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BACKGROUND: Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. METHODS: This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28. FINDINGS: Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups. INTERPRETATION: The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice. FUNDING: Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research. ispartof: LANCET vol:397 issue:10271 pages:305-317 ispartof: location:England status: published

To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc).Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests.Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p0.03 and p0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p0.05) and on morning stiffness at 6 and 12 months (p0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p0.05). No changes in lung or gastrointestinal involvement were found.ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.

Patient-reported outcomes (PROs) are currently poorly integrated in the clinical evaluation of disease activity in patients with ANCA-associated vasculitis (AAV).To assess the distribution of the Patient Global Assessment (PtGA) in patients with AAV in stable remission, and to identify correlates of PtGA; to assess the discordance between PtGA score and Physician Global Assessment (PhGA).Patients with a diagnosis of AAV in stable remission (BVAS=0) and with a Physician Global Assessment (PhGA)=0 were included. The following PROs on a 0-100 visual analogue scale (VAS) were assessed: PtGA, fatigue, pain, general health, sleep quality, and chronic damage according to the patient's opinion. The Cragg Hurdle model was used to assess the predictors of PtGA.65 patients were included, female 57%, mean age 61±12 years. Median disease duration 6 years (IQR 3-12). Vasculitis damage index (VDI) was 4.4±2.3. Despite having been classified as being in remission, PtGA was elevated in 37% of patients. The PtGA was not associated with older age, comorbidities, educational level, the type of AAV diagnosis, number of organ-systems involved, previous relapses, disease duration, nor higher VDI. Female sex was significantly associated with PtGA: 51% of female patients reported an elevated PtGA compared to 18% of males (p=0.009). PtGA significantly correlated with all the other assessed PROs. Pain and fatigue were the main determinants of an elevated PtGA.A significant proportion of patients with AAV considered to be in remission by the physician still declares to have persistent aspects of uncontrolled disease. PtGA is significantly influenced by pain and fatigue, which should receive more attention in the future assessment of patients with AAV.

Resume Les protheses de hanche a couple de frottement metal-metal contenant du cobalt peuvent etre a l’origine d’une toxicite systemique provoquee par le relargage d’ions cobalt dans la circulation sanguine. Des taux eleves de cobalt dans le sang peuvent provoquer diverses manifestations cliniques imitant d’autres maladies, notamment auto-immunes, hematologiques et infectieuses. Nous rapportons un cas d’intoxication au cobalt a partir d’une prothese de hanche , imitant une maladie auto-immune avec des signes d’inflammation systemique, des douleurs articulaires et musculaires sans synovite et la positivite de plusieurs auto-anticorps. Une femme de 69 ans presentait depuis un an une douleur de hanche droite, une fievre recurrente, des arthralgies et myalgies, des adenopathies mediastinale et iliaque droite. Elle avait une prothese de hanche depuis sept ans. L’examen physique etait normal, a l’exception d' une douleur de la hanche droite. Les analyses biologiques ont revele une nette elevation des marqueurs de l’inflammation et tous les tests microbiologiques etaient negatifs. Une ponction articulaire guidee par echographie de la hanche droite a permis de prelever un liquide limpide dont la mise en culture s’est averee negative. Des taux eleves de cobalt dans le plasma et les urines indiquaient la presence d’une intoxication a ce metal. L’imagerie par resonance magnetique en sequence de reduction des artefacts metalliques (MARS) a confirme la presence d’une masse periprothetique caracteristique d’une reaction a des debris metalliques. Les manifestations cliniques et les taux de cobalt se sont normalises apres le remplacement de la prothese.

Autoimmune diseases (AID) are increasingly prevalent conditions which comprise more than 100 distinct clinical entities that are responsible for a great disease burden worldwide. The early recognition of these diseases is key for preventing their complications and for tailoring proper management. In most cases, autoantibodies, regardless of their potential pathogenetic role, can be detected in the serum of patients with AID, helping clinicians in making a definitive diagnosis and allowing screening strategies for early -and sometimes pre-clinical- diagnosis. Despite their undoubted crucial role, in a minority of cases, patients with AID may not show any autoantibody, a condition that is referred to as seronegative AID. Suboptimal accuracy of the available laboratory tests, antibody absorption, immunosuppressive therapy, immunodeficiencies, antigen exhaustion, and immunosenescence are the main possible determinants of seronegative AID. Indeed, in seronegative AID, the diagnosis is more challenging and must rely on clinical features and on other available tests, often including histopathological evaluation and radiological diagnostic tests. In this review, we critically dissect, in a narrative fashion, the possible causes of seronegativity, as well as the diagnostic and management implications, in several AID including autoimmune gastritis, celiac disease, autoimmune liver disease, rheumatoid arthritis, autoimmune encephalitis, myasthenia gravis, Sjögren's syndrome, antiphospholipid syndrome, and autoimmune thyroid diseases.

Background: Prevalence and outcomes of Coronavirus Disease (COVID)-19 in relation to immunomodulatory medications are still unknown. The aim of the study is to investigate the impact of glucocorticoids and immunosuppressive agents on COVID-19 in a large cohort of patients with chronic immune-mediated inflammatory arthritis. Methods: The study was conducted in the arthritis outpatient clinic at two large Academic Hospitals in the COVID-19 most endemic area of Northern Italy (Lombardy). We circulated a cross-sectional survey exploring the prevalence of Severe Acute Respiratory Syndrome-Coronavirus-2 nasopharyngeal swab positivity and the occurrence of acute respiratory illness (fever and/or cough and/or dyspnea), administered face-to-face or by phone to consecutive patients from 25th February to 20th April 2020. COVID-19 cases were defined as confirmed or highly suspicious according to the World Health Organization criteria. The impact of medications on COVID-19 incidence was evaluated. Findings: The study population included 2050 adults with chronic inflammatory arthritis receiving glucocorticoids, conventional-synthetic (cs), or targeted-synthetic/biological (ts/b) disease-modifying drugs (DMARDs). Laboratory-confirmed COVID-19 and highly suspicious infection were recorded in 1.1% and 1.4% of the population, respectively. Treatment with glucocorticoids was independently associated with increased risk of COVID-19 (adjusted OR [95% CI] ranging from 1.23 [1.04-1.44] to 3.20 [1.97-5.18] depending on the definition used). Conversely, patients treated with ts/bDMARDs were at reduced risk (adjusted OR ranging from 0.46 [0.18-1.21] to 0.47 [0.46-0.48]). No independent effects of csDMARDs were observed. Interpretation: During the COVID-19 outbreak, treatment with immunomodulatory medications appears safe. Conversely, glucocorticoids, even at low-dose, may confer increased risk of infection. Funding: None. Declaration of Interests: Authors declare no competing interest. Ethics Approval Statement: The current analysis was approved by the Ethics Committees of the Gaetano Pini Institute and Policlinico San Matteo as part of a project to collect observational data from rheumatological patients followed at the two involved rheumatology units. All included patients have signed an informed consent to participate in the data collection. The possibility of including this survey within the abovementioned data collection project has been waived by the same ethics committee.

The aim of the study was to evaluate the rate of obstetric complications and the burden of obstetric outcomes in antiphospholipid syndrome (APS), non-criteria APS and asymptomatic antiphospholipid antibodies (aPL) carriers. From 2013-2018, 163 pregnant subjects with aPL antibodies and 785 controls were enrolled. Penalized logistic regression was used to compare obstetric complications. Cases included 62 complete APS (38 %), 48 non-criteria APS (29.4 %) and 53 (32.5 %) asymptomatic aPL-carriers. Connective tissue diseases (CTDs) were diagnosed in 31.3 % of cases. The rate of high-risk aPL profile was higher (p < .01) in APS (67.7 %) compared to non-criteria (14.6 %) and aPL-carriers (9.4 %). Double/triple positivity was 33.9 % (p < .05 compared to non-criteria and aPL-carriers) in APS, 10.4 % in non-criteria and 9.4 % in aPL-carriers. The rate of adverse pregnancy outcomes were 5.6 % in controls, 41.9 % (adj.OR = 6.95 %CI = 2.7-13.5) in APS, 25 % (adj.OR = 4.4,95 %CI = 2-9.4) in non-criteria and 28.3 % (OR = 4.95 %CI = 1.8-8.8) in aPL-carriers. CTDs were independently associated with an increased risk of adverse obstetric outcomes (OR = 2.8,95 %CI = 1.36-5.89). The attributable fraction (AF) of adverse obstetric events was higher among low-risk antibodies compared to high-risk (AF = 0.27,95 %CI = 0.22-0.31 vs AF = 0.16,95 %CI = 0.16-0.2,p < .01) and among single positivity compared to double/triple positivity (AF = 0.32,95 %CI = 0.26-0.37 vs AF = 0.11,95 %CI = 0.09-0.13,p < .01) suggesting that low-risk subjects are responsible for a high burden of obstetric complications.

Objective Arthritis, myositis and interstitial lung disease (ILD) constitute the classic clinical triad of anti-synthetase syndrome (ASSD). These patients experience other accompanying features, such as Raynaud's phenomenon, fever or mechanic's hands. Most ASSD patients develop the complete triad during the follow-up. In the present study we aimed to determine whether the subsequent appearance of accompanying features may suggest the development of triad findings lacking at the onset in anti-Jo1 positive ASSD patients. Methods Anti-Jo1 positive patients presenting with incomplete ASSD (no >2 classic triad features) were assessed. Clinical characteristics and clusters of disease manifestations were retrospectively collected and analyzed in a large international multicenter cohort of ASSD patients. Results 165 patients (123 women) with incomplete ASSD were identified. Ninety-five patients (57.5%) developed new classic triad manifestations after 15months median (IQR 9–51) and 40 (24%) developed new accompanying features after 19months median (IQR 6–56) from disease onset. During the follow-up, the ex-novo occurrence of triad features was observed in 32 out of 40 patients (80%) with new accompanying findings and in 63 out of 125 patients (50.5%) without new accompanying findings (p=0.002). In patients with at least one new accompanying feature the odds ratio for the occurrence of new triad manifestations was 3.94 with respect to patients not developing ex-novo accompanying findings (95% CI 1.68–9.21, p=0.002). Conclusion Anti-Jo1 ASSD patients with incomplete forms at disease onset are at high risk for the subsequent occurrence of lacking classic triad findings. Although all ASSD patients should be carefully assessed for the occurrence of new triad features, a closer follow-up should be considered in the subgroup of patients developing ex novo accompanying findings. These patients, indeed, have near four-fold increased risk for new classic triad manifestation occurrence with respect to patients not presenting ex novo accompanying findings.

To investigate the rates and coexistence of autoimmune thyroid and connective tissue diseases (CTD) during the first trimester of pregnancy and their influence on pregnancy outcome.A cohort study of 150 women with CTD diagnosed during first trimester of pregnancy and 150 negative controls.Screening of CTD by a self-reported questionnaire, rheumatic and thyroid autoantibody detection, clinical rheumatological evaluation and obstetric outcomes.Out of 3852 women screened, 61 (1.6%) were diagnosed with undefined connective tissue disease (UCTD), 28 (0.7%) with major CTD (six rheumatoid arthritis, five systemic lupus erythematosus, eight Sjogren syndrome, five anti-phospholipid syndrome, two systemic sclerosis, one mixed CTD and one monoarticular arthritis) and 61 (1.6%) had insufficient criteria for a diagnosis of a rheumatic disease. The overall prevalence of either thyroid peroxidase (TPO-a) or thyroglobulin (TG-a) autoantibodies detection was 8% (12/150) among controls, 62.3% (38/61) among UCTD and 60.7% (17/28) in women with a major CTD (p.001 compared to controls for both comparisons). After adjustment for confounders, overall CTDs (major or undefined) (OR=3.54, 95% CI; 1.61-7.78) and TPO-a plus TG-a positivity (OR=2.78, 95% CI;1.29-5.98) were independently associated with increased risks of moderate-severe complications of pregnancy (miscarriage, fetal growth restriction, preeclampsia, delivery before 34 weeks).Rheumatic and thyroid autoantibodies during pregnancy are closely associated. Thyroid antibodies could add to the risk of adverse pregnancy outcome associated with connective tissue diseases.

Autoimmune rheumatic diseases in pregnancies are associated with increased adverse obstetric outcomes. We compared maternal soluble human leucocyte antigen-G (sHLA-G) blood levels in subjects with a rheumatic disease preexisting pregnancy and unaffected controls. Third-trimester blood maternal sHLA-G concentrations were significantly higher in subjects with rheumatic diseases than in controls (mean 93.1ng/ml [SD 42.1] vs 58.1ng/ml [SD 96.3], p=0.003). Cord blood sHLA-G concentrations were significantly higher in rheumatic disease than in those born to control mothers (median 41.2ng/ml [IQR: 3.3-44.0] vs 17.9ng/ml [IQR: 17.2-88.1], p=0.007). A strict positive correlation (r=0.88, p

Objective The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. Methods Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. Results An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild–moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low–medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild–moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. Conclusion Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS.

B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). Rituximab is a chimeric monoclonal antibody that depletes B-cells by binding to the CD20 surface antigen that has been approved for the treatment of RA. Its efficacy has been clearly demonstrated by different clinical trials and, recently, in long-term observational studies. The use of rituximab in clinical practice has highlighted its efficacy and safety over more than 5 years of treatment, as well as to try to understand the timing for retreatment of patients relapsing after a good initial response.

Patients with rheumatoid arthritis (RA) has an increased infections risk and morbidity and mortality related to infections. This increased risk may occur due to the disease itself with intrinsic cellular immunity alterations or as a results of drugs used to control the disease. The potential risk of infections related to conventional disease modifying anti-rheumatic drugs (DMARDs) is not completely clarified. Methotrexate (MTX) may increase the infectious risk, but its positive effect on disease activity results in a reduction of further risk factors for infections. Data about the increased risk of pneumonia or reactivation of silent infection remain controversial. Leflunomide (LEF) seems safe in controlled trial even if it has been associated with the onset of infections requiring hospitalization, such as pneumonia. Data about other DMARDs are scanty and the main cause of interruption of therapy is related to toxicity different from infection. Beside the general positive profile of DMARDs as for infectious risk, a careful use and tight control of the patients is recommended.

Cold-precipitating monoclonal immunoglobulins can rarely aggregate in form of crystals (cryocrystalglobulins) and cause serious clinical manifestations. The structural basis underlying this phenomenon remains to be defined. This study was undertaken to provide the first characterization of the heavy (VH) and light chain (VL) variable regions of two human pathogenic cryocrystalglobulins. The immunoglobulins used different heavy and light chain constant regions and germline gene fragments, underwent high degrees of somatic hypermutation, and showed distributions of replacement and silent nucleotide changes suggestive of antigenic selection. Primary sequences analyses and computer-generated modeling identified a positive charge and the introduction of unusual hydrophobic residues in exposed areas of VH and VL. In particular, a rare replacement of a polar residue with proline is shared at the beginning of the VH complementarity-determining region 2, and this residue might be involved in intermolecular contacts.

Resume Objectifs. – Determiner les caracteristiques cliniques, serologiques, radiologiques et immunogenetique des patients atteints de polyarthrite rhumatoide et ayant un trait beta-thalassemique et les comparer avec celles des patients ayant une polyarthrite rhumatoide issus de la meme region geographique. Materiel et methodes. – Vingt-huit patients ayant un trait beta-talassemique satisfaisaient les criteres ACR de la polyarthrite rhumatoide. Ils ont ete compares a un groupe controle comprenant 28 patients atteints de polyarthrite rhumatoide apparies pour l’âge, le sexe, la duree d’evolution de la maladie et le lieu de naissance. L’examen clinique et les examens de laboratoire classiques dont les anticorps anti-keratine et anti-peptides citrullines ont ete colliges dans les deux groupes. Les patients ont egalement ete evalues pour les alleles HLADRB1 et les anomalies radiologiques. Resultat. – Aucune difference n'a ete trouvee concernant les index cliniques mesurant l'activite de la maladie, les parametres biologiques, ni les erosions articulaires. L'analyse immunogenetique n’a pas mis en evidence de difference significative, le pourcentage de patients porteurs des alleles codant pour l’epitope partage etant similaire dans les deux groupes (61 % vs 57 %). Comme pour manifestations articulaires, nous avons trouve une tendance pour une prevalence moins elevee de syndrome sec dans le groupe beta-thalassemique (14 % vs 39 % ; p = 0,06). Nous n'avons pas trouve de nodules rhumatoides chez les patients beta-thalassemiques alors que deux patients du groupe controle en avaient. Conclusions. – La polyarthrite chronique survenant chez des patients ayant un trait beta-thalassemique peut etre consideree comme une veritable polyarthrite rhumatoide similaire a celle rencontree dans les pays mediterraneens, avec peut-etre une moindre prevalence de manifestations extra-articulaires.

Resume Une observation rare, d’hypercalcemie severe survenant au cours d’un lupus erythemateux dissemine (LED) est rapportee. A l’admission, une jeune femme presente une hypercalcemie severe et une photosensibilite. Il n’y a pas suffisamment de criteres pour poser le diagnostic de LED. Toutes les causes d’hypercalcemie ont ete eliminees. Les radiographies osseuses sont normales. Un an plus tard, le diagnostic de LED est certain. De plus, une demineralisation osseuse severe et diffuse et des deformations thoraciques sont apparues. Le traitement du LED a permis de normaliser la calcemie. Une discrete elevation de la calcemie survient lors des poussees de LED. L’hypothese emise est que l’hypercalcemie des patients suivis pour LED pourrait etre due a la presence d’anticorps activateurs, antirecepteurs de la PTH. Cette observation fait penser que chez les patients avec une hypercalcemie severe associee au LED, le diagnostic et le traitement precoces du lupus pourraient prevenir la perte de masse osseuse. Chez ces patients la prevention de la perte de masse osseuse est importante. En effet une demineralisation severe pourrait favoriser les deformations osseuses et les fractures ; de plus, elle pourrait representer un serieux obstacle a l’utilisation de doses adaptees de corticoides pour le traitement du lupus.

Anti-Ro(SS-A) 52 kDa and 60 kDa specificities in undifferentiated connective tissue disease. — Objective. Autoantibodies to Ro(SS-A) may recognize two different polypeptides, of 52 kDa and 60 kDa, respectively. Methods. We used an ELISA with purified human recombinant antigens to conduct a detailed analysis of the specificities of anti-Ro(SS-A) antibodies from 170 patients with definite diagnoses (systemic lupus erythematosus [SLE], n = 55; primary Sjogren's syndrome [PSS], n = 39; systemic sclerosis, n = 9; rheumatoid arthritis [RA], n = 10) or undifferentiated connective tissue disease (UCTD, n = 57). Most of the patients with SLE or PSS had both anti-52 kDa and -60 antibodies; isolated anti-60 kDa antibodies were found in 13 % of the SLE patients and in none of the PSS patients, whereas high titers of anti-52 kDa were more common in the PSS than in the SLE patients. Results. In the UCTD patients, the anti-Ro(SS-A) profile showed no significant correlations with clinical features but was associated with the clinical outcome. Over the mean follow-up of five years, definite SLE developed in four of the five UCTD patients with isolated anti-60 kDa vs only one of the remaining 52 patients (p < 0.0001); progression to PSS was seen in seven of the 34 patients with both anti-52 kDa and anti-60 kDa vs none of the remaining 23 patients (ρ = 0.03); none of the 12 patients with isolated anti-52 kDa developed a definite connective tissue disease. Conclusion. Our study suggests that analysis of anti-Ro(SS-A) specificity may provide useful information for predicting the course of UCTD.

PATIENTS with undiagnosed cold-reactive protein (CRP) disease undergoing hypothermia are at high risk of major morbidity and mortality if they are not identified and treated before surgery.1 Chronic thromboembolic pulmonary hypertension may be cured by pulmonary thromboendarterectomy (PTE), for which deep hypothermia and circulatory arrest (DHCA) are recommended.2 Because of hypothermia, PTE is a challenging procedure in patients with sickle cell and CRP disease. Successful PTE in patients with sickle cell disease has been reported by Yung et al.3 A patient is described with a preoperative diagnosis of cold agglutinins (CA) in whom successful PTE was also performed.

Objective The purpose of this study was to evaluate pregnancy outcome in a cohort of patients with newly diagnosed undifferentiated connective tissue disease (UCTD). Study Design We conducted a nested case-control study that compared 41 patients who had early UCTD that was diagnosed at 11-14 weeks of pregnancy with 82 healthy control subjects. Results During pregnancy, UCTD progressed to a definite connective tissue disease in 2 of 41 patients (4.9%). Sixteen of the 41 patients (39%) with UCTD tested positive for anti-Ro (SSA) antibodies. Compared with the control subjects, the women with UCTD had higher rates of small for gestational age (SGA; 12/40 vs 11/80; P = .05). The rate of complications of pregnancy (preterm delivery at ≤ 37 weeks of gestation, SGA, preeclampsia, late fetal loss) was 39% (16/41) among cases and 13.4% (11/82) in control subjects (adjusted odds ratio, 3.98; 95% CI, 1.59-9.49). Conclusion Pregnant patients with UCTD are at increased risk of SGA and complications of pregnancy.

In 62 patients with multiple myeloma (MM) and related disorders, the nuclear DNA content distribution of bone marrow plasma cells was assessed by flow and conventional cytofluorometry. Abnormal distributions, suggesting the presence of aneuploid populations, were observed in 53% of MM at diagnosis, in 50% of benign monoclonal gammopathies and in 12% of Waldenström's macroglobulinemias. Eighty-six percent of aneuploid cases had DNA stem-lines falling between the diploid and triploid value. In advanced and relapsing MM, abnormal distributions were found in 75% of cases. In 4 out of 14 patients with MM serially studied during the course of disease, emergence of new abnormal clones was documented. The abnormal DNA content of bone marrow plasma cells was not correlated with any clinical and laboratory characteristic and it affected neither response to therapy nor survival in patients studied at diagnosis. In advanced phases of MM, the presence of abnormal clones was correlated with high plasma cell proliferation rates (studied by tritiated thymidine incorporation) and poor response to chemotherapy. Seven out of 8 patients in acute terminal phase of MM had abnormal clones. Among these, five had DNA stem-lines over triploid value.