Facts and controversies in mixed connective tissue disease

G Model

ARTICLE IN PRESS Med Clin (Barc). 2017;xxx(xx):xxx–xxx

www.elsevier.es/medicinaclinica

Review

Facts and controversies in mixed connective tissue disease夽 Julia Martínez-Barrio a,b,c,∗ , Lara Valor a,b , F. Javier López-Longo a,b,c a

Servicio de Reumatología, Hospital General Universitario Gregorio Mara˜ nón, Madrid, Spain Instituto de Investigación Biomédica Hospital Gregorio Mara˜ nón, Madrid, Spain c Universidad Complutense de Madrid, Madrid, Spain b

a r t i c l e

i n f o

Article history: Received 17 May 2017 Accepted 26 June 2017 Available online xxx Keywords: Mixed connective tissue disease Seronegative Anti-U1-RNP

a b s t r a c t Mixed connective tissue disease (MCTD) is a systemic autoimmune rheumatic disease (SARD) characterized by the combination of clinical manifestations of systemic lupus erythematosus (SLE), cutaneous systemic sclerosis (SSc) and polymyositis-dermatomyositis, in the presence of elevated titres of anti-U1RNP antibodies. Main symptoms of the disease are polyarthritis, hand oedema, Raynaud’s phenomenon, sclerodactyly, myositis and oesophageal hypomobility. Although widely discussed, most authors today accept MCTD as an independent entity. Others, however, suggest that these patients may belong to subgroups or early stages of certain definite connective diseases, such as SLE or SSc, or are, in fact, SARD overlap syndromes. ˜ S.L.U. All rights reserved. © 2017 Elsevier Espana,

Hechos y controversias en la enfermedad mixta del tejido conectivo r e s u m e n Palabras clave: Enfermedad mixta del tejido conectivo Seronegativo Anti-U1-RNP

La enfermedad mixta del tejido conectivo (EMTC) es una enfermedad reumática autoinmunitaria sistémica (ERAS) caracterizada por la asociación de manifestaciones clínicas de lupus eritematoso sistémico (LES), esclerosis sistémica cutánea (ESC) y polimiositis-dermatomiositis en presencia de títulos elevados de anticuerpos anti-U1-RNP en el suero de los pacientes. Sus principales síntomas son la poliartritis, el edema de manos, el fenómeno de Raynaud, la esclerodactilia, la miositis y la hipomotilidad esofágica. Actualmente, la mayoría de los autores acepta que la EMTC es una entidad independiente, pero algunos mantienen que estos pacientes podrían presentar una ERAS, definida en su fase precoz como LES o ESC, o ser, en realidad, un síndrome de solapamiento de la ERAS. ˜ S.L.U. Todos los derechos reservados. © 2017 Elsevier Espana,

Mixed connective tissue disease (MCTD) was first described by Sharp et al. in the year 1972.1,2 It is a clinical entity characterized by a combination of symptoms and signs of systemic lupus erythematosus (SLE), scleroderma (SD) and polymyositisdermatomyositis (PDM), with antibodies directed against the U1-ribonucleoprotein (U1-RNP). Subsequently, it was found that these patients can also have rheumatoid arthritis (RA)3 manifestations. According to the first descriptions of the disease, patients

夽 Please cite this article as: Martínez-Barrio J, Valor L, López-Longo FJ. Hechos y controversias en la enfermedad mixta del tejido conectivo. Med Clin (Barc). 2017. https://doi.org/10.1016/j.medcli.2017.06.066 ∗ Corresponding author. E-mail address: [email protected] (J. Martínez-Barrio).

with MCTD were characterized by an excellent response to glucocorticoid treatment and a favourable prognosis.1,4 In recent years, population studies show that the incidence and prevalence of MCTD are low; being a rare disease. Ungprasert et al.5 studied the population of Olmsted County, Minnesota, between 1985 and 2014. They identified 50 incident cases with an average age of onset of 48.1 years, predominantly women (84%). The annual incidence rate in this series was 1.9 per 100,000 individuals. In Norway, Gunnarsson et al.6 described a female/male ratio of 3.3 and a lower average age of disease onset, 37.9 years. The prevalence in 2008 was 3.8 cases per 100,000 inhabitants, with an annual incidence of 2.1 cases per million inhabitants. The prevalence and local incidence in Spain is not known. Its aetiology is unknown. The development of the disease is probably due to the interaction between genetic and environmental factors (Fig. 1). The genes of the major histocompatibility

˜ S.L.U. All rights reserved. 2387-0206/© 2017 Elsevier Espana,

MEDCLE-4217; No. of Pages 7

G Model

ARTICLE IN PRESS

2

J. Martínez-Barrio et al. / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

Possible MCTD

Preclinical MCTD

Incomplete or established MCTD

Dendritic cells

HLA-DR4 HLADRw53 HLADRB1*04:01 HLA-B*08

Antigen

Arthralgias Arthritis Apoptotic cells

Myositis Raynaud's phenomenon

T lymphocyte

Genetic factors

Oesophageal hypomotility

PAH Other

B lymphocyte

Interstitial lung disease Immunocomplexes

Environmental factors

UV Viral infection

Oedematous hands

IgG antiU1/RNP autoantibodies

Clinical manifestations with/ without diagnostic criteria Comorbidities Treatment

U1 70kD A

D

Fig. 1. The aetiology of MCTD is unknown and the development of the disease is possibly due to an interaction between genetic and environmental factors. The immune response is primarily directed against polypeptides A and C of the U1 ribonucleoprotein (U1/RNP) 70 kD fraction. PAH: pulmonary artery hypertension; UV: ultraviolet.

complex (HLA) have an important role in the presentation of the antigens to the immune system. Classically, the HLA-DR4 and HLA-DRw53 genotypes have been related to MCTD and anti-U170 kD7 antibodies, but recent studies show a strong association with HLA-DRB1*04:01 and B*08.8,9 Therefore, MCTD is genetically different from SLE, whose predisposition is associated with HLA-DR2 and HLA-DR3, HLA-DRB1, HLA-DRB1*0301 and HLADRB1*1501; SD, associated with HLA-DR5/11, HLA-DR3 and DR2 or HLA-DQA1*0501; or polymyositis (PM), associated with HLADR3, HLA-B*0801 and DRB1*0301.10–12 This different genotype strengthens the notion of MCTD as a distinct entity within systemic autoimmune rheumatic diseases (SARD).

Clinical manifestations Raynaud’s phenomenon: It is characterized by reversible vasospastic episodes, which typically manifest with pallor, cyanosis and subsequent hyperaemia due to reperfusion in fingers and toes. It is the initial symptom in up to 50% of patients and may precede the rest of the clinical manifestations in months or years.5 Up to 30% of patients with MCTD manifest the typical capillaroscopic pattern of SD at the time of diagnosis, with the presence of megacapillaries and microhaemorrhages (early pattern) or an increase in these characteristics associated with loss of capillaries (active pattern) or neoangiogenesis, fibrosis and desertification (late pattern).13 Arthralgias/arthritis: They are usually associated with morning stiffness and are usually symmetric and polyarticular. They preferentially affect the proximal metacarpophalangeal and interphalangeal joints of the hands and feet. In most cases it is a non-deforming arthritis, but up to a third of patients have erosive arthritis similar to RA.14 Oedematous hands: The skin appears thickened by the deposit of collagen and oedema in a similar way to that observed in oedematous phases of SD. It is an initial symptom in 16% of patients.5 Pulmonary manifestations: The most frequent are interstitial lung disease (ILD) and pulmonary artery hypertension (PAH). ILD is usually concentrated in the lung bases and peripheral areas.15 The most frequent findings in high resolution computerized

axial tomography are intralobular reticular opacities, groundglass images and linear opacities compatible with non-specific interstitial pneumonia.16 Between 14 and 60% of patients with MCTD have PAH,16,17 with medial hypertrophy, intimal proliferation and plexiform lesions similar to those found in PAH secondary to SD. PAH is one of the main causes of death.18 Other pulmonary manifestations are pulmonary thromboembolism, alveolar haemorrhage, diaphragmatic dysfunction and vasculitis.19 Oesophageal hypomotility: The most frequent symptom is dysphagia due to disease secondary to gastroesophageal reflux and appears in patients with clinical manifestations related to SD. A dysfunction of the upper and lower oesophageal sphincters is observed, with a decrease in peristalsis pressure and amplitude in the distal two thirds of the esophagus.20 Mesenteric vasculitis, colon perforation, protein losing enteropathy, acute pancreatitis, hemoperitoneum, diarrhoea, and chronic hepatitis have also been described, although less frequently.21 Other clinical manifestations in MCTD are sclerodactyly, predominantly proximal myositis, serositis, cardiac and central or peripheral nervous system involvement (trigeminal neuropathy, headaches, sensorineural hearing loss).14,22 Renal manifestations are rare in the context of the disease.14,23 Szodoray et al., in a series of 201 patients, described 3 disease phenotypes with differences in their prognosis18 : - Vascular manifestations. Higher incidence of PAH, Raynaud’s phenomenon, livedo reticularis and thrombosis, with anti-cellendothelial and antiphospholipid antibodies. - SD and PDM manifestations. Increased frequency of ILD, oesophageal dysmotility, myositis and immune complex deposition. - Articular manifestations. Erosive arthritis and anti-citrullinated peptide antibodies (ACPA), similar to that found in RA. Lab tests In MCTD, it is common to find low-grade chronic inflammatory anaemia or leukopenia, and sometimes thrombocytopenia and

G Model

ARTICLE IN PRESS J. Martínez-Barrio et al. / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

haemolytic anaemia. Serologically, the first indication for the diagnosis of the disease is the presence of positive, mottled-pattern, antinuclear antibodies (ANA), at high titres. The detection of high concentrations of antibodies against U1snRNP –s mall nuclear ribonucleoproteins –, usually of the IgG isotype, constitutes the characteristic immunological marker in these patients. The different subtypes of RNP are part of the spliceosome, a cytoplasmic structure where pre-messenger RNA is transformed and divided into messenger RNA. The subunits snRNP and hnRNP – heterogeneous nuclear ribonucleoproteins – constitute the main antigen of autoimmunity in different SARD. In MCTD, the immune response is directed primarily against polypeptides A and C of the 70-kD fraction, and against polypeptides B, B , D1, D2 and D3 (anti-Sm) in SLE.24–26 Although the presence of anti-U1-RNP antibodies is a sine qua non condition for the diagnosis of the disease, its role in the pathogenesis of MCTD is unknown. Different models have been proposed on the physiopathology of MCTD. It is possible that a physiological stress factor, such as a viral infection or exposure to ultraviolet light, induces the release of large amounts of apoptotic material. In individuals with a defect in the elimination of apoptotic particles containing RNP, these particles encounter circulating immunoglobulins and dendritic cells. U1-RNA and endogenous RNA adjuvants induce the activation of dendritic cells and the presentation of antigens by means of signalling via Toll-like receptors. In a host with a compatible haplotype, these cells induce the activation of specific circulating T lymphocytes against the U1-70 kD and other autoantigens. At a concurrent physiological moment or following the triggering event that leads to a new release of apoptotic material, the B lymphocytes that have escaped from anergy or deletion and are specific for antigens such as the U1-70 kD protein are exposed to their antigen. This leads to the maturation of activated IgG-secreting B lymphocytes that continue to be activated, secreting autoantibodies as long as they have an autoantigen and the necessary co-stimulation. In some individuals, the autoantibodies and T lymphocytes being produced are able to mediate in a tissue lesion, resulting in a SARD.27 In murine models, anti-U1-RNP antibodies have shown to be lung lesion mediators.28 Likewise, it is presumed that PAH may be due to the activation of endothelial cells induced by anti-U1-RNP antibodies.29 Other antibodies usually present include the rheumatoid factor (RF) of the IgM isotype, positive in almost 50% of patients, ACPA and anti-DNA antibodies or antiphospholipid antibodies in a low percentage of patients, with a lower frequency than what is observed in patients with SLE. Anti-Ro52 antibodies have been detected in half of patients with pulmonary fibrosis and only in 19% of patients without it, with an OR of 4.4.30 Most patients develop hypergammaglobulinemia.

3

Table 1 Classification criteria for the mixed connective tissue disease proposed by AlarconSegovia and Villarreal. A. Serological Anti-RNP by hemagglutination at titre >1:1600 B. Clinical 1. Oedema in hands 2. Synovitis 3. Myositis 4. Raynaud’s phenomenon 5. Sclerodactyly RNP: ribonucleoprotein. Serological criteria are required plus at least 3 clinical criteria, as long as synovitis or myositis are included. Source: Alarcon-Segovia and Villarreal.31

Table 2 Classification criteria for mixed connective tissue disease proposed by Sharp. A. Major criteria 1. Severe myositis 2. Lung involvement a. Decreased diffusion capacity < 70% b. Pulmonary hypertension c. Proliferative vasculopathy in lung biopsy 3. Raynaud’s phenomenon or oesophageal hypomotility 4. Sclerodactyly or oedematous hands 5. Anti-ENA > 1:10,000 and anti-U1-RNP antibodies in the absence of anti-Sm B. Minor criteria 1. Alopecia 2. Leukopenia (<4000 leukocytes) 3. Anaemia 4. Pleuritis 5. Pericarditis 6 Arthritis 7 Trigeminal neuropathy 8 Malar erythema 9. Thrombocytopenia 10 Moderate myositis 11. History of oedematous hands MCTD: mixed connective tissue disease; ENA: extractable nuclear antigen; RNP: ribonucleoprotein. The patient is classified as MCTD when 4 major criteria are met and probable MCTD when 3 major or 2 major and one minor criteria are met, always in the presence of major criterion no. 5. Source: Sharp.32

sensitive (75%) compared to those of Alarcon-Segovia and Villarreal (73%) and Sharp (42%) to classify patients with MCTD throughout their progression.37 Treatment

Diagnosis Clinical manifestations or alterations detected in the laboratory usually occur sequentially, which is why many patients do not meet the classification criteria for MCTD at the beginning of the disease or could even meet the classification criteria for SLE, SD, PDM or RA. Given the heterogeneity of clinical manifestations, several classification proposals have been made.31–34 Regardless of its clinical variability, the only essential criterion common to all of them for the diagnosis of the disease is the detection of antiU1-RNP antibodies. The most commonly used classification criteria are shown in Tables 1–3. The first studies considered that the criteria of Alarcon-Segovia and Villarreal, Sharp and Kasukawa et al. were equivalent in terms of sensitivity and specificity,35 or that the criteria of Alarcon-Segovia and Villarreal were superior.36 More recent studies indicate that the criteria of Kasukawa et al. are more

There are no specific treatment guidelines for MCTD. The therapy must be individualized and adapted to the severity of the manifestations at the time of presentation. The treatment is analogous to that of other SARD, therefore, many of the medications used are typical of SLE, SD, PM or RA. The treatment is aimed at the control of symptoms and should take place early, considering the occurrence of potentially serious manifestations, such as PAH, ILD, myocarditis or others. The choice of the drug depends on the clinical manifestations. General manifestations such as fatigue, fever, arthralgias, myalgias, adenopathies, some haematological alterations, nonscleroderma-like skin lesions and serositis usually remit with low or medium doses of glucocorticoids (prednisone 5–10 mg/day) or with antimalarial agents (hydroxychloroquine). For chronic arthritis, the initial treatment, in addition to glucocorticoids, is usually

G Model

ARTICLE IN PRESS

4

J. Martínez-Barrio et al. / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

Table 3 Classification criteria for mixed connective tissue disease proposed by Kasukawa et al. A. Common symptoms 1. Raynaud’s phenomenon 2. “Swollen” fingers or hands B. Anti-RNP antibodies C. Miscellaneous 1. Lupus Manifestations a. Polyarthritis b. Adenopathies c. Malar erythema d. Serositis (pleuritis or pericarditis) e. Cytopenia (leukopenia or thrombocytopenia) 2. Sclerodermiform manifestations a. Sclerodactyly b. Pulmonary fibrosis, restriction or decrease of diffusion < 70% c. Hypomotility or oesophageal dilation 3. Myositis a. Muscular weakness b. Muscle enzymes (CK) increase c. Myopathic pattern in the EMG CK: creatine phosphokinase; EMG: electromyogram; ENA: extractable nuclear antigen; RNP: ribonucleoprotein. At least one of the 2 common symptoms is required, plus positive anti-U1-RNP antibodies, plus one or more of the miscellaneous symptoms in at least 2 of the 3 categories. Source: Kasukawa et al.33

methotrexate, as well as for cutaneous sclerosis (scleroderma) and myositis.38,39 Raynaud’s phenomenon of mild-moderate severity can be controlled with general measures, such as the use of gloves and maintain an adequate body temperature, hence, pharmacological treatment is not always administered. When necessary, calcium antagonists are the treatment of choice. Endothelin inhibitors (bosentan) prevent the occurrence of digital ulcers40 associated with the most severe cases, in which prostaglandins are also sometimes used intravenously. The manifestations and, therefore, the treatment of lung disease in MCTD are considered similar to those of SD. In patients with ILD associated with SD, the first controlled clinical trials have been conducted to compare the efficacy of mycophenolate mofetil (MMF) against cyclophosphamide (Scleroderma Lung Study II),41 with favourable outcomes for both drugs in relation to lung disease, but better tolerance and less toxicity for MMF. Rituximab, a murine/human chimeric monoclonal antibody that binds specifically to the CD20 antigen of B lymphocytes, could also play an important role in the treatment of this disease. New drugs, such as endothelin antagonists, prostaglandin analogues and phosphodiesterase-5 inhibitors, have changed the prognosis of PAH in recent years. No less important are the support measures, such as the use of oxygen, diuretics, low sodium diet, calcium channel inhibitors and anticoagulation, when indicated. In severe cases, cardiopulmonary transplantation should be considered. Treatment is usually symptomatic in cases of gastrointestinal manifestations. Due to oesophageal hypomotility and secondary gastroesophageal reflux esophagitis can occur, so metoclopramide, ranitidine or proton pump inhibitors should be chronically used. Measuring clinical activity The activity of the disease has had to be defined in order to determine the efficacy of the new treatments. In daily clinical

practice, activity criteria “borrowed” from other diseases, such as RA or SLE, are used. In 2010, Lage et al. proposed the MCTD activity criteria listed in Table 4.42 These criteria have not been validated and prospective studies are needed to determine the sensitivity, specificity and positive and negative predictive values. Regardless of the controversy over its nomenclature, the fact that the MCTD identifies a group of patients in whom there may be an involvement of vital organs requires a consensus for the surveillance of specific manifestations and the prognostic stratification according to different clinical and serological criteria, in order to improve the quality of patient care. Mortality Similar to what we observed in patients with SD, PAH is the main cause of death in the MCTD,14 so that early diagnosis is essential. The essential diagnostic tools are, in addition to clinical evaluation, respiratory function tests and echocardiogram. The diagnosis is confirmed by measuring the pulmonary artery pressure through cardiac catheterization. Currently, with the available treatments, such as immunosuppressants, endothelin antagonists, prostanoids and phosphodiesterase-5 inhibitors, the survival of patients with PAH has significantly improved.23 The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease ManagementREVEAL-study, which included patients with PAH associated with SARD from 54 centres in the USA, found that one-year survival rates were lower in patients with SD than in other SARD such as SLE or RA, and similar in patients with MCTD.43 Other important causes of death are ILD15 and myocarditis.44 Mixed connective tissue disease in children Just over 20% of cases of MCTD begin during childhood or adolescence. The average age of onset is around 11 years,45,46 with an interval of 2–16 years. The female:male ratio at this stage is 6:1.47 In the 55 paediatric patients of Hetlevik et al., one of the longest series published to date, the most frequent manifestations throughout the disease were Raynaud’s phenomenon (100%), arthritis (94%), oedematous hands (77%) and pulmonary involvement (58%). The

Table 4 Proposed activity criteria for mixed connective tissue disease. (A) Major manifestations Cutaneous vasculitis Decreased lung function Manifestations of CNS Severe myositis Urinary casts/proteinuria (B) Minor manifestations Arthritis Cutaneous rash Diarrhoea Mild myositis Weight loss (C) Laboratory Lymphopenia or thrombocytopenia Increase of CRP or ESR Hypergammaglobulinemia Active disease 2A 1 A+2 B 3 B+C CRP: C-reactive protein; CNS: central nervous system; ESR: erythrocyte sedimentation rate. Source: Lage et al.42

G Model

ARTICLE IN PRESS J. Martínez-Barrio et al. / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

typical findings of SLE (arthritis, facial erythema, serositis, leukopenia) and PDM (muscle weakness, muscle enzyme elevation, altered EMG) were more evident at the time of diagnosis. The frequency of these manifestations decreased during the course of the disease, giving way to the prevalence of SD manifestations (sclerodactyly, pulmonary disease, oesophageal dysmotility).46 It has been suggested that pulmonary disease may be less frequent than in the adult population.15,46 In the aforementioned cohort, mortality was 51.8% after an average of 16.8 years of follow-up. None of the deaths was due to ILD. Haematological manifestations such as anaemia, leukopenia and thrombocytopenia are common. Serologically, high titres of ANA are observed along with the anti-U1-RNP. The RF is also positive in a significant number of patients (70%); to a lesser extent, anti-Sm (10%), anti-DNA (20%), anti-Ro (13%) and anti-La (14%) antibodies are also found.47 As in adults, juvenile MCTD does not have a specific treatment, but is similar to other SARD. Glucocorticoids, antimalarial agents and methotrexate will be the first-line drugs. Cabrera et al. report the improvement of 2 children treated with tocilizumab, a humanized monoclonal antibody directed against the IL-6 receptor and indicated in juvenile idiopathic arthritis; this improvement was especially noticeable in joint involvement.48 There are also reports of cases treated with rituximab.49 The controversy of mixed connective tissue disease The concepts of overlapping syndrome (patients with manifestations of 2 or more defined SARD) and MCTD are controversial.25,37,50–52 Whether its aetiology is less defined or because it is thought that these entities derive into another rheumatological process, there are those who maintain that MCTD is actually an overlapping syndrome or an undifferentiated and early phase of another SARD. The controversy regarding the existence of MCTD still persists. Although well-defined entities, such as SLE, are assumed to be very heterogeneous and have a broad spectrum of clinical and serological characteristics that may change over time, MCTD does not enjoy this benefit. The main objections to the concept of MCTD as an independent entity51,52 are the following: - Patients with MCTD can progress to other defined SARD. - MCTD was described as a relatively benign disease, but it is not uncommon for it to present with serious organ manifestations. - Anti-U1-RNP antibodies are not exclusive to MCTD and patients with typical MCTD data have other antibodies apart from antiU1-RNP. - A set of diagnostic criteria or classification that is widely accepted is not yet available. These controversies associated with the rarity of the disease and the limited epidemiological information have made it difficult to design studies on MCTD, even reducing the possibility of comparative studies with other SARD. The concept of MCTD as a defined entity51 is based on the existence of a specific clinical pattern, a characteristic antibody and specific immunological and genetic findings: - MCTD has a specific clinical pattern characterized by the association of Raynaud’s phenomenon, arthralgias or polyarthritis, swelling in the hands with sausage-like fingers, oesophageal hypomotility and myositis. The overlap of the manifestations of SLE, SD and PDM that make up the classification criteria is sequential. The ability of patients with MCTD to develop characteristic

5

manifestations of other SARD should be considered as a clinical expression, rather than a differentiation. Although, throughout the course of the disease, patients with MCTD can meet the criteria for the classification of more than one defined SARD,53 they are not strictly overlapping syndromes if it is assumed that this term defines patients with 2 independently coexisting diseases. - Anti-U1-RNP antibodies are characteristic of MCTD. Patients with high titres of anti-U1-RNP antibodies without criteria of MCTD or other SARD usually progress to MCTD in 2 years. In contrast, patients with low titres often develop SLE or other defined SARD.54 - Patients with MCTD have specific genetic factors. Unlike what is observed in SLE or SD, MCTD is fundamentally related to HLA-DR4, in particular DRB1*15:01, DRB1*04 and *09:01.8

Therefore, the concept of MCTD is useful in the definition of a subgroup of patients with unique clinical characteristics, treatment profile and prognosis and different from the rest of SARD. In the case of MCTD and antiphospholipid syndrome (APS), the classification criteria always require the detection of anti-U1-RNP and antiphospholipid antibodies, respectively. Recently, the existence of patients with seronegative APS has been recognized,55 that is, patients with clinical manifestations indicative of APS whose anticardiolipin antibodies, lupus anticoagulant and anti␤2-glycoprotein-1 determinations are persistently negative using the conventional laboratory techniques. Then, with the same reasoning, could we find patients with MCTD manifestations without detecting anti-U1-RNP antibodies? Although the detection of anti-U1-RNP antibodies is part of the diagnostic criteria for MCTD, this does not imply that they necessarily play a determining role in the development of the disease. The presence of anti-U1-RNP antibodies and other antibodies throughout the progression of patients is not always maintained and antibody levels can fluctuate; even anti-U1-RNP antibodies can disappear.56 Cappelli et al. describe, in their retrospective multicenter cohort, positive results for anti-U1-RNP at the time of diagnosis of 100 versus 91% with an average duration of the disease of 7.9 ± 5.9 years,37 which implies that certain patients diagnosed with MCTD have been seronegative at some point of their progression. On the other hand, anti-U1-RNP antibodies are not specific to MCTD, and may occur in patients with SLE, other defined SARD or even in patients with no specific diagnosis. As described, between 20–40% of patients with SLE, 2–14% of patients with SD and 6–9% of patients with PDM have anti-U1-RNP antibodies.37,57,58 The relevance of the U1-RNP antigens regarding breaking the tolerance and generating the autoimmune response on which the development of the MCTD is based remains to be established, and whether the immune responses to U1-RNP mediate the tissue lesions and the inflammatory manifestations observed in the disease.27 The relationship between the antibody and the activity of the disease is also to be established, since it has been shown that its disappearance implies remission in certain patients59 and that anti-U1-RNA titres could be related to the activity of the disease in patients with SLE and SARD overlaps.60 In conclusion, the concept of MCTD is very useful from a clinical point of view since it identifies a group of patients with a different prognosis, including potentially serious manifestations. MCTD’s clinical and epidemiological knowledge has increased in recent years, but the controversy regarding its classification as a defined entity, subgroup of SLE or SD, or overlapping syndrome remains unresolved. Probably, the criteria for classifying the

G Model

ARTICLE IN PRESS

6

J. Martínez-Barrio et al. / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

disease should be re-evaluated and, with the new validated criteria, develop new epidemiological studies. Conflict of interests The authors declare no conflict of interest. References 1. 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). Am J Med. 1972;52:148–59. 2. Sharp GC, Irvin WS, May CM, Holman HR, McDuffie FC, Hess EV, et al. Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective-tissue disease, systematic lupus erythematosus and other rheumatic diseases. N Engl J Med. 1976;295:1149–54. 3. Bennett RM, O’Connell DJ. The arthritis of mixed connective tissue disease. Ann Rheum Dis. 1978;37:397–403. 4. Bennett RM, O’Connell DJ. Mixed connective tissue disease: a clinicopathologic study of 20 cases. Semin Arthritis Rheum. 1980;10:25–51. 5. Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, Matteson EL. Epidemiology of mixed connective tissue disease 1985–2014: a population based study. Arthritis Care Res (Hoboken). 2016;68:1843–8. 6. Gunnarsson R, Molberg O, Gilboe IM, Gran JT. The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Ann Rheum Dis. 2011;70:1047–51. 7. Hoffman RW, Rettenmaier LJ, Takeda Y, Hewett JE, Pettersson I, Nyman U, et al. Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients. Arthritis Rheum. 1990;33:666–73. ´ ´ ´ 8. Paradowska-Gorycka A, Stypinska B, Olesinska M, Felis-Giemza A, Manczak M, Czuszynska Z, et al. Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients. HLA. 2016;87:13–8. 9. Flåm ST, Gunnarsson R, Garen T, Lie BA, Molberg Ø, Norwegian MCTD Study Group. The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases. Rheumatology (Oxford). 2015;54:528–35. 10. Barcellos LF, May SL, Ramsay PP, Quach HL, Lane JA, Nititham J, et al. Highdensity SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS Genet. 2009;5:e1000696. 11. Agarwal SK, Tan FK, Arnett FC. Genetics and genomic studies in scleroderma (systemic sclerosis). Rheum Dis Clin N Am. 2008;34:17–40. 12. O’Hanlon TP, Carrick DM, Arnett FC, Reveille JD, Carrington M, Gao X, et al. Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in caucasians. Medicine (Baltimore). 2005;84:338–49. 13. Cutolo M, Matucci Cerinic M. Nailfold capillaroscopy and classification criteria for systemic sclerosis. Clin Exp Rheumatol. 2007;25:663–5. 14. Hajas A, Szodoray P, Nakken B, Gaal J, Zöld E, Laczik R, et al. Clinical course, prognosis, and causes of death in mixed connective tissue disease. J Rheumatol. 2013;40:1134–42. 15. Gunnarsson R, Aalokken TM, Molberg O, Lund MB, Mynarek GK, Lexberg AS, et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study. Ann Rheum Dis. 2012;71:1966–72. 16. Mira-Avendano IC, Abril A. Pulmonary manifestations of Sjögren syndrome, systemic lupus erythematosus, and mixed connective tissue disease. Rheum Dis Clin N Am. 2015;41:263–77. 17. Ahmed S, Palevsky HI. Pulmonary arterial hypertension related to connective tissue disease. A review. Rheum Dis Clin N Am. 2014;40:103–24. 18. Szodoray P, Hajas A, Kardos L, Dezso B, Soos G, Zold E, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus. 2012;21:1412–22. 19. Bull TM, Fagan KA, Badesch DB. Pulmonary vascular manifestations of mixed connective tissue disease. Rheum Dis Clin N Am. 2005;31:451–64. 20. Fagundes MN, Caleiro MT, Navarro-Rodriguez T, Baldi BG, Kavakama J, Salge JM, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med. 2009;103:854–60. 21. Ortega-Hernandez OD, Shoenfeld Y. Mixed connective tissue disease: an overview of clinical manifestations, diagnosis and treatment. Best Pract Res Clin Rheumatol. 2012;26:61–72. 22. Hajas A, Szodoray P, Barath S, Sipka S, Rezes S, Zeher M, et al. Sensorineural hearing loss in patients with mixed connective tissue disease: immunological markers and cytokine levels. J Rheumatol. 2009;36:1930–6. 23. Nimelstein SH, Brody S, McShane D, Holman HR. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine (Baltimore). 1980;59:239–48. 24. Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. 2000;12:386–90. 25. Sharp GC. MCTD: a concept which stood the test of time. Lupus. 2002;11:333–9.

26. Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm and anti-RNP antibodies. Autoimmunity. 2005;38:47–54. 27. Greidinger EL, Hoffman RW. Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheum Dis Clin N Am. 2005;31:437–50. 28. Keith MP, Moratz C, Egan R, Zacharia A, Greidinger EL, Hoffman RW, et al. Anti-ribonucleoprotein antibodies mediate enhanced lung injury following mesenteric ischemia/reperfusion in Rag-1(−/−) mice. Autoimmunity. 2007;40:208–16. 29. Bodolay E, Csipo I, Gal I, Gyimesi E, Szekanecz Z, Szegedi G. Anti-endothelial cell antibodies in mixed connective tissue disease: frequency and association with clinical symptoms. Clin Exp Rheumatol. 2004;22:409–15. 30. Gunnarsson R, El-Hage F, Aaløkken TM, Reiseter S, Lund MB, Garen T, et al. Associations between anti-Ro52 antibodies and lung fibrosis in mixed connective tissue disease. Rheumatology (Oxford). 2016;55:103–8. 31. Alarcon-Segovia D, Villarreal M. Classification and diagnostic criteria for mixed connective tissue disease. Amsterdam: Elsevier; 1987. p. 33–40. 32. Sharp G. Diagnostic criteria for classification of MCTD. In: Kasukawa R, Sharp G, editors. Mixed connective tissue diseases and anti-nuclear antibodies. Amsterdam: Elsevier Science Publishers B. V. (Biomedical Division); 1987. p. 23–30. 33. Kasukawa R, Tojo T, Miyawaki S, Yoshida H, Tanimoto K, Nobunaga M, et al. Prelimary diagnostic criteria for classification of mixed connective tissue disease. In: Kasukawa R, Sharp G, editors. Mixed connective tissue disease and anti-nuclear antibodies. Amsterdam: Elsevier Science Publishers B.V. (Biomedical Division); 1987. p. 41–7. 34. Kahn MF, Appelboom T. In: Kahn MF, Peltier AP, editors. Les maladies systemiques. Paris: Flammarion; 1991. p. 545–56. 35. Alarcón-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol. 1989;16:328–34. 36. Amigues JM, Cantagrel A, Abbal M, Mazieres B. Comparative study of 4 diagnosis criteria sets for mixed connective tissue disease in patients with anti-RNP antibodies. Autoimmunity Group of the Hospitals of Toulouse. J Rheumatol. 1996;23:2055–62. 37. Cappelli S, Bellando Randone S, Martinovic´ D, Tamas MM, Pasalic´ K, Allanore Y, et al. To be or not to be, ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. 2012;41:589–98. 38. Kowal-Bielecka O, Distler O. Use of methotrexate in patients with scleroderma and mixed connective tissue disease. Clin Exp Rheumatol. 2010;28 Suppl. 61. 39. Walker KM, Pope J. Expert agreement on EULAR/EUSTAR recommendations for the management of systemic sclerosis. J Rheumatol. 2011;38:1326–8. 40. Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2011;70:32–8. 41. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al. 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;4:708–19. 42. Lage LV, Caleiro MTC, Carvalho J. Proposed disease activity criteria for mixed connective tissue disease. Lupus. 2010;19:223–4. 43. Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB, et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest. 2010;138:1383–94. 44. Lundberg I. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus. 2005;14:708–12. 45. Tsai YY, Yang YH, Yu HH, Wang LC, Lee JH, Chiang BL. Fifteen-year experience of pediatric-onset mixed connective tissue disease. Clin Rheumatol. 2010;29:53–8. 46. Hetlevik SO, Flatø B, Rygg M, Nordal EB, Brunborg C, Hetland H, et al. Longterm outcome in juvenile-onset mixed connective tissue disease: a nationwide Norwegian study. Ann Rheum Dis. 2017;76:159–65. 47. Berard RA, Laxer RM. Pediatric mixed connective tissue disease. Curr Rheumatol Rep. 2016;18:28. 48. Cabrera N, Duquesne A, Desjonquères M, Larbre JP, Lega JC, Fabien N, et al. Tocilizumab in the treatment of mixed connective tissue disease and overlap syndrome in children. RMD Open. 2016;2:e000271. 49. Jansson AF, Sengler C, Kuemmerle-Deschner J, Gruhn B, Kranz AB, Lehmann H, et al. B cell depletion for autoimmune diseases in paediatric patients. Clin Rheumatol. 2011;30:87–97. 50. Aringer M, Steiner G, Smolen JS. Does mixed connective tissue disease exist? Yes. Rheum Dis Clin N Am. 2005;31:411–20. 51. Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be? Arthritis Rheum. 1998;41:768–77. 52. Swanton J, Isenberg D. Mixed connective tissue disease: still crazy after all these years. Rheum Dis Clin N Am. 2005;31:421–36. 53. Hoffmann-Vold AM, Gunnarsson R, Garen T, Midtvedt Ø, Molberg Ø. Performance of the 2013 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis (SSc) in large, welldefined cohorts of SSc and mixed connective tissue disease. J Rheumatol. 2015;42:60–3. 54. López-Longo FJ, Fernández J, Monteagudo I, Rodríguez-Mahou M, Atrio AS, Pérez T. Evolución clínica y serológica en pacientes con enfermedad mixta del tejido conjuntivo. Rev Clin Esp. 1994:682–8. 55. Rodriguez-Garcia JL, Bertolaccini ML, Cuadrado MJ, Sanna G, Ateka-Barrutia O, Khamashta Ma. Clinical manifestations of antiphospholipid syndrome (APS)

G Model

ARTICLE IN PRESS J. Martínez-Barrio et al. / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

with and without antiphospholipid antibodies (the so-called ‘seronegative APS’). Ann Rheum Dis. 2012;71:242–4. 56. Faria AC, Barcellos KS, Andrade LE. Longitudinal fluctuation of antibodies to extractable nuclear antigens in systemic lupus erythematosus. J Rheumatol. 2005;32:1267–72. 57. Ihn H, Yamane K, Yazawa N, Kubo M, Fujimoto M, Sato S, et al. Distribution and antigen specificity of anti-U1RNP antibodies in patients with systemic sclerosis. Clin Exp Immunol. 1999;117:383–7. 58. Brouwer R, Hengstman GJ, Egberts V, Ehrfeld H, Bozic B, Ghirardello A, et al. Autoantibody profiles in the sera of European patients with myositis. Ann Rheum Dis. 2001;60:116–23.

7

59. Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 1999;42: 899–909. 60. Hoet RM, Koornneef I, de Rooij DJ, van de Putte LB, van Venrooij WJ. Changes in anti-U1 RNA antibody levels correlate with disease activity in patients with systemic lupus erythematosus overlap syndrome. Arthritis Rheum. 1992;35:1202–10.