyclophosphamide: consult consultant for guidance on dose » In more severe cases with motor neuropathy or transverse myelitis, immunosuppressive therapy with high-dose corticosteroids and, rarely, cytotoxic agents may be required. Of the cytotoxic drugs, cyclophosphamide has been the most frequently employed agent; the roles of less toxic regimens using mycophenolate are still under investigation. All drugs should only be used under the care of an experienced rheumatologist. adjunct transcutaneous electrical nerve stimulation Treatment recommended for SOME patients in selected patient group » Has been found to be effective and may be added on to existing therapy or used alone. with serositis plus non-steroidal anti-inflammatory drug or oral corticosteroid Treatment recommended for ALL patients in selected patient group 32 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Management Ongoing Primary options » naproxen: 500 mg orally twice daily when required, maximum 1500 mg/day OR » ibuprofen: 300-400 mg orally every 6-8 hours when required, maximum 2400 mg/day Secondary options » prednisolone: 0.5 to 1 mg/kg/day orally for 4-6 weeks, then taper dose gradually according to response » Mild serositis may respond to non-steroidal anti-inflammatory drugs. » Corticosteroids are the mainstay of management for more severe disease. » Depending on the severity of the serosal involvement, moderate or high doses of prednisolone may be required; the response is generally good.[17] with pulmonary hypertension plus pulmonary vasodilator Treatment recommended for ALL patients in selected patient group Primary options » nifedipine: 30-60 mg orally (extendedrelease) once daily, increase according to response, maximum 90-120 mg/day depending on formulation used Secondary options » sildenafil: 20 mg orally three times daily OR » bosentan: 62.5 mg orally twice daily for 4 weeks, then increase to 125 mg twice daily Tertiary options » epoprostenol: consult consultant for guidance on dose OR » iloprost inhaled: consult consultant for guidance on dose M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 33 Overlap syndromes Management M A N A G E M E N T Ongoing OR » treprostinil: consult consultant for guidance on dose » Treatment should be guided by results of rightheart catheterisation, including documentation of vasomotor responsiveness to vasodilators. » If responsive, patients should be treated with optimally tolerated doses of calcium-channel blockers as first-line therapy. » Non-responders to vasoreactivity testing and patients without sustained response to calciumchannel blockers should be started on another pulmonary arterial hypertension-specific therapy. » The oral phosphodiesterase-5 inhibitor sildenafil has been shown to improve symptoms, functional capacity, and haemodynamics when used in patients with primary pulmonary hypertension and in pulmonary hypertension secondary to rheumatic diseases.[19] » The endothelin receptor antagonist bosentan has also been shown to improve symptoms and functional capacity, but its long-term use and effects on pulmonary haemodynamics are less certain.[20] [21] It should be used only by physicians experienced in its use, as very close monitoring for adverse effects, including hepatotoxicity, is needed. » The prostacyclin analogues epoprostenol, inhaled iloprost, and treprostinil have been tried singly and in combination regimens.[22] [23] [24] Close follow up with a respiratory physician with experience in the treatment of pulmonary arterial hypertension is mandatory. adjunct immunosuppressant Treatment recommended for SOME patients in selected patient group Primary options » methylprednisolone: 500 mg intravenously once daily for 3 days, followed by oral prednisolone -and- » prednisolone: 0.5 to 1 mg/kg/day orally following methylprednisolone, maximum 80 mg/day -and- » cyclophosphamide: 600 mg/square metre of body surface area intravenously once monthly 34 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Management Ongoing » Immunosuppressive agents, alone or in combination with vasodilators, may be used in refractory cases.[25] [26] » Combination therapy with corticosteroids and cyclophosphamide is effective.[25] with interstitial lung disease plus immunosuppressant Treatment recommended for ALL patients in selected patient group Primary options Overlap connective tissue disease » prednisolone: 1-2 mg/kg/day orally --AND-- » mycophenolate mofetil: 1 to 1.5 g orally twice daily -or- » cyclophosphamide: 1-2 mg/kg/day orally; or 600 mg/square metre of body surface area intravenously once monthly OR Antisynthetase syndrome » prednisolone: 1 mg/kg/day orally, taper dose according to response » Immunosuppressive treatment for interstitial lung disease in the overlap syndromes is similar to that used in systemic sclerosis and systemic lupus erythematosus. » In patients with mixed connective tissue disease, high-dose corticosteroid therapy with prednisolone is started, with the subsequent introduction of either mycophenoate or monthly intravenous or daily oral cyclophosphamide. » Careful monitoring for side effects, including cytopenia, haematuria, and the subsequent development of malignancy, is indicated. Advice on contraception and reproductive health should be given. » Among patients with antisynthetase syndrome and interstitial lung disease involvement, corticosteroids have been the most frequently used therapy, although additional immunosuppressive agents are increasingly being used. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 35 Overlap syndromes Management M A N A G E M E N T Emerging TNF-alpha blockers Experience with TNF-alpha blockers in arthritis and arthralgias is very limited. They should be administered only with great caution, given that these agents have been known to induce systemic lupus erythematosuslike symptoms. Immunosuppressants There are only anecdotal data on the use of newer immunosuppressive agents such as mycophenolate and the B-cell-depleting agent rituximab in myositis. Among patients with antisynthetase syndrome and interstitial lung disease involvement, case reports and small case series exist of the utility of other immunosuppressive therapies,[29] including mycophenolate, ciclosporin (cyclosporine), cyclophosphamide, and tacrolimus, but there is no well-defined treatment approach. Rituximab is an emerging agent that has shown benefit in the treatment of systemic sclerosis related interstitial lung disease, but its place remains to be clarified by larger randomised controlled trials.[30] Secondary prevention Smoking cessation, and avoidance of injury and other vasospastic triggers (cold and emotional stress), are important for prevention of digital ulcers in people with Raynaud's phenomenon. For patients with GORD, the following should be avoided: eating within several hours of bedtime, recumbency within several hours after meals, and tight-fitting clothes. Patient discussions Avoidance of exposure to cold may help to reduce the incidence of episodes of Raynaud's phenomenon. For patients with GORD, the following should be avoided: eating within several hours of bedtime, recumbency within several hours after meals, and tight-fitting clothes. 36 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Follow up Monitoring Monitoring The frequency and specifics of patient follow-up depend on the type and severity of the clinical manifestations, and the need to monitor for medication side effects. Yearly pulmonary function tests (with spirometry, lung volumes, and diffusion capacity) and echocardiography should be done for surveillance in all patients with mixed connective tissue disease (MCTD), to identify and assess for the development of pulmonary hypertension. Serological tests are not generally used to monitor disease activity in MCTD. However, they may be of value in the following circumstances: • In patients who have anti-double-stranded DNA titres, increasing titres may herald a disease flare.[33] • In patients with antisynthetase antibodies, titres may fluctuate during the course of the disease; their disappearance suggests a good prognosis. Monitoring for corticosteroid treatment side effects • Bone density is measured at baseline. Calcium and vitamin D supplementation is recommended for all patients on supraphysiological doses of glucocorticoids. Specific therapies for osteoporosis should be considered when the estimated risk of fracture is high. • Initial fasting blood glucose and regular blood glucose levels are recommended in chronic corticosteroid treatment. • H2 antagonists or proton pump inhibitors may be prescribed if the patient develops gastrointestinal discomfort or has a history of peptic ulcer disease. • BP is measured on each visit, as accelerated hypertension and renal failure could occur, particularly in patients with scleroderma or MCTD and overlap syndrome. • Eye examinations are performed periodically to check for cataracts and glaucoma. • Serum potassium levels are monitored. Potassium supplementation may be required if the patient becomes hypokalaemic. Monitoring for immunosuppressant treatment side effects • Methotrexate: FBC, serum creatinine and LFTs including gamma-GT are checked every 1 to 2 weeks until the dose is stable, then every 8 to 12 weeks. • Azathioprine: FBC and LFTs including gamma-GT are checked every 1 to 2 weeks until the dose is stable, then every 8 to 12 weeks. • Hydroxychloroquine: ophthalmological evaluation for the development of retinopathy should be done at a frequency consistent with local practice. • Intravenous immunoglobulin (IVIG): Measurement of baseline renal function is recommended because of risk of IVIG-induced renal failure. Serum immunoglobulin (IgA) levels should be checked prior to first administration as anaphylaxis may occur in IgA deficient patients. F O L L O W U P This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 37 Overlap syndromes Follow up F O L L O W U P Complications Complications Timeframe Likelihood osteoporosis long term high All patients on supraphysiological doses of corticosteroids are at increased risk for development of osteoporosis and should be evaluated for other risk factors. Supplemental calcium and vitamin D, and consideration of bisphosphonate therapy, may be appropriate. azathioprine toxicity variable high Cytopenias occur commonly, and a FBC should be obtained 2 weeks after a dose increase, and then every 4 to 6 weeks when the dose is stable. Drug-induced hepatitis may also occur, and monitoring of liver enzymes every 2 months is reasonable. In terms of infertility, oligospermia may be seen in men and is generally reversible on discontinuation of therapy. cyclophosphamide toxicity variable high Cytopenias are common, and a FBC should be obtained every 2 weeks while on oral cyclophosphamide; a decrease in the total WBC count to <3.5 should prompt dose reduction. Renal function should be monitored monthly, as a decline in renal function warrants dose adjustment. Urinalysis for the detection of haematuria should be done monthly. Metabolites of cyclophosphamide may cause cystitis: patients should be encouraged to maintain adequate fluid intake of at least 2 L/day. Because of teratogenesis, patients must be reminded of, and counselled on, the importance of effective contraception. Because of the risk for infertility, sperm banking and hormonal manipulation to preserve ovarian function should be discussed prior to initiation of therapy. Bladder malignancies may develop years after therapy has been completed, and early referral for cystoscopy should be sought for persistent haematuria. Patients on cyclophosphamide are at increased risk of opportunistic infections, including Pneumocystis jirovecii . All patients should be placed on prophylactic therapy and have their vaccinations updated prior to initiation of therapy and should not receive live vaccines while being treated with immunosuppressive regimens. methotrexate toxicity variable low The American College of Rheumatology guidelines for monitoring methotrexate toxicity (based on use of methotrexate in the treatment for rheumatoid arthritis) recommend baseline determination of FBC, renal function, liver enzymes, albumin, and hepatitis B and C serologies prior to initiation of methotrexate use.[31] 38 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes Follow up Complications Timeframe Likelihood Liver enzymes and albumin should be monitored every 4 to 8 weeks, and referral for liver biopsy done if persistent elevations of the AST are noted or if albumin falls below the normal range. A baseline CXR is indicated. The British Association of Dermatologists recommend checking varicella zoster virus (VZV) serology in patients without a history of chickenpox. VZV vaccination is considered where serology is negative.[32] Referral for liver biopsy prior to therapy should be considered in patients who have a history of significant alcohol intake; have persistent baseline abnormalities of liver transaminases; or are positive for chronic hepatitis B or C serology. Methotrexate is not recommended for use in women of childbearing age. Alcohol should not be consumed while taking methotrexate. Administration of folic acid (1 mg/day) may decrease the incidence of side effects and is recommended for all patients. Prognosis Mixed connective tissue disease (MCTD) and the other overlap syndromes are chronic diseases that have highly variable courses. The overall outlook is defined by the severity of individual organ involvement. Some patients will have minor symptoms easily controlled with few pharmacological interventions. Others will have progressive internal organ dysfunction, with the development of life-threatening complications that may or may not be responsive to immunosuppressive therapy. In these patients the onset of pulmonary hypertension, cardiac involvement, or interstitial lung disease each portends a poorer prognosis, and they are indications for aggressive immunosuppressive therapy. Pulmonary hypertension is the commonest disease-related cause of death in patients with MCTD. Although overall prognosis is largely determined by the internal organ involvement and the response to treatment, morbidity due to complications of therapy takes on progressively more importance as the need for aggressive immunosuppressive regimens increases. Patients with antisynthetase syndrome are generally considered to have a poor prognosis, with mortality 3 times greater than that of myositis without antisynthetase syndrome. F O L L O W U P This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 39 Overlap syndromes Guidelines G UID E LIN E S Treatment guidelines United Kingdom Guidelines for the safe and effective prescribing of methotrexate for skin disease (https://www.bad.org.uk/healthcare-professionals/clinical-standards/ clinical-guidelines) Published by: British Association of Dermatologists Last published: 2016 40 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes References Key articles • Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 1999;42:899-909. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/10323445?tool=bestpractice.bmj.com) • Spath M, Schroder M, Schlotter-Weigel B, et al. The long-term outcome of anti-Jo-1-positive inflammatory myopathies. J Neurol. 2004;251:859-864. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/15258790?tool=bestpractice.bmj.com) • Thompson AE, Shea B, Welch V, et al. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum. 2001;44:1841-1847. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/11508437?tool=bestpractice.bmj.com) References 1. Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 1999;42:899-909. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/10323445?tool=bestpractice.bmj.com) 2. Spath M, Schroder M, Schlotter-Weigel B, et al. The long-term outcome of anti-Jo-1-positive inflammatory myopathies. J Neurol. 2004;251:859-864. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/15258790?tool=bestpractice.bmj.com) 3. Hirakata M, Nagai S. Interstitial lung disease in polymyositis and dermatomyositis. Curr Opin Rheumatol. 2000;12:501-508. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11092199? tool=bestpractice.bmj.com) 4. Cortes S, Clemente-Coelho P. Nailfold capillaroscopy in the evaluation of Raynaud's phenomenon and undifferentiated connective tissue disease [in Portuguese]. Acta Reumatol Port. 2008;33:203-209. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18604184?tool=bestpractice.bmj.com) 5. Bodolay E, Csiki Z, Szekanecz Z, et al. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol. 2003;21:313-320. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12846049?tool=bestpractice.bmj.com) 6. Imbert-Masseau A, Hamidou M, Agard C, et al. Antisynthetase syndrome. Joint Bone Spine. 2003;70:161-168. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12814758? tool=bestpractice.bmj.com) 7. Alarcon-Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed connective tissue disease and anti-nuclear antibodies. Amsterdam, the Netherlands: Elsevier; 1987:33-40. R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 41 Overlap syndromes References R E F E R E N C E S 8. Kasukawa R, Tojo T, Miyawaki S, et al. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed connective tissue disease and antinuclear antibodies. Amsterdam, the Netherlands: Elsevier; 1987:41-47. 9. Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud's phenomenon: a metaanalysis. Rheumatology (Oxford). 2005;44:145-150. Full text (http://rheumatology.oxfordjournals.org/ content/44/2/145.full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15546967? tool=bestpractice.bmj.com) 10. Thompson AE, Shea B, Welch V, et al. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum. 2001;44:1841-1847. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/11508437?tool=bestpractice.bmj.com) 11. Rirash F, Tingey PC, Harding SE, et al. Calcium channel blockers for primary and secondary Raynaud's phenomenon. Cochrane Database Syst Rev. 2017 Dec 13;12:CD000467. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486273) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/29237099?tool=bestpractice.bmj.com) 12. Coleiro B, Marshall SE, Denton CP, et al. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford). 2001 Sep;40(9):1038-43. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11561116?tool=bestpractice.bmj.com) 13. Fries R, Shariat K, von Wilmowsky H, et al. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation. 2005;112:2980-2985. Full text (http://circ.ahajournals.org/content/112/19/2980.full) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/16275885?tool=bestpractice.bmj.com) 14. Korn JH, Mayes M, Matucci-Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004;50:3985-3993. Full text (http://onlinelibrary.wiley.com/doi/10.1002/art.20676/full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15593188?tool=bestpractice.bmj.com) 15. Hall S, Hanrahan P. Muscle involvement of mixed connective tissue disease. Rheum Dis Clin North Am. 2005;31:509-517,vii. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16084322? tool=bestpractice.bmj.com) 16. Fox RI, Dixon R, Guarrasi V, et al. Treatment of primary Sjogren's syndrome with hydroxychloroquine: a retrospective, open-label study. Lupus. 1996;5(suppl 1):S31-S36. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/8803908?tool=bestpractice.bmj.com) 17. Man BL, Mok CC. Serositis related to systemic lupus erythematosus: prevalence and outcome. Lupus. 2005;14:822-826. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16302677? tool=bestpractice.bmj.com) 18. Khanna D, Gladue H, Channick R, et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum. 2013 Dec;65(12):3194-201. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883571) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/24022584?tool=bestpractice.bmj.com) 42 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Overlap syndromes References 19. Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol. 2007;34:2417-2422. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/17985403?tool=bestpractice.bmj.com) 20. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. Full text (http://www.nejm.org/doi/full/10.1056/NEJMoa012212#t=article) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11907289?tool=bestpractice.bmj.com) 21. Marotta H, Montisci R, Tiso F, et al. Two-years therapy with bosentan of pulmonary arterial hypertension related to connective tissue diseases [in Italian]. Reumatismo. 2007;59:299-303. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18157286?tool=bestpractice.bmj.com) 22. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353-359. Full text (http:// erj.ersjournals.com/content/24/3/353.full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15358690? tool=bestpractice.bmj.com) 23. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257-1263. Full text (http://www.atsjournals.org/doi/full/10.1164/rccm.200603-358OC#.UoNu3fnxobA) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/16946127?tool=bestpractice.bmj.com) 24. Channick RN, Olschewski H, Seeger W, et al. Safety and efficacy of inhaled treprostinil as addon therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006;48:1433-1437. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17010807?tool=bestpractice.bmj.com) 25. Sanchez O, Sitbon O, Jaïs X, et al. Immunosuppressive therapy in connective tissue diseasesassociated pulmonary arterial hypertension. Chest. 2006;130:182-189. Full text (http:// journal.publications.chestnet.org/article.aspx?articleid=1084518&issueno=1) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/16840400?tool=bestpractice.bmj.com) 26. Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum. 2008;58:521-531. Full text (http://onlinelibrary.wiley.com/doi/10.1002/art.23303/full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18240255?tool=bestpractice.bmj.com) 27. Tashkin DP, Roth MD, Clements PJ, et al; Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016 Sep;4(9):708-19. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014629/pdf/nihms810304.pdf) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/27469583?tool=bestpractice.bmj.com) 28. Barnes H, Holland AE, Westall GP, et al. Cyclophosphamide for connective tissue diseaseassociated interstitial lung disease. Cochrane Database Syst Rev. 2018 Jan 3;1:CD010908. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491200) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/29297205?tool=bestpractice.bmj.com) 29. Sauty A, Rochat T, Schoch OD, et al. Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodies. Eur Respir J. 1997;10:2907-2912. Full text (http://erj.ersjournals.com/ R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 43 Overlap syndromes References R E F E R E N C E S content/10/12/2907.full.pdf+html) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/9493684? tool=bestpractice.bmj.com) 30. Sircar G, Goswami RP, Sircar D, et al. Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial. Rheumatology (Oxford). 2018 Dec 1;57(12):2106-2113. Full text (https://academic.oup.com/ rheumatology/article/57/12/2106/5060036) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30053212? tool=bestpractice.bmj.com) 31. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 May;64(5):625-39. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081542) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/22473917?tool=bestpractice.bmj.com) 32. Warren RB, Weatherhead SC, Smith CH, et al. British Association of Dermatologists' guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol. 2016 Jul;175(1):23-44. Full text (https://onlinelibrary.wiley.com/doi/full/10.1111/bjd.14816) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/27484275?tool=bestpractice.bmj.com) 33. Linnik MD, Hu JZ, Heilbrunn KR, et al; LJP 394 Investigator Consortium. Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;52:1129-1137. Full text (http://onlinelibrary.wiley.com/ doi/10.1002/art.20980/full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15818711? tool=bestpractice.bmj.com) 44 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 05, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 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Contributors: // Authors: Larry Young, MD Associate Professor of Medicine Division of Rheumatology, Miller School of Medicine, University of Miami, Miami, FL DISCLOSURES: LY has developed educational materials for the Duke University workshop on evidencebased practice and received sponsored travel and hotel accommodations as one of the workshop codirectors. Carlos Lozada, MD Associate Professor of Medicine Division of Rheumatology and Immunology, Miller School of Medicine, University of Miami, Miami, FL DISCLOSURES: CL declares that he has no competing interests. // Acknowledgements: Dr Larry Young and Dr Carlos Lozada would like to gratefully acknowledge Dr Robert Hoffman, a previous contributor to this topic. RH has received NIH grants greater than 6 figures USD. RH is the author of some studies referenced in this topic. RH declares that he has no competing interests. // Peer Reviewers: Robert Ortmann, MD Associate Professor and Director Division of Rheumatology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR DISCLOSURES: RO declares that he has no competing interests. Alan Bridges, MD Professor and Vice Chair Department of Medicine, University of Wisconsin Hospital, Madison, WI DISCLOSURES: AB declares that he has no competing interests. Simon Bowman, PhD, FRCP Consultant Rheumatologist and Honorary Senior Clinical Lecturer in Rheumatology Selly Oak Hospital, Birmingham, UK DISCLOSURES: SB declares that he has no competing interests.