Abstract
The concept of mixed connective tissue disease (MCTD) as a separate connective tissue disease (CTD) has persisted for more than four decades. High titers of antibodies targeting the U1 small nuclear ribonucleoprotein particle (U1 snRNP) in peripheral blood are a sine qua non for the diagnosis of MCTD, in addition to distinct clinical features including Raynaud’s phenomenon (RP), “puffy hands,” arthritis, myositis, pleuritis, pericarditis, interstitial lung disease (ILD), and pulmonary hypertension (PH). Recently, population-based epidemiology data from Norway estimated the point prevalence of adult-onset MCTD to be 3.8 per 100,000 and the mean annual incidence to be 2.1 per million per year, supporting the notion that MCTD is the least common CTD. Little is known about the etiology of MCTD, but recent genetic studies have confirmed that MCTD is a strongly HLA (human leukocyte antigen)-linked disease, as the HLA profiles of MCTD differ distinctly from the corresponding profiles of ethnically matched healthy controls and other CTDs.
In the first section of this review, we provide an update on the clinical, immunological, and genetic features of MCTD and discuss the relationship between MCTD and the other CTDs. Then we proceed to discuss the recent advances in therapy and our current understanding of prognosis and prognostic factors, especially those that are associated with the more serious pulmonary and cardiovascular complications of the disease. In the final section, we discuss some of the key, unresolved questions related to anti-RNP-associated diseases and indicate how these questions may be approached in future studies.
Introduction
The concept of mixed connective tissue disease (MCTD) as a separate immune-mediated connective tissue disease (CTD) was first introduced by Gordon C. Sharp and coworkers > 40 years ago, but there is still no consensus regarding the disease definitions, the classification criteria, or the relationship with other CTDs . Some rheumatologists argue that MCTD is a distinct disease entity; others believe that it represents an overlap syndrome or an early and unspecific phase of an evolving, more distinct CTD; however, few studies still disregard the whole concept .
In their initial report, Sharp and coworkers described MCTD as a mild disease with favorable outcomes and an excellent response to oral prednisolone . This description holds true for some patients, but the overall impression from published cohorts and case series is that MCTD is a complex disease, with large interindividual variations in clinical features, responses to therapy, and outcomes . The disease appears in all age groups, but the peak incidence of MCTD is around 40 years . Previous studies have reported that 7–23% of the total MCTD population have a juvenile onset . Whether there are any systematic differences between adult and juvenile MCTD (JMCTD) remains unclear.
To date, there are no uniform guidelines for evaluating patients presenting with systemic disease features and a high titer of serum autoantibodies directed against the U1 ribonucleoprotein (anti-RNP), and there is no international consensus on how, when, and in whom MCTD should be diagnosed . Nevertheless, most physicians working in the CTD clinics would probably agree that the diagnosis of MCTD should be considered in an anti-RNP-positive patient presenting with Raynaud’s phenomenon , diffuse hand edema (“puffy hands”), and at least two of the following features: arthritis, myositis, leukopenia, esophageal dysmotility, pleuritis, pericarditis, interstitial lung disease (ILD) , or pulmonary hypertension (PH) . However, none of these features are unique to MCTD. They can also be observed in patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and polymyositis/dermatomyositis (PM/DM), the three CTDs that mostly resemble MCTD. Diagnosing MCTD in clinical practice is therefore an issue of pattern recognition and clinical decision with rich possibilities for different opinions and practices across the rheumatology communities.
The four coexisting criteria sets for MCTD further complicate this issue ( Supplementary Table 1 ). Even though all these four criteria sets were originally presented as diagnostic criteria, they are distinctly different ( Table 1 ), and within a clinical MCTD population, they do not capture the same patients ( Fig. 1 ). Three of the proposed criteria sets were first presented at an international conference on MCTD held in Japan in 1986 and the last criteria set was published in France in 1991 . Only two of these four criteria sets have been regularly used for research purposes in adult populations: the Alarcón-Segovia criteria and the Kasukawa criteria . The Kasukawa criteria have mostly been used in juvenile MCTD (JMTCD) . Sharp’s modified criteria set has not been widely used for several reasons, the most obvious being their complexity and the need for autoantibody data that are no longer available from routine immunology laboratories (see Table 1 ). The limited use of the Kahn criteria may be related to accessibility as the criteria were originally presented in French, and the fact that they closely resembled one of the already published criteria sets ( Table 1 ).
| Sharp | Kasukawa et al. | Alarcón-Segovia and Villareal | Kahn and Appelboom | |
|---|---|---|---|---|
| Immunological marker ( obligatory ) | anti-U1RNP -high titer anti-ENA Positive anti-Sm excludes definite MCTD | anti-nRNP | anti-RNP -high titer (by HA assay) | anti-RNP -high titer by immune-diffusion or immunoblot (U1 68kd) |
| Raynaud’s phenomenon | -one of four major criteria | -one of two obligatory criteria | -one of five clinical criteria | -obligatory criteria |
| Swollen/‘puffy’ hands | -one of four major criteria | -one of two obligatory criteria | -one of five clinical criteria | -one of three clinical criteria |
| Joint involvement | Arthritis -one of 11 minor criteria | Polyarthritis -one of five SLE-like findings | Synovitis -one of five clinical criteria | Synovitis -one of three clinical criteria |
| Muscle involvement | Myositis (mild) -one of 11 minor criteria | ≥1 of muscle weakness, elevated CK, myogenic EMG -disease category (2/3 needed) | Myositis (lab. or biopsy proven) -one of five clinical criteria | Myositis -one of three clinical criteria |
| Peripheral sclerosis | Sclerodactyly – can substitute swollen hands as one of four major criteria | Sclerodactyly -one of three SSc-like findings | Acrosclerosis (+/−scleroderma) -one of five clinical criteria | Not included |
| Lung involvement | DLCO < 70%, PAH or lung biopsy with proliferative vascular lesions – one of four major criteria | Pulmonary fibrosis, vital capacity < 80% or DLCO < 70% – one of three SSc-like findings | Not included | Not included |
| Esophageal disease | Hypomotility -can substitute Raynaud’s as one of four major criteria | Hypomotility or dilatation -one of three SSc-like findings | Not included | Not included |
| Serositis | Pleuritis, Pericarditis -two of 11 minor criteria | Pericarditis or pleuritis -one of five SLE-like findings | Not included | Not included |
| Hematopathology | Leukopenia, Anemia, Thrombocytopenia -three of 11 minor criteria | Leukocytopenia or thrombocytopenia -one of five SLE-like findings | Not included | Not included |
| Other | Alopecia, Trigeminus neuropathy, Malar rash, History of swollen hands -four of 11 minor criteria | Lymphadenopathy, Facial erythema -two of five SLE-like criteria | Not included | Not included |
Compared to the other CTDs, the research activity on MCTD has been relatively low from the late 1990s. Unfortunately, as a result, a large proportion of the standard textbook references on MCTD include >20 years old and originate from relatively small and potentially skewed single-center hospital cohorts . An extensive study of MCTD has not been conducted recently due to the following four interrelated reasons: (1) the controversies regarding the concept may have dampened the enthusiasm of some researchers; (2) the apparent rarity of the disease, with a concomitant lack of population-based epidemiology estimates, has made it difficult to plan and design MCTD studies; (3) the lack of clear disease definitions has made it difficult to delineate MCTD from the other CTDs; and (4) the lack of internationally accepted consensus criteria for disease classification has reduced the possibility of comparative studies.
Recently, we focused on the concept of MCTD and decided to tackle some of the unresolved issues related to the disease. Initially, we took advantage of the research possibilities provided by the organizational structure of the Norwegian Public Health System. In this system, care for CTDs is a specialist task. All CTD cases are therefore referred to, and routinely followed by, rheumatologists based at public hospitals. This organizational structure makes it possible to set up national level CTD case-finding strategies based on ICD-10 (10th revision of The International Statistical Classification of Diseases and Related Health Problems) searches across all hospital administrative databases and manual review of electronic patient journals (EPJs). Using these strategies, we were able to provide the first population-based data on the epidemiology of MCTD . The study cohort included every adult patient (≥18 years) in Norway who was (A) diagnosed with MCTD by a rheumatologist, (B) who met the modified Sharp’s criteria or the criteria of Alarcón-Segovia and Villareal or those of Kasukawa, and for whom (C) other CTD diagnoses were excluded by consensus by the study physicians. We found that the point prevalence of MCTD in Norway by 2008 was 3.8 per 100,000 adults and estimated the mean annual incidence of an adult-onset MCTD to be 2.1 per million per year. The female-to-male ratio was 3.3. The observed female-to-male ratio in our cohort was lower than in most other studies, including a recent large ( n = 280) Hungarian cohort study that reported a ratio of 12.3. There are currently no population-based studies on juvenile MCTD, but the available data indicate that the female-to-male ratio in this age group may be in the range of 3–6 . In the Norwegian cohort study, the prevalence of MCTD was similar across the three criteria sets of MCTD . The vast majority of the patients (97.3%) met at least two of the three MCTD criteria and 75% met the three criteria sets applied ( Fig. 1 A). There were, however, differences, particularly in relation to patients with ILD .
Update on the immunological and clinical features of MCTD
Immunological features
High titers of antibodies targeting the U1 small nuclear ribonucleoprotein particle (U1 snRNP) in peripheral blood are a sine qua non for the diagnosis of MCTD ( Table 1 ). These antibodies were originally detected by immunodiffusion. They were first described in sera from SLE patients, but they did not gain much attention before 1972 when Sharp et al. presented their concept of MCTD as a distinct CTD . Biochemical analyses have shown that the anti-RNP antibodies bind three U1-specific proteins A, C, and 70 kDa in the macromolecular U1–snRNP complex . ( Fig. 2 ) This complex contains many other antigens targeted by CTD-associated autoantibodies, including anti-Smith (Sm). An optimal protein purification was therefore critical for the diagnostic performance of anti-RNP antibodies. This has become less of a problem with the current enzyme-linked immunosorbent assays (ELISAs) as mixtures of recombinant proteins A, C, and 70 kDa are predominantly used as the antigen source.
The available data indicate that the 70-kDa antigen is the main target of serum anti-RNP antibodies in MCTD . It should, however, be noted that the relative frequencies of the circulating anti-U1 protein A, anti-U1 C, and anti-U1 70 kDa antibodies have not been widely assessed, either in MCTD or in any other CTD marked by anti-RNP antibodies.
The role of the anti-RNP antibodies in the pathogenesis of MCTD remains unknown, but recent data have reinforced the notion that the autoantibody production may be genetically determined and driven by distinct subsets of HLA-restricted T cells. Recently, we compared the HLA profiles, determined by sequence-based typing of HLA-B* and DRB1* in four groups of CTD patients of Norwegian ancestry: MCTD ( n = 155), SLE ( n = 96), SSc ( n = 95), PM/DM ( n = 84), and a control group of healthy individuals ( n = 282). The HLA DRB1*04:01 (OR 2.82; p = 3.64 × 10 −8 ) was confirmed to be a major risk allele for MCTD, in addition to HLA-B*08 (OR 2.05; p = 1.31 × 10 −4 ), while DRB1*04:04, DRB1*13:01, and DRB1*13:02 were protective . This was to date the largest HLA study on MCTD, and results obtained herein are similar to those in the previous, much smaller studies . Very recently, a study from Poland confirmed HLA DRB1*04:01 as a risk allele for MCTD . A large genetics study conducted in the UK on juvenile dermatomyositis (JDM) and JDM–scleroderma (JDM–SSc) overlap showed that all anti-U1-RNP antibody-positive patients (6% of the total patient cohort) had at least one copy of HLA-DRB1*04, thus probably reflecting that the HLA–DR4 association observed in adult MCTD is also present in children . Whether the observed HLA DRB1*04:01 association is primarily linked to anti-RNP or MCTD is of major concern. If it were linked to anti-RNP, one would expect to see the same HLA–DR4 association in anti-RNP-positive SLE or SSc. Unfortunately, the data on this issue are conflicting; Hoffman et al. and Smolen et al. reported a clear association between anti-RNP and HLA–DR4 in SLE, whereas Olsen et al. did not find any such association.
Data from HLA transgenic mice with MCTD-like disease suggested that the anti-RNP antibodies could be pathogenic, but no human data are available on this issue . To our knowledge, no studies are available on the pathogenic role of anti-RNP in other CTDs.
Clinical features
Raynaud’s phenomenon and “puffy hands”
Raynaud’s phenomenon (RP) was first described by Dr. Maurice Raynaud in 1862, which occurs in a primary and secondary form . Secondary RP, associated with the underlying chemical and/or structural changes in the vessel walls, is seen in all CTDs, but it is most prevalent in SSc and MCTD . It has been reported that patients with secondary RP due to SSc, MCTD, and DM have characteristic structural changes in their nailfold capillaries . Unfortunately, the nailfold capillaroscopy patterns of the different CTDs have not been systematically compared. No nailfold capillaroscopy data are currently available from the Norwegian cohort, but capillaroscopy data from the Hungarian MCTD cohort showed that 38% had a scleroderma capillaroscopy pattern . In the nationwide Norwegian cohort , RP was reported in 99% of the patients, comparable with the previous studies .
Swollen or “puffy” hands are among the most common disease manifestations reported in adult and juvenile MCTD cohorts ( Table 2 ). The mechanisms behind the symmetrical hand swelling are not clear, but tenosynovitis and/or endothelial cell dysfunction have been suggested . Adult MCTD cohort studies have reported “puffy hands” in 60–94% of the patients .
| Clinical features | Adult onset % a | Juvenile onset % b |
|---|---|---|
| Raynaud phenomenon | 99 | 93–100 |
| Puffy hands | 93 | 61–91 |
| Anti-RNP positive | 100 | 93–100 |
| SLE-like manifestations | ||
| Arthritis | 79 | 78–97 |
| Facial erythema | 41 | 9–69 |
| Leukopenia | 31 | 30–50 |
| Thrombocytopenia | 12 | 6–21 |
| Pleuritis | 14 | 10–21 |
| Pericarditis | 12 | 16–28 |
| Lymphadenopathy | N/A | 21–43 |
| SSc-like manifestations | ||
| Sclerodactyly | 34 c | 26–86 |
| Pulmonary fibrosis on CT | 35 | 25–30 |
| Hypomotility or dilatation of esophagus | 50 | 7–21 |
| PM-like manifestations | ||
| Muscle weakness | 33 | 29–70 |
| Elevated CK | 33 | 35–68 |
| Myogenic pattern in EMG | N/A | 25–38 |
| Other manifestations | ||
| Pulmonary arterial hypertension | 4 | 9 |
| Nephritis | 3 | 6–21 |
| Anemia | 27 | 64 |
a Reported frequencies on adult onset disease are from the population based Norwegian, nation-wide MCTD cohort study .
b Reported frequencies in juvenile onset disease are range with percentages from four different cohort studies .
c Sclerodactyly was reported as distal to PIP (proximal interphalangeal) joints.
Myositis
Myositis is included as one of the major criteria in all the four criteria sets for MCTD ( Table 1 ), but the actual data on muscle involvement are quite limited . The available data indicate that 35–79% of the MCTD patients will develop signs of myositis during the course of the disease , but myositis is rarely present at disease onset . It appears that the MCTD-associated muscle involvement has the same distribution as PM/DM, but seems to cause less permanent damage . Data on muscle histology in MCTD are limited and there are no studies on the potential role of muscle magnetic resonance imaging (MRI).
In a large European primary myositis cohort , autoantibodies to anti-U1 snRNP antibodies were reported in 6% (25/417). The anti-RNP-positive patients were treated with a lower steroid dose compared to the patients with classical PM or DM and succeeded in reducing it earlier and seemed to have a better prognosis regarding muscle involvement. Whether any of the anti-RNP-positive patients were diagnosed with MCTD has not been reported.
Arthritis and arthralgia
Joint symptoms are commonly associated with MCTD in most studies , and arthritis is included in all the criteria sets ( Table 1 ). The most common pattern appears to be polyarthritis, but the extent of joint damage caused remains unclear. In a study dating back to 1977, erosive lesions were described in as many as 53% (9/17) of the MCTD cases, but the representative nature of this study is not clear. Reports on the use of MRI and ultrasound are emerging, but no systematic data have been published .
Interstitial lung disease
Several small, single-center reports have indicated that ILD is one of the most severe disease complications in MCTD . Cross-sectional data from the Norwegian nationwide study showed that 52% of the patients examined ( n = 126) had abnormal findings on high-resolution computed tomography (HRCT) of the lungs, most commonly reticular patterns consistent with lung fibrosis (35%). Fibrosis was quantified as minor in 7%, moderate in 9%, and severe in 19% of the patients. Fibrosis was uniformly concentrated in the lower parts of the lungs and was not associated with smoking. Patients with severe lung fibrosis had lower pulmonary function test (PFT) values, shorter 6-min walk distance, a higher mean NYHA (New York Heart Association Functional Classification) functional class, and increased mortality (see section on prognosis). A newly published retrospective cohort study of 39 MCTD patients compared baseline and follow-up PFT and HRCT data over a 10-year period . At baseline, 51% of the patients had abnormal PFTs. Forced vital capacity (FVC) was slightly reduced at baseline (77% of predicted) but remained stable after 10 years. The diffusion capacity for carbon monoxide (DLCO) decreased from 84% to 71%, and the median lower lobe ILD–HRCT score progressed from 7.5% at baseline to 11.2% at follow-up . Few studies have investigated ILD in JMCTD, but a HRCT-based study showed that discrete ILD changes were present in 25% (6/24) patients, possibly indicating that JMCTD patients have less severe lung involvement than adult-onset MCTD .
Pulmonary hypertension
Precapillary PH is an important cause of morbidity and mortality in CTD, particularly in SSc . According to the 2015 European Society of Cardiology (ESC) and the European Respiratory Society (ERS) , pre-capillary PH is defined as a mean pulmonary arterial pressure (mPAP) of ≥25 mm Hg at rest by right-sided heart catheterization (RHC), coinciding with a pulmonary artery wedge pressure (PAWP) within normal limits of ≤15 mm Hg. According to the 2013 updated clinical classification of PH , patients with CTD-related precapillary PH belong to two main categories. They have either isolated pulmonary arterial hypertension (PAH; Group 1.4.1) or PH-associated with ILD (PH–ILD; Group 3.2).
Data on PH in MCTD are limited. The national PAH registry in the UK (with a population of about 60 million) included 36 MCTD patients with PH, thus indicating a total MCTD–PH prevalence of 0.6 per million.
Three earlier small single-center cohort follow-up studies estimated the total frequency of PH in adult MCTD at 23–24% . PH seems to be frequent (6–9%) in single-center JMCTD cohorts . In the Norwegian cohort study, all the MCTD patients were screened at study enrollment by echocardiography and patients suspected to have PH were referred for RHC. After enrollment, the patients were followed up for a mean period of 5.6 years. At baseline, 2.0% of the patients (3/147) had an established PH. Two additional PH patients were identified during follow-up, thereby yielding a total PH frequency in the cohort of 3.4% (5/147). Two of these patients had PAH and three had PH–ILD. A recently published study from Hungary reported that 18% of the MCTD patients (50/280) developed PAH after a mean follow-up time of 14.5 years . There are several possible reasons for the much higher PH frequency observed in this study, the most obvious being the difference in follow-up time. Another possible difference is the patient selection: the Norwegian study was population based, while the Hungarian cohort was derived from a large CTD center .
There are no published CTD–PAH epidemiological studies conducted in Asia, but recent data from a single-center Japanese cohort study of 70 patients with PAH associated with CTDs (PAH–CTD) showed that among CTDs, MCTD was most commonly associated with PAH (43%, 30/70), followed by SLE (29%, 20/70) and SSc (19%, 13/70). This is in contrast with the studies from Europe and USA, where the majority of patients with PAH–CTD have SSc. For example, in the national UK registry study referred earlier, 74% (315/429) of the CTD–PAH patients had SSc, 8% MCTD (36/429), and 8% SLE (35/429) . In the US-based REVEAL prospective PAH Registry (Registry to Evaluate Early and Long-Term PAH Management), the majority of the CTD PAH patients had SSc (500/804; 62%), while 16% had SLE and 9% had MCTD .
Skin manifestations and alopecia
Skin involvement is included in the Sharp and Kasukawa criteria sets ( Table 1 ) . There is a lack of newer data on rash in MCTD, but the long-term study by Burdt et al. described erythematous skin rash at onset in 13% and cumulatively in 53% . A Hungarian cohort study of Hajas et al. reported that a cumulative 36% of the patients developed some sort of skin involvement in the course of the disease, including photosensitivity, malar rash, telangiectasia, or hypo- and hyperpigmentation . In the study of Sullivan and coworkers, 29% had malar rash and 41% had alopecia . Interestingly, a small pathology study including eight patients with MCTD showed that the epidermal pathology mimicked that of subacute cutaneous lupus erythematosus (SCLE), but a concomitant vasculopathy parallel to that observed in DM distinguished it from SCLE .
Gastrointestinal involvement
The available data indicate that esophageal dysmotility and hypomotility are common in MCTD , and these findings are included in the Sharp and Kasukawa criteria sets but not in the other two ( Table 1 ). There are isolated reports of MCTD with autoimmune hepatitis , primary biliary cirrhosis , portal hypertension , and protein-losing enteropathy ; however, overall, it appears that GI (gastrointestinal) complications other than dysmotility of the esophagus are infrequent in MCTD. Interestingly, angiodysplasia of the gastric antrum, a recognized complication of SSc , has only been reported in a single MCTD patient .
Hematological manifestations
There are no recent data on the hematological alterations in MCTD, but the older studies indicate that anemia and leucopenia are common during the disease course whereas thrombocytopenia is reported to be infrequent .
Neurological manifestations
Trigeminal neuropathy is the only neurological complication included in any of the criteria sets and probably the most common nervous system problem encountered in the disease . Neuropsychiatric manifestations that are commonly observed in SLE and other central nervous complications appear to be very rare in MCTD . A recent study from Hungary showed that the frequency of sensory-neural hearing loss, as registered by audiograms, was twice as high in patients with MCTD compared with healthy controls . This potentially important finding has not been reproduced in other cohorts.
Renal involvement
Renal involvement is not included in any of the four criteria of MCTD, but data accumulated from several studies indicate that up to one-fifth (20%) of the MCTD patients eventually will develop some form of renal disease, most commonly, an immune complex nephropathy histologically classified as membranous glomerulonephritis (GN) . It does, however, seem that the kidney involvement in MCTD is mostly subclinical, with a good prognosis. In the Norwegian nation-wide cohort, <3% had minor kidney involvement during the course of the disease (unpublished data). In the Hungarian cohort, 4% had kidney involvement, with 27% (3/11) of those having thrombotic thrombocytopenic purpura-associated nephropathy and the remaining 73% (8/11) with GN, mostly ISN/RPS 2003 class II mesangial GN .
Update on the immunological and clinical features of MCTD
Immunological features
High titers of antibodies targeting the U1 small nuclear ribonucleoprotein particle (U1 snRNP) in peripheral blood are a sine qua non for the diagnosis of MCTD ( Table 1 ). These antibodies were originally detected by immunodiffusion. They were first described in sera from SLE patients, but they did not gain much attention before 1972 when Sharp et al. presented their concept of MCTD as a distinct CTD . Biochemical analyses have shown that the anti-RNP antibodies bind three U1-specific proteins A, C, and 70 kDa in the macromolecular U1–snRNP complex . ( Fig. 2 ) This complex contains many other antigens targeted by CTD-associated autoantibodies, including anti-Smith (Sm). An optimal protein purification was therefore critical for the diagnostic performance of anti-RNP antibodies. This has become less of a problem with the current enzyme-linked immunosorbent assays (ELISAs) as mixtures of recombinant proteins A, C, and 70 kDa are predominantly used as the antigen source.
The available data indicate that the 70-kDa antigen is the main target of serum anti-RNP antibodies in MCTD . It should, however, be noted that the relative frequencies of the circulating anti-U1 protein A, anti-U1 C, and anti-U1 70 kDa antibodies have not been widely assessed, either in MCTD or in any other CTD marked by anti-RNP antibodies.
The role of the anti-RNP antibodies in the pathogenesis of MCTD remains unknown, but recent data have reinforced the notion that the autoantibody production may be genetically determined and driven by distinct subsets of HLA-restricted T cells. Recently, we compared the HLA profiles, determined by sequence-based typing of HLA-B* and DRB1* in four groups of CTD patients of Norwegian ancestry: MCTD ( n = 155), SLE ( n = 96), SSc ( n = 95), PM/DM ( n = 84), and a control group of healthy individuals ( n = 282). The HLA DRB1*04:01 (OR 2.82; p = 3.64 × 10 −8 ) was confirmed to be a major risk allele for MCTD, in addition to HLA-B*08 (OR 2.05; p = 1.31 × 10 −4 ), while DRB1*04:04, DRB1*13:01, and DRB1*13:02 were protective . This was to date the largest HLA study on MCTD, and results obtained herein are similar to those in the previous, much smaller studies . Very recently, a study from Poland confirmed HLA DRB1*04:01 as a risk allele for MCTD . A large genetics study conducted in the UK on juvenile dermatomyositis (JDM) and JDM–scleroderma (JDM–SSc) overlap showed that all anti-U1-RNP antibody-positive patients (6% of the total patient cohort) had at least one copy of HLA-DRB1*04, thus probably reflecting that the HLA–DR4 association observed in adult MCTD is also present in children . Whether the observed HLA DRB1*04:01 association is primarily linked to anti-RNP or MCTD is of major concern. If it were linked to anti-RNP, one would expect to see the same HLA–DR4 association in anti-RNP-positive SLE or SSc. Unfortunately, the data on this issue are conflicting; Hoffman et al. and Smolen et al. reported a clear association between anti-RNP and HLA–DR4 in SLE, whereas Olsen et al. did not find any such association.
Data from HLA transgenic mice with MCTD-like disease suggested that the anti-RNP antibodies could be pathogenic, but no human data are available on this issue . To our knowledge, no studies are available on the pathogenic role of anti-RNP in other CTDs.
Clinical features
Raynaud’s phenomenon and “puffy hands”
Raynaud’s phenomenon (RP) was first described by Dr. Maurice Raynaud in 1862, which occurs in a primary and secondary form . Secondary RP, associated with the underlying chemical and/or structural changes in the vessel walls, is seen in all CTDs, but it is most prevalent in SSc and MCTD . It has been reported that patients with secondary RP due to SSc, MCTD, and DM have characteristic structural changes in their nailfold capillaries . Unfortunately, the nailfold capillaroscopy patterns of the different CTDs have not been systematically compared. No nailfold capillaroscopy data are currently available from the Norwegian cohort, but capillaroscopy data from the Hungarian MCTD cohort showed that 38% had a scleroderma capillaroscopy pattern . In the nationwide Norwegian cohort , RP was reported in 99% of the patients, comparable with the previous studies .
Swollen or “puffy” hands are among the most common disease manifestations reported in adult and juvenile MCTD cohorts ( Table 2 ). The mechanisms behind the symmetrical hand swelling are not clear, but tenosynovitis and/or endothelial cell dysfunction have been suggested . Adult MCTD cohort studies have reported “puffy hands” in 60–94% of the patients .
| Clinical features | Adult onset % a | Juvenile onset % b |
|---|---|---|
| Raynaud phenomenon | 99 | 93–100 |
| Puffy hands | 93 | 61–91 |
| Anti-RNP positive | 100 | 93–100 |
| SLE-like manifestations | ||
| Arthritis | 79 | 78–97 |
| Facial erythema | 41 | 9–69 |
| Leukopenia | 31 | 30–50 |
| Thrombocytopenia | 12 | 6–21 |
| Pleuritis | 14 | 10–21 |
| Pericarditis | 12 | 16–28 |
| Lymphadenopathy | N/A | 21–43 |
| SSc-like manifestations | ||
| Sclerodactyly | 34 c | 26–86 |
| Pulmonary fibrosis on CT | 35 | 25–30 |
| Hypomotility or dilatation of esophagus | 50 | 7–21 |
| PM-like manifestations | ||
| Muscle weakness | 33 | 29–70 |
| Elevated CK | 33 | 35–68 |
| Myogenic pattern in EMG | N/A | 25–38 |
| Other manifestations | ||
| Pulmonary arterial hypertension | 4 | 9 |
| Nephritis | 3 | 6–21 |
| Anemia | 27 | 64 |
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