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Objective MCTD manifests with microvasculopathy and overlapping clinical features of SLE, SSc and idiopathic inflammatory myopathies (IIM). The aim of this study was to investigate the clinical significance of microvasculopathy in patients with MCTD using nailfold videocapillaroscopy (NVC). Methods Fifty patients with newly diagnosed and untreated MCTD were enrolled in this multicentre, prospective and observational study. Clinical features and NVC findings were assessed at baseline and after 1 year post-intervention, along with disease controls [SLE (n = 40), SSc (n = 70) and IIM (n = 50)]. Results All MCTD patients presented Raynaud’s phenomenon and were positive for anti-U1 RNP antibodies, and 22.0% (11/50) had pulmonary arterial hypertension (PAH). The prevalence of NVC scleroderma patterns in MCTD was 38.0%, which was lower than SSc (88.6%) but higher than SLE (10.0%). In addition, when we divided MCTD patients into two groups by presence or absence of NVC scleroderma patterns, we found a higher prevalence of PAH in patients with NVC scleroderma patterns. Namely, NVC scleroderma patterns were observed in all MCTD patients with PAH, and in 21.0% of those without PAH. After intensive immunosuppressive therapy, NVC scleroderma patterns disappeared in half of the MCTD patients but were not changed in SSc patients. Conclusions MCTD differed from SLE, SSc and IIM in terms of the prevalence and responsiveness of NVC scleroderma patterns to immunosuppressive therapy. Detection of nailfold microvascular abnormalities in MCTD could contribute to predicting PAH and help us to understand further aspects of the pathogenesis of MCTD.

Background/Aims We aimed to establish the validity of the SLE-key® rule-out test and analyse its utility in distinguishing systemic lupus erythematosus (SLE) from other autoimmune rheumatic connective tissue diseases. Methods We used data from the Lupus Extended Autoimmune Phenotype (LEAP) study, which included a representative cross-sectional sample of patients with a variety of rheumatic connective tissue diseases, including SLE, mixed connective tissue disease (MCTD), inflammatory myositis, systemic sclerosis, primary Sjögren’s syndrome and undifferentiated connective tissue disease (UCTD). The modified 1997 ACR criteria were used to classify patients with SLE. Banked serum samples were sent to Immune-Array’s CLIA- certified laboratory Veracis (Richmond, VA) for testing. Patients were assigned test scores between 0 and 1 where a score of 0 was considered a negative rule-out test (i.e. SLE cannot be excluded) whilst a score of 1 was assigned for a positive rule-out test (i.e. SLE excluded). Performance measures were used to assess the test’s validity and measures of association determined using linear regression and Spearman’s correlation. Results Our study included a total of 155 patients of whom 66 had SLE. The mean age in the SLE group was 44.2 years (SD 13.04). 146 patients (94.1%) were female. 84 (54.2%) patients from the entire cohort had ACR SLE scores of ≤ 3 whilst 71 (45.8%) had ACR SLE scores ≥ 4. The mean ACR SLE total score for the SLE patients was 4.85 (SD 1.67), ranging from 2 to 8, with mean disease duration of 12.9 years. The Sensitivity of the SLE-Key® Rule-Out test in diagnosing SLE from other connective tissue diseases was 54.5%, specificity was 44.9%, PPV 42.4% and NPV 57.1 %. 45% of the SLE patients had a positive rule-out test. SLE could not be ruled out in 73% of the MCTD patients whilst 51% of the UCTD patients had a positive Rule-Out test and >85% of the inflammatory myositis patients had a negative rule-out test. ROC analysis generated an AUC of 0.525 illustrating weak class separation capacity. Linear regression established a negative correlation between the SLE-key Rule-Out score and ACR SLE total scores. Spearman’s correlation was run to determine the relationship between ACR SLE total scores and SLE-key rule-out score and showed very weak negative correlation (rs = -0.0815, n = 155, p = 0.313). Conclusion Our findings demonstrate that when applied in clinical practice in a rheumatology CTD clinic setting, the SLE-key® rule-out test does not accurately distinguish SLE from other CTDs. The development of a robust test that could achieve this would be pivotal. It is however important to highlight that the test was designed to distinguish healthy subjects from SLE patients and not for the purpose of differentiating SLE from other connective tissue diseases. Disclosure S. Achieng: None. J.A. Reynolds: None. I.N. Bruce: Other; I.N.B is a National Institute for Health Research (NIHR) Senior Investigator and is funded by the NIHR Manchester Biomedical Research Centre. M. Bukhari: None.

Background Vocal cord lesions related to autoimmune diseases have been described as early as 1959, when Scarpelli et.al described a case of a woman with systemic lupus erythematosus (SLE) presented with laryngeal oedema. Pathological examination of the tissue revealed inflammatory cells and the lesions were labeled as “inflammatory nodules”. Since then numerous case reports were published describing patients with rheumatic diseases and abnormal vocal cords with Hosako et al. in 1993 proposing the term “bamboo nodes”. Methods A 27 year old female, lifelong nonsmoker, developed a husky voice which persisted through the day. She had no odynophagia or dysphagia and occasionally suffered from heartburn.She reported feeling fatigue and described a non-blanching purpuric rash affecting her lower limbs. She was referred to rheumatology and also to ear, nose and throat (ENT) specialist for further assessments including laryngeal endoscopy and autoimmune screen. Results The video laryngeal endoscopy revealed an area of linear thickening of the left mid-vocal fold. There was no evidence of reflux or muscle tension. Immunological test's revealed positive antinuclear, ribonuclear and Sm antibodies, with normal serum complement. The erythrocyte sedimentation rate was raised with normal C-reactive protein and there was a polyclonal increase of immunoglobulins. A diagnosis of mixed connective tissue disease with bamboo nodes was made. Her treatment consisted of local corticosteroid injections into the vocal cords with prednisolone 5mg (Solu-DecortinR) and systemic corticosteroids followed by hydroxychoroquine 5mg/kg and azathioprine 2mg/kg. Patient improved clinically but still requires speech therapy as adjunctive to the pharmacological treatment. Conclusion Bamboo nodes are a rare manifestation of autoimmune diseases and currently there is no gold standard on how to manage them. This case highlights the need of close collaboration between ENT, rheumatology and speech&language therapy. Disclosures D.C. Christidis None. M. Lloyd None.

Background Spontaneous pneumomediastinum refers to dissection of free air from the airways on lung parenchyma into the mediastinal structures without any antecedent thoracic trauma or surgical intervention. Pneumomediastinum has been described as a rare complication of connective tissue disease, most commonly in dermatomyositis and polymyositis. Here we report 2 cases of mixed connective tissue disease (MCTD) who developed pneumomediastinum. Methods The first case was a 76 year old male undergoing assessment for MCTD. During assessment, he was found to have bi-basal crepitations without any obvious respiratory symptom. He was on steroids for last 4 weeks for proteinuria. His High- resolution CT scan (HRCT) showed pneumomediastinum with evidence of Interstitial lung disease (ILD) without any complication. He was monitored closely and his pneumomediastinum resolved without any intervention. The second case was a 49 year old female with known MCTD & was on steroids for 5 months. She was admitted to the hospital with weight loss and dysphagia. This was a long hospital stay during which she developed pneumomediastinum with pneumothorax and surgical emphysema around the neck. She required ICU admission and was transferred to cardiothoracic centre where she underwent bronchoscopy, VATS inspection and required chest drains. Results In both cases there were similarities where both patients with MCTD were on variable duration of steroids & had ILD. They then developed pneumomediastinum with surgical emphysema, however their course was quite contrasting where the first case was relatively benign & resolved without any intervention while the second one required long ITU stay with multiple complications and interventions. Conclusion Spontaneous pneumomediastinum is an uncommon manifestation of CTD and only few cases have been reported with MCTD. Although spontaneous mediastinum seems to be associated with a relatively benign short-term course, one should be wary of complications and have low threshold for investigating for any new lung symptoms in context of CTD. It is uncertain whether severity of MCTD or duration of steroids use impacts the progress of spontaneous pneumomediastinum as there are very limited number of cases. Disclosures F. Hasan None. V. Kumar None. S. Silburn None. R. Thomson None.

Objectives To assess the prevalence, extent, progression, functional impact and mortality of interstitial lung disease (ILD) in a nationwide unselected MCTD cohort. Methods The study cohort included patients with high-resolution CT lung scans available at baseline (n = 135) and at follow-up (n = 119). The extent of disease was expressed as percentage of total lung volume (TLV). Results ILD was present in 41% of MCTD patients at follow-up. Median (interquartile) extent (% of TLV) was 5 (8) at baseline and 7 (17) at follow-up, mean length 6.4 years later. The lung disease progressed in 19% of patients across the observation period. Predictors of ILD progression were elevated anti-RNP titre [hazard ratio (HR) 1.5, 95% CI: 1.1, 2.0; P = 0.008], presence of anti-ro52 antibodies (HR = 3.5, 95% CI: 1.2, 10.2; P = 0.023), absence of arthritis (HR = 0.2, 95% CI: 0.1, 0.6; P = 0.004) and male gender (HR = 4.0, 95% CI: 1.4, 11.5; P = 0.011) after age and baseline disease adjustments. The risk of death increased by 2.9 (95% CI: 1.1, 7.9; P = 0.038) in patients where disease involved ⩾5% of TLV. Conclusion Lung disease extent and progression in MCTD are modest. Yet, the extension continues several years after MCTD diagnosis causing lung function decline and increasing the risk of mortality. The study identified male gender, elevated anti-RNP titre, presence of anti-ro52 antibodies and absence of arthritis as the strongest predictors of ILD progression.

Atherosclerosis is a chronic inflammatory disease of the arteries associated with various risk factors that promote lipid abnormalities, development and progression of atherosclerotic lesions, plaque rupture, and vascular thrombosis. Atherosclerosis is accelerated in autoimmune diseases. Non-invasive investigations showed increased intima-media thickness (IMT), carotid plaque, and coronary artery calcifications in patients with antiphospholipid syndrome, systemic lupus erythematosus and mixed connective tissue disease compared to controls. The balance between the proinflammatory and anti-inflammatory cytokines allows the immune equilibrium to be maintained. In autoimmune diseases the prevalence of proinflammatory factors leads to premature atherosclerosis. This review presents complementary knowledge on innate and adaptive immunity, cytokines and the role of inflammasomes in progression of early atherosclerosis.

Mixed connective tissue disease (MCTD) is a rare autoimmune syndrome, signified by complex interactions between disease-related phenomena, including inflammation, proliferative vascular arteriopathy, thrombotic events and humoral autoimmune processes. It is still controversial whether MCTD is a distinct clinical entity among systemic connective tissue diseases, although several authors consider that it is distinct and underline characteristic, distinct clinical, serological and immunogenetic features. The putative target of autoimmunity in MCTD is U1-RNP, which is a complex of U1-RNA and small nuclear RNP. Both the U1-RNA component and the specific proteins, particularly U1-70K, engage immune cells and their receptors in a complex network of interactions that ultimately lead to autoimmunity, inflammation, and tissue injury. U1-RNA is capable of inducing manifestations consistent with TLR activation. Stimulation of innate immunity by native RNA molecules with a double-stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins.

OBJECTIVE The Norwegian nationwide MCTD cohort was established to obtain unbiased data on key disease issues, and thereby reappraise the concept of MCTD. In the current study, the aims were to obtain detailed HLA profile data on the large Norwegian MCTD cohort and compare these with the HLA profiles of ethnically matched healthy controls and related CTD controls. METHODS HLA profiles, determined by sequence-based typing of HLA-B* and DRB1*, were compared between four control groups of Norwegian ancestry, SLE (n = 96), SSc (n = 95), PM/DM (n = 84), healthy individuals (n = 282), the complete MCTD cohort (n = 155) and MCTD subsets defined by key clinical parameters. RESULTS HLA-B*08 [odds ratio (OR) 2.05, P = 1.31 × 10(-4)) and DRB1*04:01 (OR 2.82, P = 3.64 × 10(-8)) were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE and PM/DM were B*08 and DRB1*03:01. SSc risk was associated with DRB1*08:01. Analyses of MCTD subsets identified B*18 [OR 3.32 (95% CI 1.38, 8.01)] and DRB1*03:01 [OR 1.83 (95% CI 1.03, 3.25)] as independent risk factors for lung fibrosis. CONCLUSION Novel HLA alleles associated with MCTD and disease subsets were identified and DRB1*04:01 was confirmed as a major risk allele. Altogether, the data reinforce the notion of MCTD as a disease entity distinct from SLE, SSc and PM/DM.

OBJECTIVE In this study the alteration of endothelial function, arterial stiffness and autoantibodies was investigated in patients with UCTD. METHODS Thirty-one patients with UCTD were included in this prospective study. All the patients remained in the UCTD stage during the average 3.8 years follow-up period. The onset of UCTD was denoted as UCTD1, while the end of the follow-up period was called UCTD2. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), autoantibodies [such as anti-SSA, anti-SSB, anti-DNA, anti-RNP, anti-CCP, aCL, anti-oxidized low-density lipoprotein (oxLDL) and AECA], von Willebrand factor antigen, thrombomodulin (TM), endothelin 1 (ET-1) and lipid parameters were measured. RESULTS In the UCTD1 stage, high-sensitivity CRP (hsCRP) and endothelial cell activation and/or damage markers such as TM, ET-1 and AECA levels were significantly higher compared with controls (controls vs UCTD1: hsCRP, P < 0.0001; TM, P = 0.001; ET-1, P < 0.0001). In the UCTD2 stage, the carotid IMT increased (UCTD1 vs UCTD2, P = 0.01) and FMD further deteriorated (UCTD1 and UCTD2, P = 0.001). In UCTD2 there was a close correlation between the carotid IMT, and duration of the disease (r = 0.612, P < 0.001), the level of TM (r = 0.673, P < 0.001) and anti-oxLDL (r = 0.800, P < 0.001). CONCLUSION Our data suggest that the presence of inflammation and autoantibodies provoke endothelial cell activation and/or injury in UCTD patients. The persistent endothelial dysfunction may provoke the development of atherosclerosis. FMD was found to be the most sensitive marker for arterial stiffness, and the increase of IMT clearly indicated the existence of preclinical atherosclerosis in UCTD patients.

OBJECTIVES The aim of this study was to assess the overall prevalence of pulmonary hypertension (PH) in an unselected MCTD cohort and review the current knowledge with a systematic database search. METHODS A nationwide multicentre cohort of 147 adult MCTD patients were initially screened for PH by echocardiography, high-resolution computed tomography (HRCT), pulmonary function tests and N-terminal pro-brain natriuretic peptide (NT-proBNP) and then followed up for a mean of 5.6 years. Right-sided heart catheterization was performed when estimated pulmonary artery systolic pressure was >40 mmHg on echocardiography. PH was diagnosed according to the 2009 European Society of Cardiology and European Respiratory Society guidelines. RESULTS At inclusion, 2.0% (3/147) had established PH. Two additional PH patients were identified during follow-up, giving a total PH frequency in the cohort of 3.4% (5/147). All five had elevated serum NT-proBNP. Two had isolated pulmonary arterial hypertension (PAH) and three PH associated with interstitial lung disease (PH-ILD). Three PH patients died during follow-up. Nine other patients in the cohort also died, but none of them had echocardiographic signs of PH prior to death. CONCLUSION The data from the current unselected MCTD cohort suggest that the prevalence of PH is much lower than expected from previous studies but confirm the seriousness of the disease complication.

Objectives. Blood flow in fingers and toes is often impaired in patients with CTDs, mandating amputation in some. Our previous study showed that a single implantation of autologous bone marrow cells is as effective as peripheral blood mononuclear cells (MNCs) to restore impaired blood flow, although neither has long-lasting efficacy. In this study, autologous peripheral blood MNCs were implanted repeatedly to evaluate a better efficacy. Methods. Three patients with SSc, two with microscopic polyangiitis and one with MCTD were enrolled. All patients had severe RP, ulcers and/or necrosis in the extremities. MNCs were obtained from 400 to 1600 ml of peripheral blood and implanted into 2080 different sites in the palms and/or soles. This procedure was repeated every 3 months up to 1 year. Humoral factors were measured by ELISAs. Results. Visual analogue scale scores for pain, coldness and subjective satisfaction were improved after implantation in all patients. Pre-treatment ulcers in five patients were cured after repeated implantations. Angiography showed increased vasculature compared with baseline. Serum levels of VEGF increased after implantation, whereas levels of IL-1b, fibroblast growth factor and endostatin had variable results. None of the patients had any adverse reactions during a follow-up period of up to 3 years. Conclusions. Repeated implantation of peripheral blood MNCs was effective and safe for the treatment of recalcitrant ulcers developing in ischaemic digits and toes in patients with CTD.

Objective. We analysed our experience with the use of iloprost for the treatment of critical ischaemic digits (ID) in children with connective tissue diseases (CTD) in order to assess its safety and efficacy. Methods. This was a retrospective analysis of paediatric patients with CTD who were treated with iloprost for critical ID resistant to conventional therapy. Information on demographics, clinical and laboratory features, the regimen of iloprost treatment and outcome were collected. Results. Fifteen patients (10 female, five male) treated one or more times with iloprost were included (total of 19 treatments). Six had juvenile systemic sclerosis, five had systemic lupus erythematosus, three had mixed connective tissue disease and one had cutaneous polyarteritis nodosa. Thirteen patients were already taking calcium channel blockers with no improvement; in two patients ID were the presenting signs of the disease without prior treatment. Eleven patients had more than two fingers involved; one child had involvement of all 10 fingers. Normal digital blood flow was achieved in 74% of treatments and significant improvement was noted in 26%. Fingertip necrosis was present in 11 patients (14 treatments). It healed completely in seven, improved in one and remained unchanged in six. Raynaud’s phenomenon (RP) was present in 14 patients (17 treatments): in two no RP attack occurred during the follow-up period, eight improved both in the number of attacks per week and in the duration of each attack. Complete pain relief was observed in 10/17 treatments (59%) and there was a significant decrease in pain in the remaining seven. No major side-effects or withdrawal symptoms were reported. Minor side-effects reported include reversible headache (seven patients), hypotension or irritability (three), nausea/vomiting (two) and injection site reaction (one). Conclusions. Iloprost appears to be a safe and effective treatment for ischaemic digits and digital ulcers in children with CTD. In conjunction with immunosuppressive drugs, it has a potential role in preventing irreversible complications, such as digital gangrene and amputation.

Objectives. Previous reports have suggested that patients who have fibrosing alveolitis in association with a connective tissue disease (FA-CTD) have a better prognosis than patients with ‘lone’ cryptogenic fibrosing alveolitis (LCFA). The present study was designed to compare the survival of a general population-based sample of patients with FA-CTD and LCFA both with each other and with the general population. Methods. A survival analysis was performed using data for 107 patients with FA-CTD, 872 with LCFA and 5958 controls matched for age, sex and general practice, drawn from the General Practice Research Database. The data were analysed using Cox regression, adjusting for a number of potential confounders, including age, gender, smoking habit and use of oral corticosteroids. Results. The median follow-up period was 2.1 yr and during this time 54 (50%) patients with FA-CFA, 386 (44%) patients with LCFA and 601 (10%) controls died. The mortality rates for patients with FA-CTD, LCFA and the controls were 284, 270 and 41 per 1000 person-yr respectively. After adjusting for age, gender, smoking habit and exposure to oral corticosteroids, patients with FA-CTD had a marginally worse survival than patients with LCFA (hazard ratio 1.20, 95% confidence interval 0.90‐1.61). Compared with the general population controls, patients with either LCFA or FA-CTD had a considerably worse prognosis (hazard ratio 5.56, 95% confidence interval 4.77‐6.49). Conclusions. The median survival in patients with fibrosing alveolitis is less then 3 yr. We found no evidence to support previous reports of a better prognosis amongst patients with FA-CTD.

Objective. Although primary Sjogren's syndrome is often a benign condition, characterized by lymphocytic infiltration of salivary and lacrimal glands, some patients develop systemic features. We have previously found that anti-Ro antibodies identified patients with more systemic disease, with increased incidence of parotid swelling, lymphadenopathy and lymphoma. Methods. We have followed up a cohort of 100 patients over 10 yr, to establish whether the phenotypic expression of disease changed, and whether the diVerent autoantibody patterns expressed at presentation could be used to predict outcome. Results. While seronegative patients (ANA, RF, Ro and La negative) remained polysymptomatic, they did not develop systemic complications or serological changes. Thirty- nine per cent of ANA- or RF-positive patients who were negative for Ro and La were given revised diagnoses over the follow-up period, including rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease and scleroderma. Parotid swelling and lymphadenopathy were more common in Ro/La-positive patients, where the relative risk of developing non-Hodgkin's lymphoma was 49.7. Conclusion. Both HLA B8 and DR3 were present in 79% of Ro/La-positive patients, but were found together in only 4% of seronegative patients, supporting the view that these clinical subgroups of primary Sjogren's syndrome are both serologically and immuno- genetically distinct. Patients who are initially autoantibody (including Ro and La) negative do not evolve into 'systemic' Sjogren's syndrome or other connective tissue diseases.

Thirty-four patients (24 females and 10 males) selected from 300 consecutive patients with established systemic sclerosis (SSc), with a current or past history of articular symptoms, were clinically documented and further studied using thermography and bone scan to define the pattern of arthritis. Clinical evidence of synovitis was observed in 30 (88%) and joint inflammation was detected in 31 (91%) by the above-mentioned imaging techniques. A distinctive subset of 10 patients with deforming arthritis was characterized in which seven (70%) patients fulfilled criteria for both rheumatoid arthritis and SSC; three of these satisfied the criteria for diagnosis of CREST, but none met the criteria of mixed connective tissue disease. These patients, as a group, when compared with the rest showed limited skin involvement (skin score of 19 +/- 11 vs 33 +/- 14; P < 0.05) and were positive for rheumatoid factor (80 vs 13%; P < 0.05) and anticentromere antibodies (37 vs 4%; P < 0.05).

Twenty-nine anti-RNP positive patients were followed prospectively with a mean observation time of 65 months (29-120 months). The clinical course was correlated to the presence of IgM and IgG anti-(U1)snRNP antibodies as revealed by immunoblotting from sequentially obtained sera. There was a striking dissociation between the fluctuating course, with the appearance of new manifestations followed by remissions, and the stability of the anti-snRNP antibody specificities where an appearance or a disappearance of anti-snRNP specificities was a rare phenomenon. The main epitope recognized by the IgG antibodies was the 70 kDa protein and of the IgM antibodies the B/B' proteins. No shift from the IgM to the IgG isotype was observed. The presence of IgG anti-70 kDa and IgM anti-B/B' antibodies was highly associated with presence of arthralgias, Raynaud's phenomenon and arthritis. Further, an association was noted between the combined presence of IgG anti-70 kDa, anti-A and anti-C antibodies and IgM anti-B/B' and puffy hands, myositis, pulmonary fibrosis and sclerodactyly, i.e. all manifestations of mixed connective tissue disease (MCTD). On the contrary, serositis as often seen in SLE was correlated to the presence of IgG anti-B/B' antibodies. Thus the longitudinal analysis of the correlation between anti-snRNP antibody specificities and clinical manifestations support the concept of MCTD as a distinct entity.

One thousand consecutive patients with systemic connective tissue diseases were screened clinically and serologically to determine the existence of mixed connective tissue disease (MCTD) in the Indian population. After completion only three patients could be diagnosed as having MCTD using the standard diagnostic criteria. The results of this study point to MCTD existing but it appears to be a rare entity in the Indian population.

We completed ocular examination, including retinal fluoroangiography, in 19 unselected patients with diffuse systemic sclerosis (scleroderma) and compared the findings with those made in 50 consecutive patients with systemic lupus erythematosus, 18 with primary Sjögren's syndrome, 20 with mixed connective tissue disease, and 20 healthy women. Five of 19 scleroderma patients had atrophy of the retinal pigment epithelium (26.3%) while none of the controls and only four of the 88 (4.5%) patients with other connective tissue diseases (P less than 0.01) had this anomaly. Atrophy of the pigmented epithelium of the retina may occur in scleroderma as a result of damage of the choroidal plexus.

SIR, We wish to report the first successful use of rituximab in Raynaud’s phenomenon associated with mixed connective tissue disease, with disappearance of associated anti-RNP antibodies. A 40-yr-old lady presented in 1997 with swelling of the small joints of her hands, Raynaud’s phenomenon and a restrictive lung defect on pulmonary function tests. She did not have features of other connective tissue diseases. She had a positive test for antibodies to ribonuclear protein (RNP) on two occasions and a diagnosis of mixed connective tissue disease was made. She remained stable on prednisolone 5–10 mg and hydroxycloroquine 200 mg bd until 2001. Raynaud’s phenomenon then worsened, requiring intravenous infusion of iloprost (titrated from 0.5 to 2 mcg/kg/min on three successive days) every 3 months. Later, bosentan (125 mg bd) and tadalafil (10 mg bd) were tried. A digital sympathectomy helped briefly, but 3-monthly iloprost infusion continued, with infection of a femoral line on two occasions.

The past decade has been marked by rapid advances in molecular biology techniques, which are now routinely and commercially available for research groups around the world. Examples include the microarray technique and methods for gene silencing such as small interference RNA (siRNA) and cell transfection with antisense constructs. For research groups interested in the pathogenesis of certain diseases, these novel techniques allow a rapid high throughput screening for genes which are differentially expressed in health and disease, and might thus be of functional importance for disease development or disease progression [1]. In this context, there has been major progress in our understanding of the pathophysiology of connective tissue diseases. Connective tissue diseases form a wide spectrum of disorders including, among others, systemic lupus erythematosus, systemic sclerosis, dermato-polymyositis, mixed connective tissue disease and Sjogren’s syndrome. The pathophysiology and clinical presentation of these diseases are diverse. However, the discovery of key molecules as well as key mechanisms in the specific pathogenesis have significantly increased the options to treat their organ-based complications. While the conventional non-selective therapies are still of importance in daily clinical life, most of the new agents target specific molecules or mechanisms that have been shown to play a functional role in the pathogenesis of the overall disease or certain organ manifestations [2, 3]. To provide a comprehensive background for these new therapeutic options and to summarize novel developments, this supplement of Rheumatology has gathered experts in the fields of rheumatology, dermatology and nephrology to cover different aspects in the epidemiology, pathophysiology, clinical features and their pathophysiology, and treatment of patients with connective tissue diseases. Regarding epidemiology, it is shown in this supplement that the incidence and prevalence of connective tissue diseases are low compared with other inflammatory rheumatic diseases such as rheumatoid arthritis or spondarthropathies; however, they are potentially life-threatening. As connective tissue diseases often occur in younger women during the childbearing period, treatment and clinical care during pregnancy is a major challenge for clinicians. Classification criteria used in clinical studies to obtain well-defined study populations frequently underestimate the prevalence of the disease by excluding patients with early disease or incomplete disease manifestations. Since novel

The reported prevalence and incidence of connective tissue disorders are quite variable, depending on differences in study methodology. Most important differences are the study duration, the classification criteria used for diagnosis and the country in which the study was undertaken. Sjögren's syndrome has the highest prevalence ranging between 0.5 and 3% of a given population. The prevalence of systemic lupus erythematosus (SLE) is estimated between 15 and 50 per 100 000 individuals, with a female:male ratio of 6-10:1 in the age group between 15 and 40 yrs. The prevalence of systemic sclerosis is lower, however, varying significantly between different studies and countries. The prevalence of overlap syndromes, especially mixed connective tissue disease, is unknown, and polymyositis and dermatomyositis are regarded as very rare rheumatic diseases. Though the classification criteria for the connective tissue disorders have not been developed for the purpose of diagnosing an individual patient, these criteria still are the most valuable tool for the identification of patients with systemic rheumatic diseases such as connective tissue disorders.

A young female with mixed connective tissue disease (MCTD) presented with the unusual occurrence of abdominal pseudolymphoma. Although the pseudolymphoma could be related to concomitant sicca complex, some data suggest that MCTD, as such, could carry a high incidence of malignancy.