Best Practice & Research Clinical Rheumatology 26 (2012) 61–72 Contents lists available at SciVerse ScienceDirect Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh 5 Mixed connective tissue disease: An overview of clinical manifestations, diagnosis and treatment Oscar-Danilo Ortega-Hernandez a, Yehuda Shoenfeld a, b, * a b The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune Diseases, Israel Keywords: Mixed connective tissue disease Raynaud’s phenomenon Erosive arthritis Anti-RNP antibodies Myositis Organ involvement and treatment The most common clinical manifestations of mixed connective disease are Raynaud’s phenomenon, arthralgias, swollen joints, esophageal dysfunction, muscle weakness and ﬁngers sausage-like appearance together with the presence of anti-ribonucleoprotein (RNP) antibodies. However, organ involvement is more extensive than ﬁrst descriptions reported. The disease can be serious with development of pulmonary, kidney, cardiovascular, gastrointestinal and central nervous system manifestations. The worst prognosis and high mortality are associated with the presence of pulmonary disease. Although a different set of clinical criteria have been proposed, there is no consensus about the most accurate. There is no full agreement about treatment and the initial impression of a satisfactory response to low doses of steroids is not always the rule. Herein, we review available evidence to a better approach to all previous topics. Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. Mixed connective tissue disease: from the criticism to the concept Mixed connective tissue disease (MCTD) was ﬁrst described in 1972 as an entity with mixed features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/ DM) and rheumatoid arthritis (RA) together with the presence of high-titre anti-U1small nuclear (sn) anti-ribonucleoprotein (anti-RNP) antibodies [1,2]. The disease has been reported in children and in * Corresponding author. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer 52621, Israel. Tel.: þ972 3 530 8070; fax: þ972 3 535 2855. E-mail address: [email protected] (Y. Shoenfeld). 1521-6942/$ – see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2012.01.009 62 O.-D. Ortega-Hernandez, Y. Shoenfeld / Best Practice & Research Clinical Rheumatology 26 (2012) 61–72 individuals over 80 years and is more prevalent in women in the third decade of life (from 80% to 90%) . Since 1972, the concept of MCTD has been criticised because of the following aspects: (1) the difﬁculty to distinguish MCTD patients from SLE, SSc or RA  and (2) because many patients who have anti-U1-RNP antibodies satisfy the criteria for SLE or SSc during the clinical course, and may experience a shift of symptoms from MCTD to the true features of SLE . However, after years, other studies supported the concept of MCTD as a different disease. In this regard, different set of diagnostic criteria were proposed [5–8]. MCTD has also been associated with HLA class II alleles and such linkage is distinct from that one for SLE, SSc or PM/DM. HLA-DR4, -DR1 and less frequent -DR2 are the main HLAassociated alleles [9,10]. To remark, relevant similar conditions have different HLA-DR associations; SLE is mainly associated with HLA-DR2 and DR3 , whereas SSc shows an association with HLA-DR3 or DR5 [12,13]. PM/DM shows association with HLA-DR3 . A murine model also suggests some genetic linkage, HLA-DR4 transgenic mice C57BL/6-derived mice immunised with UI-70k in combination with complete freund’s adjuvant developed anti-70K autoantibodies and perivascular inﬁltrates resembling histopathological ﬁndings in MCTD . Regarding clinical manifestations, the most common at disease onset are Raynaud’s phenomenon (RP), arthralgias, swollen hands, ﬁngers sausage-like appearance and muscle weakness. They appear in 90% of patients and usually develop insidiously . Asthenia and myalgias are also frequent. However, organ involvement is more extensive than ﬁrst descriptions reported [1,2], and the initial impression of a satisfactory response to low doses of steroids and a favourable prognosis is not the rule. MCTD can be a serious disease with development of pulmonary arterial hypertension (PAH), glomerulonephritis (GNF), vasculitis, gastrointestinal bleeding and severe central nervous involvement, which does not always have a good prognosis. Overview of clinical manifestations MCTD may begin with any clinical manifestations of SLE, SSc, PM or RA, at disease onset or during clinical course. The most common clinical features are polyarthritis, RP, sclerodactyly, swollen hands, muscle disorders and oesophageal dysmotility. Alopecia, malar rash, lymphadenopathy or kidney damage are less common but can be present . Unspeciﬁc constitutional symptoms such as fever, fatigue, arthralgias or myalgias are also common. In general, a broad spectrum of signs and symptoms can be present some of which, we intent to abridge herein. Joint and forearm manifestations Joint involvement varies from minimal arthralgias, arthritis in small or large joints and erosions typical of RA to arthritis mutilans . Although rheumatoid factor can be positive in up to 70% of patients with erosive arthritis , no speciﬁc ﬁndings are found. In general, polyarthralgia is an early and common symptom in MCTD, occurs in approximately 60% of patients and may be accompanied by joint deformities with changes in radiographs [19,20]. In addition, small peritendinous nodules in forearms have also been reported in some patients . Muscle disease Between 80% and 90% of patients develop some muscle involvement. Proximal muscles are the more frequently affected with elevation of creatine kinase. However, it does not present any peculiar pattern different from other connective tissue diseases (CTDs) with muscle involvement. Electromyography is typical of inﬂammatory myopathy, although, focal myositis may also occur. Histological ﬁndings reveal myositis which is reminiscent of patients with PM or SLE [19,22]. In most patients, myositis presents acutely in the setting of general disease activity and may be associated with fever. Nevertheless, patients may also present with a more insidious onset, and persistent myopathy [23,24]. Skin manifestations RP is one of the most consistent features. RP appears in approximately 75–90% of patients and may precede other clinical manifestations in months or years and correlates with vascular disease in O.-D. Ortega-Hernandez, Y. Shoenfeld / Best Practice & Research Clinical Rheumatology 26 (2012) 61–72 63 middle-sized vessels as well . Almost 70% of patients develop swollen hands and sausage-like appearance of the digits. The histological appearance of the skin of the hands is remindful greatly to ﬁndings in SSc . Nailfold capillaroscopy of ﬁngers demonstrates changes that are more evocative of SSc than SLE, but bushy formations seem to be characteristic of MCTD . Dermatomyositis-like rash, orogential ulceration and sicca complex syndrome have also been reported [19,25]. Although uncommon, hypocomplementemic urticarial vasculitis was informed in some patients with MCTD . In general, clinical manifestations such as SLE-like skin rash, oral ulcerations and photosensitivity may also be present [24,27]. Lung manifestations Pulmonary abnormalities are found in up to 85% of patients. Although various abnormalities have been described such as ﬁbrosis, interstitial disease and pulmonary arterial hypertension (PAH), most of them have an asymptomatic course. In prospective studies, it has been found that PAH and congestive heart failures as well as infections are the most common causes of death in those patients. However, the clinical picture is less severe than in other conditions [17,24,28]. In a recent study named the ‘registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL)’, it was found that patients with MCTD with PAH had better haemodynamic and favourable right ventricular echocardiographic ﬁndings but a higher prevalence of pericardial effusions. Additional ﬁndings were higher levels of B-type natriuretic peptide and lower diffusing capacity of carbon monoxide. One-year survival and discharge from hospitalisation were lower in patients with MCTD and PAH when compared to patients with SLE, SSc and RA with PAH . Other common clinical pulmonary manifestations include dyspnea and pleuritic chest pain. Radiographic ﬁndings include interstitial changes, pleural effusions, pneumonic inﬁltrates and pleural thickening [30,31]. Patients can also develop interstitial lung disease, which is usually mild or even asymptomatic. Cases of acute interstitial pneumonia and pulmonary haemorrhage have been reported as well [3,32,33]. Cardiovascular disease Cardiac involvement varies between 11% and 85%, depending on the method used to detect abnormalities and the deﬁnition of cardiac involvement [34,35]. The most frequent manifestation is pericarditis (10–29%), which is usually mild . Myocarditis, conduction disturbances (heart block) and abnormal left ventricular diastolic ﬁlling failure besides mitral valve prolapsed (26%) have also been detected by echocardiography in several patients [34,35]. Vasculopathy in MCTD is usually similar to SSc, and is characterised by a bland intimal proliferation and medial hypertrophy that affects small and medium-sized vessels. Other cardiovascular events, such as stroke, are rarely reported in patients with MCTD . Low levels of vitamin D have been found in patients with MCTD. Among the clinical symptoms, the cardiovascular involvement has showed an inverse correlation with vitamin D status . Gastrointestinal disease Gastrointestinal involvement is common (66–74%) and often represents a major feature of overlap with SSc . Oesophageal dysfunction is the most prevalent gastrointestinal manifestation. It is initially subclinical, and when it is symptomatic, dysphagia the most common symptom . Oesophageal dysmotility and reﬂux disease occur more frequently in patients who have clinical manifestations mostly related to SSc rather than to SLE. However, manometric abnormalities are not related to skin disorders and are less severe than in SSc . Such abnormalities consist of decreased oesophageal sphincter pressure, reduced amplitude of peristalsis in distal oesophagus and, less common, reduced upper sphincter pressure . Other gastrointestinal manifestations that have been described are mesenteric vasculitis, colonic perforation, protein-losing enteropathy, acute pancreatitis, haemoperitoneum, haemobilia, diarrhea and chronic active hepatitis [43–46]. 64 O.-D. Ortega-Hernandez, Y. Shoenfeld / Best Practice & Research Clinical Rheumatology 26 (2012) 61–72 Gastrointestinal abnormalities appear to correlate with the time of disease course but not with its clinical expression . Renal complications Renal involvement is one of the major complications of MCTD. It has been observed in some studies in approximately 25% of patients and it is often asymptomatic . Severe renal disease is rare and the presence of anti-U1-RNP antibodies may be protective against the development of diffuse proliferative glomerulonephritis (GNF) . Although focal or diffuse proliferative GNF can be present, membranous and mesangial GNF are the most common presentation. Immune complex-mediated nephritis has also been reported [49,50]. Interstitial nephropathy or renal vascular disease which is characteristic of SSc is less frequent in MCTD patients [3,24]. By contrast, juvenile MCTD is associated with a higher risk of nephritis than in adults with renal involvement. Hypocomplementemia observed in those patients suggests higher frequency of GNF, including membranous lesions. A more aggressive indication of renal biopsy should be considered in children with MCTD because of the high incidence of non-clinical nephritis . Other patients with MCTD may also develop accelerated hypertension, acute renal insufﬁciency and microangiopathic haemolytic anaemia with similar histopathologyﬁndings to those of scleroderma renal crisis . Haematological manifestations Conceiving haematological manifestations; leucopenia, anaemia of chronic disease, broad-based hypergammaglobulinemia and positive Coomb’s test without haemolysis are the most frequent reported haematological features . Other less common haematological features include thrombocytopenia, thrombotic thrombocytopenic purpura (TTP) and red cell aplasia [53,54]. Although they are not speciﬁc of MCTD, anaemia and leucopenia tend to correlate with disease activity and usually improve with therapies employed to treat other organ manifestations [3,17]. Neurological disease Although the nervous system involvement is less frequent than other organ manifestations, there are an increased number of studies suggesting that prevalence may be greater than reported before [55,56]. The studies show that the most common manifestation of the peripheral nervous system is the trigeminal neuropathy, which may be an early manifestation of an undiagnosed MCTD [55,57]. Headaches and peripheral neuropathies have also been reported but most likely related to a vascular origin [56,58]. Regarding central nervous system manifestations, some patients can develop aseptic meningitis with increased concentrations of interferon (IFN)-gamma, interleukin (IL)-6 and higher titres of anti-U1-RNP antibodies in cerebrospinal ﬂuid (CSF) than in serum. Titres of anti-U1-RNP antibodies in CSF correlate well with disease activity . Sato T, et al.  recently tested the presence of anti-U1-RNP antibodies in both CSF and sera of 24 patients with SLE and four patients with MCTD with neuropsychiatric symptoms. It was found that titres of anti-U1-RNP antibodies in the CSF were useful indicators of central neuropsychiatric manifestations in patients with anti-U1-RNP antibodies . Intrathecal production was predominant in patients with neuropsychiatric symptoms. Otherwise, isolated cases of intracraneal haemorrhage, transverse myelitis, cauda equine syndrome, optic neuropathy and retinal vasculitis have been reported as well [61–65]. Autoantibodies in MCTD The anti-U1-RNP antibodies are the hallmark of the disease. Patients with high titres without any criteria of MCTD or other deﬁned CTD, usually evolve into MCTD over 2 years. A pathogenic role of antiU1-RNP has not been proven, but clinical associations that have been observed in SLE and SSc patients may suggest so [66,67]. Anti-RNP antibodies are directed against the U1-snRNP (one of the major components of the spliceosome), which is associated with three proteins, U1-A, U1-C and U1-70K; all of these autoantigens may be targeted by anti-U1-RNP speciﬁc antibodies [1,17]. Vlachoyiannopoulos O.-D. Ortega-Hernandez, Y. Shoenfeld / Best Practice & Research Clinical Rheumatology 26 (2012) 61–72 65 et al.  described that anti-U1-RNP IgG isotype may be characteristic of MCTD, whereas IgM isotype are more commonly found in SLE patients, although two types can be detected in both diseases. In any case, antigen recognition by anti-U1-RNP antibodies seems to be different between SLE and MCTD. In an epitope mapping study, 94% of the patients who had MCTD, but only 20% of SLE patients, recognised the 35–58 peptide of the U1-A-protein . The targeted region is different and limited to the second of the two RNA-binding domains in SLE patients while antibodies of patients who have MCTD recognise a larger epitope that contains sequences of both RNA-binding domains [4,70]. In most instances, any patient with new onset of MCTD with positive anti-U1-RNP antibodies will present with new-onset RP; polyarticular joint pain with or without frank sinovitis, and swollen, together with puffy hands rater with the typical sclerodactyly and muscle weakness [5,71]. Otherwise, anti-U1-RNP antibodies are not the only antibodies found in the sera of patients with MCTD. Anti-Ro/SS-A, antisingle-stranded DNA (ssDNA) , anti-Sm and anti-double-stranded DNA (dsDNA) antibodies  have also been detected, nevertheless, they are not speciﬁc of MCTD. Antiphospholipid antibodies have been reported in patients with MCTD. Anticardiolipin antibodies (aCL) are present in approximately 15% of patients; however, they are less prevalent than in patients with SLE [73,74]. aCL have been associated with PAH in patients with MCTD but not with thrombotic events or other manifestations of the antiphospholipid syndrome (APS). It might be explained by low titres of IgG antibodies with higher prevalence of IgM isotype when compared to APS patients [73,74]. Additional autoantibodies may be associated with speciﬁc clinical manifestations in patients with MCTD. Recently, autoantibodies to angiotensin-converting enzyme 2 (ACE2) were associated with constrictive vasculopathy, PAH and persistent digital ischaemia in patients with MCTD, SLE and SSc . Consistent with this, immunosuppressive therapy given to one SLE patient with digital necrosis markedly decreased the anti-ACE2 antibody titre and restored serum ACE2 activity, together with a substantial improvement in clinical symptoms . In another study, anti-endothelial cell antibodies (AECA) were more frequently seen in patients with MCTD than in patients with SSc . Although the pathogenic role of AECA in MCTD remains uncertain, serum AECA may constitute a useful marker of endothelial activation and disease activity. How to approach the diagnosis of MCTD? Due to the wide spectrum of clinical ﬁndings in MCTD, the diagnosis is not often easy . Different forms of CTD such as transitory conditions and early phases of deﬁned CTDs, which will become fully deﬁned within a few months or years should be considered in the differential diagnosis . There are also uncompleted forms of deﬁned CTDs, where a diagnosis is possible based on clinical and serological manifestations, but classiﬁcation criteria are not met . Many years ago, a different set of criteria were proposed [5–8] (Table 1). Nowadays, the most common approach for diagnosis in clinical practice requires the serological criteria plus at least three clinical criteria. However, when only hand edema, RP or sausage-like appearance of the digits are present, four clinical criteria should be considered . In this regard, different studies have tested the accuracy of the available clinical criteria to identify patients with MCTD rightly. In one study, Alarcon-Segovia and Cardiel  compared three different set of criteria in a series of 593 patients, including 80 cases of MCTD. Results revealed that criteria by Alarcón-Segovia had 100% sensitivity and with the presence of anti-RNP antibodies, the speciﬁcity raises to 99.6%. Similar ﬁndings were found for Kasukawa criteria, the sensitivity was 96.2% and speciﬁcity was 99.8%. The speciﬁcity for Sharp criteria was 87.7% . This is important to remark that testing of criteria was made internally, so results may be different in a multicentre study. In another study, it was found that the criteria that best identiﬁed patients with MCTD were those proposed by Alarcón-Segovia, with 62.5% sensitivity and 86.2% speciﬁcity, comparable to Kahn’s criteria. The overlap with other CTDs was found in 16% of patients . In a recent study performed by Capelli S. et al. , three different classiﬁcation criteria for MCTD (Kasukawa, Alarcón-Segovia and Sharp) were compared together with deﬁne predictors (clinical features and autoantibodies) of potential evolution towards other CTD. It was found that after a mean of 7.9 years of disease follow-up, 57.9% of patients remained meeting the MCTD-classiﬁcation criteria of Kasukawa; 17.3% evolved into SSc, 9.1% into SLE, 2.5% into RA, 11.5% was reclassiﬁed as affected by UCTD and 1.7% as suffering from overlap syndrome. Kasukawa’s criteria were more sensitive (75%) in comparison to those of Alarcón-Segovia (73%) and Table 1 Criteria proposed to diagnose mixed connective tissue disease. Sharp (1987) Major criteria 1. Myositis 2. Pulmonary involvement: a. Diffuse capacity <70% of normal values b. Pulmonary hypertension c. Proliferative vascular lesions on lung biopsy 3. Raynud’s phenomenon or esophageal hypomotility 4. Swollen hands 5. Anti-ENA > 1:10.000 amd anti-U1 RNP positive and anti-Sm negative. Alarcón-Segovia Serological (1987) Anti-RNP titer > 1:1.600 Kasukawa (1987) Minor criteria 1. Alopecia 2. Leuckoepnia 3. Anemia 4. Pleuritis 5. Pericarditis 6. Arthritis 7. Trigeminal neuropathy 8. Malar rash 9. Thrombocytopenia 10. Mild myositis 11. History of swollen hands. Requirements for diagnosis Sensitivity At least four major criteria S:42% plus anti-U1-RNP titer of  at least 1:4000. Exclusion criteria: positivity for anti-Sm antibody. Two major criteria from among criteria 1, 2 and 3 plus 2 minor criteria plus anti-U1-RNP titer of at least 1:1000. Speciﬁcity Ref. 87.7% [1,5]  Clinical Requirements for diagnosis Sensitivity Speciﬁcity Ref. Edema in hands, synovitis, myositis, raynaud’s phenomenon, acrosclerosis. Mixed Symptoms Serological criteria plus at least three clinical criteria, included either synovitis or myositis. 62.5%  86.2%  Requirements for diagnosis At least 1 of 2 common symptoms plus positive for anti-RNP plus 1 more of the mixed symptoms in at least 2 of the 3 disease categories. Serological 1. SLE-like symptoms: a. Polyarthritis b. Lymphadenopathy c. Facial erythema d. Pericarditis or Pleuritis e. Leukothrombocytopenia. 2. SSc-like ﬁndings: a. Sclerodactyly b. Pulmonary ﬁbrosis, restrictive changes of lung, or reduced diffusion capacity c. Hypomotility or dilatation of esophagus. 3. PM-like ﬁndings: a. Muscle weakness b. Eleveated serum levels of muscle enzymes (CPK) c. Myogenic pattern on EMG Clinical criteria Sensitivity/ Speciﬁcity Ref. speciﬁcity 99.8%  S:75%   Presence of high titer anti-RNP corresponding to speckled ANA at titer 1:2000 a. Raynauds phenomenon b. synovitis c. myositis d. swollen ﬁngers Common symptoms 1.Raynaud’s phenomenon 2.Swollen ﬁngers or hands Anti-RNP antibody positive Kahn (1991) Requirements for diagnosis Serological criteria plus Raynaud’s phenomenon and at least two of the three following signs (synovitis, myositis and swollen ﬁngers).  Sensitivity Speciﬁcity Ref. 63%  86. %   ENA: extractable nuclear antigen, SnRNP: small nuclear RNP, SLE: systemic lupus erythematosus, SSc: systemic sclerosis, PM: polymyositis, CPK: creatine phosphokinase, EMG: electromyogram. O.-D. Ortega-Hernandez, Y. Shoenfeld / Best Practice & Research Clinical Rheumatology 26 (2012) 61–72 67 Sharp criteria (42%) (Table 1) . In summary, the concordance between serologic features and clinical ﬁndings together with close clinical follow-up is still being the elementary strategy to approach the diagnosis of MCTD. Overview of treatment Patients diagnosed of MCTD were initially described as having a good prognosis [1,2], being extremely responsive to corticosteroid therapy. However, subsequent long-term studies have revealed that not all patients have a benign clinical course and that not all clinical manifestations are responsive to steroids [3,23,24,27,82]. Some patients may have mild self-limited disease, whereas others may develop severe major organ involvement with life-threatening manifestations . Unfortunately, no controlled clinical trials have been performed, so treatment clues must rely largely upon the conventional therapies that are used to treat similar clinical manifestations in other rheumatic diseases such as SLE, SSc and PM. [28,83]. In any case, therapy should be individualised for each patient to address the speciﬁc organs involved and the severity of underlying disease activity. Inﬂammatory manifestations such as fever, serositis, myositis, arthritis and skin rash usually respond to steroid treatment, whereas clinical sclerodermatous manifestations such as sclerodactyly, moderate oesophagueal disease, RP, sclerodermatous bowel disease and pulmonary interstitial disease more often require cytotoxic immunosuppressive treatment . In general, corticosteroids (prednisone and methylprednisolone) and cytotoxic agents, most often cyclophosphamide, are the most frequently employed immunosuppressants. Antimalarials (hydroxychloroquine), methotrexate and different types of vasodilators have also been used with varying degrees of success . Approach for speciﬁc organ involvement is described below. Constitutional symptoms Fever, fatigue, unspeciﬁc arthralgias or myalgias usually respond to non-steroidal anti-inﬂammatory drugs (NSAIDs), hydroxychloroquine or low-dose of prednisone, it depends on the severity. The possibility of ﬁbromyalgia or reactive depression should always be considered and treated optimally [16,23]. However, when a patient debuts with fever, careful search of occult infection or neoplasm should also be included. Joint involvement Continuous evaluation of joint symptoms should be performed. All patients who have arthritis should have baseline radiographs to determine if erosive changes are present. Most of the mild joint involvement has been treated with NSAIDs, hydroxychloroquine and/or oral prednisone with good response [16,17,27]. For more severe forms, methotrexate has been reported to be indicated . If methotrexate is contraindicated, other disease-modifying agents used in RA, such as leﬂunomide or azathioprine, may be considered. Anti-tumour necrosis factor (TNF) inhibitors are not recommended and if needed, patients must be followed carefully for the development of SLE-like syndrome . Muscle disease Most of patients with acute onset of severe myositis, often accompanied by fever, respond to high doses of corticosteroids [24,27]. Some reports have suggested a more favourable prognosis for muscle disease in MCTD with less steroid requirements [23,24]. Myalgias in the absence of myositis can be treated with NSAIDs, hydroxycloroquine and/or low-dose prednisone. Otherwise, SLE-like skin rash, oral ulcerations and photosensitivity have been treated effectively with topical steroids, prednisone and/or hydroxycloroquine [16,17,27]. Immunosupressants such as cyclophosphamide or cyclosporine might be considered for more severe cases. Intravenous immunoglobulin (IVIG) may constitute another option for refractory symptoms. The effects of IVIG are beneﬁcial, but do not last very long. Repeat infusions every 6–8 weeks are often enough if it is necessary. 68 O.-D. Ortega-Hernandez, Y. Shoenfeld / Best Practice & Research Clinical Rheumatology 26 (2012) 61–72 Sclerodermatous involvement Sclerodermatous-like skin manifestations are often responsive to steroid therapy. RP in MCTD usually responds to conventional vasodilator therapies such as calcium channel blockers together with preventive measures like avoidance of cold temperatures and other triggering factors such as smoking, and sympathomimetic agents. The use of warm and protection techniques of ﬁngers are also beneﬁcial. In recent years, therapy with prostaglandin-analogues was considered to treat severe ischaemic digital lesions . However, current strategies include Bosentan (a dual endothelin receptor antagonist) as the recommended treatment of RP as well as for the prevention of new digital ulcers especially in patients who have SSc . Prazocin, losartan or pentoxifylline may cause modest improvement of vascular symptoms in some patients. There is a report of successful treatment of severe, refractory RP with rituximab (anti-CD20) (in combination with methylprednisolone, cyclophosphamide and iloprost, a prostacyclin analogue), in a patient with MCTD . Lung involvement Regarding treatment of patients with PAH, recent advances have expanded the therapeutic options. First, an early detection is mandatory, all patients with MCTD must undergo screening echocardiography and high-resolution computed tomography at the time of diagnosis . Mild cases must be followed with serial testing monitoring for any signs of progression. Traditional regimen of calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, immunosuppression and conventional heart failure therapies should be considered [90,91]. Currently, prostacyclin analogues (Treprostinil) represent a useful tool for its treatment. Treatment with Treprostinil has demonstrated to improved exercise capacity, symptoms of PAH and haemodynamics in patients with moderate to severe PAH. In patients requiring combination therapy, the addition of oral Bosentan to Treprostinil-based therapy is well tolerated, and associated with further clinical improvements [90–93]. Conceiving other pulmonary manifestations, mild cases with pleurisy usually respond to NSAIDs and if symptoms persist, varying doses of corticosteroids are often useful. In some other patients, pleurisy is self-limited and resolve without treatment. Immunosuppressive agents are rarely indicated to treat them [30,31]. In any case, the possibility of infection and thromboembolic events must always be excluded. Cardiovascular disease Concerning cardiovascular involvement, pericarditis usually responds to NSAIDs and/or varying doses of corticosteroids depending on the severity. Massive pericardial effusion with cardiac tamponade rarely occurs and it may need surgical drainage. It depends of the severity. Moderate to severe myocarditis should be treated with high-dose steroid therapy together with common therapy employed to treat congestive heart failure if it is present. Patients with myocarditis often require additional therapies with azathioprine, cyclophosphamide or IVIG with variable rates of response [36,94]. Although uncommon, hypocomplementemic urticarial vasculitis has also been reported in some patients, and usually responds to hydroxychloroquine after a period of corticosteroid dependence . The ofﬁcial European League against Rheumatism (EULAR) recommendations on the assessment and management of cardiovascular disease in CTDs are to be developed soon . Gastrointestinal involvement Gastrointestinal disease in MCTD can be treated following common recommendations to treat similar disorders such as SSc. In any case, the ﬁrst-line therapy is the conventional treatment with proton-pump inhibitors, H2-receptor antagonists and lifestyle modiﬁcations, together with oesophageal PH monitoring in patients with persistent reﬂux symptoms. However, there is one remarkable difference when treating oesophageal dysfunction in patients with MCTD . In contrast to SSc, it usually improves with corticosteroid therapy showing a signiﬁcant change in lower oesophageal pressure and a trend to ameliorate peristaltic pressures in the oesophagus body [39,40]. Screening for Barrett’s oesophagus is also recommended . O.-D. Ortega-Hernandez, Y. Shoenfeld / Best Practice & Research Clinical Rheumatology 26 (2012) 61–72 69 Renal impairment As previously mentioned, renal involvement can be asymptomatic and although, nephrotic syndrome can develop, this may respond to high-dose of corticosteroid therapy. Approximately, 70% of nephropathy episodes resolved or improve signiﬁcantly , with a few percentage of progression to renal failure [47,96]. If a patient presents SSc-like renal crisis, treatment with ACE inhibitors as well as intravenous prostacyclin (Epoprostenol) are indicated. They are believed to improve microvascular lesions without precipitating hypotension, and should be administered at the onset of hypertensive renal crisis. The combined therapy may be a more effective treatment for this complication. Short-term haemodialysis can be started if necessary, and continuous peritoneal dialysis often works well if longterm renal replacement is needed . Neurological disease Although nervous system involvement can be serious and sometimes fatal, it is potentially treatable. Unfortunately, there is a lack of randomised clinical trials in MCTD, so clinical trials performed for SLE patients and isolated observations provide the main evidence [97,98]. In general, to treat nervous system involvement, corticosteroids are used in low-dose oral, high-dose oral or high-dose intravenous regimens according to the severity of potential damage. Therapeutic efforts to treat major intracranial manifestations in MCTD largely fall into three categories: stroke prevention, immunosuppression and symptomatic treatment if it is necessary . Trigeminal neuropathy (the most common neurological symptom) and peripheral neuropathies are less responsive to treatment; however, attempts with intensive traditional symptomatic treatment are recommended [55,57]. We are aware of only a single randomised trial assessing steroids and/or immunosuppression in neurolupus, and this included only 32 patients [97,98]. Results suggest that for serious (non-stroke) neurological complications including neuropsychiatric manifestations, optic neuritis, neuropathy, coma, brainstem disease or transverse myelitis, steroids alone were inferior to steroids plus cyclophosphamide. A common recommendation is therefore to start with high dose intravenous methylprednisolone followed by oral prednisone, decreasing doses at weekly intervals accompanied by oral or intravenous cyclophosphamide [97,98]. Careful monitoring of the blood count for bone marrow suppression should be performed. Cyclophosphamide is associated with haemorrhagic cystitis which can be reduced by adequate hydration. Cyclophosphamide is also associated with high increase in bladder cancer. Other malignancies, infertility, cardiotoxicity and pulmonary ﬁbrosis have been described as well. Additional clinical syndromes such as aseptic meningitis are usually treated with high doses of steroids with good response . Conclusions MCTD is a well-deﬁned entity with a wide spectrum of clinical manifestations. Long-term studies reveal that some patients may have mild self-limited disease, whereas others may develop severe major organ involvement. Although there is a different set of clinical criteria, the most common approach for the diagnosis requires the serological criteria plus at least three clinical criteria. The worst prognosis and high mortality is associated with the presence of pulmonary arterial hypertension. There is no consensus about the treatment of MCTD. Speciﬁc clinical manifestations should be addressed according to recommendations to treat the same manifestations in other diseases such as SLE, SSc and RA. In all cases, therapy should be individualised for each patient to address the speciﬁc organs involved. Life-threatening manifestations require aggressive treatment. Further prospective clinical trials are needed to evaluate clinical course, long-term prognosis and response to therapy. References * Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease–an apparently distinct rheumatic disease syndrome associated with a speciﬁc antibody to an extractable nuclear antigen (ENA). 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