[TNFalpha blockers and infectious risk in rheumatoid arthritis]. / I farmaci biologici anti-TNFalpha e il rischio infettivo nell'artrite reumatoide.

Patients suffering from rheumatoid arthritis have increased risk of infections when compared with general population. The risk depends directly from disease activity and severity. Furthermore, risk increases with aging, immunosuppressive agents and comorbidities such as diabetes, pulmonary and cardiac diseases. In particular corticosteroids, even at low doses, are a major risk factor. Due to disease related risk it is difficult to separate the risk deriving from the use of TNF alpha blockers. Data from clinical trials, meta-analysis and national registers are somewhat contradictory. In patients with rheumatoid arthritis on routine follow-up, treatment with TNF alpha blockers seems to carry an increased risk of infections compared to traditional DMARDs but not associated with increased risk of overall serious infection. Physicians should carefully monitor for signs of infection when using TNF alpha blockers, particularly shortly after treatment initiation.

MonitorNet: the Italian multi-centre observational study aimed at estimating the risk/benefit profile of biologic agents in real-world rheumatology practice.

MonitorNet is a database established by the Italian Society of Rheumatology (SIR) in January 2007 and funded by the Italian Medicines Agency (AIFA), for the active long-term follow-up of patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis treated with biologic agents. All hospital Rheumatology Units in Italy were invited to participate in a non-interventional, observational, epidemiological study. The study is conducted in a routine clinical setting (real-world practice) where biologics are prescribed on the basis of current recommendations. In this report we describe the design, methodology, and present preliminary data of the study. At the time of the analysis (April 2009) the database included 3510 patients: 2469 (70.3%) with established RA, 675 (19.2%) with PsA and 366 (10.4%) with AS. The cumulative follow up period was 8,787 patient-years (RA: 8,388, PsA: 157; AS: 242). There were 1,538 adverse events in 938 (26.7%) patients. Infections were recorded in 630 patients, skin-related adverse events in 142 and post-infusion reactions in 90. A total of 30 malignancies were reported. An interim analysis of efficacy was conducted on 2,148 RA patients. Seven hundred and thirty-one patients (35.8%) achieved EULAR remission (defined as DAS28<2.4). When assessed with the more restrictive CDAI and SDAI criteria, the frequency of remission was lower (17.9% and 14.7% respectively). Availability of funding for this study provided an opportunity to organize a collaborative national network of rheumatology clinics to develop a large multicentre observational study.

Laboratory findings in psoriatic arthritis.

Psoriatic arthritis (PsA) has been classically defined as an inflammatory arthritis associated with psoriasis. However, in comparison with other relevant inflammatory arthropathies, in which a definite diagnosis is frequently possible only by means of laboratory investigations, in PsA true laboratory diagnostic markers are lacking. Some markers are utilised more to differentiate other diseases than to characterise PsA. For example in polyarticular PsA, which may be in some cases indistinguishable from RA, the rheumatoid factor (RF) or the more specific and recently introduced antibodies to cyclic citrullinated peptides (anti-CCP), may be useful to better identify RA. However, RF was found in 5% to 13% of patients with PsA, and anti-CCP may be observed in almost similar percentage. The determination of ESR and/or CRP is frequently disappointing in PsA, since they are both elevated in only half of the patients with PsA. However, ESR and/or CRP are included in the most utilised response criteria for RA, such as ACR and DAS, and, in addition are also considered reliable in the assessment of PsA. Furthermore, elevated levels of ESR have been proposed as one of the best predictors of damage progression and, in addition, a low ESR seems protective, while an ESR >15 mm/h is one of the factors associated with an increased mortality in PsA. The synovial fluid (SF) effusion is much higher in PsA, in comparison with other arthropathies. When available, SF analysis may offer additive information useful for the diagnosis, such as the increased number of leukocytes, which underlines the inflammatory nature of the effusion even in a patient with normal serum levels of acute phase response. We found that elevated IL-1 levels in SF of patients with early disease (<6 months), may be predictive of an evolution in polyarticular form at follow-up. This observation is in keeping with the crucial role that inflammatory cytokines play in PsA, probably related to a genetic predisposition. The recent introduction in PsA of anti-TNF-alpha agents and the demonstration of their efficacy in the management of many clinical disease expressions including peripheral arthropathy, axial involvement, enthesopathy and skin manifestations, have stimulated the research also in the field of the possible laboratory markers.

[Anakinra, a recombinant human IL-1 receptor antagonist, in clinical practice. Outcome in 60 patients with severe rheumatoid arthritis]. / Anakinra, antagonista umano ricombinante del recettore dell'IL-1, nella pratica clinica. Outcome in 60 pazienti con artrite reumatoide severa.

OBJECTIVE: We evaluated both the efficacy and safety of anakinra in daily routine rheumatoid arthritis clinical practice. METHODS: We studied 60 cases, including patients with previous anti-TNFalpha exposure, treated with anakinra (100 mg/daily s.c.) in combination with methotrexate (7.5-10 mg/week i.m.) or leflunomide (20 mg/die) in a two year observational study. Efficacy measures were assessed using the American College of Rheumatology (ACR) response criteria. Safety was evaluated according to a modified World Health Organization adverse reaction term dictionary. RESULTS: At week 14, ACR 20% response criteria have been fulfilled by 53 (91.3%) out of 58 patients, 51 (87.9%) of them achieving also an ACR 50%and 15 (25.8%) an ACR 70%response. Thirteen patients touched 102 weeks of treatment: ACR 20% response was achieved in 92.3%, while ACR 50% and ACR 70% were respectively found in 84.6% and 38.4% of the cases. The mean decrease in HAQ score was 0.38, p<0.001. Of the 16 patients who were previously treated with anti-TNFalpha blockers, 81.2% responded to anakinra. There was no significant difference in the ACR response between groups with and without previous anti-TNFalpha exposure. Seventeen patients (28.3%) stopped anakinra because of side-effects (5%) or failure to respond (23.3%). Only 4 cases of pulmonitis, of which 2 have been hospitalised, and 1 case with tuberculosis (previously treated with infliximab) were observed. CONCLUSIONS: Our clinical experience confirms that anakinra is effective and safe in the treatment of rheumatoid arthritis. Anakinra seems also useful in patients with previous anti-TNFalpha blockers failures. Even though major adverse events were rare, clinicians should be aware of such a possibility.

Bosentan therapy of pulmonary arterial hypertension in connective tissue diseases.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life-threatening and debilitating complication of several connective tissue diseases. We aimed to evaluate the effects of long-term treatment with bosentan, an oral dual endothelin ET(A)/ET(B) receptor antagonist, in a cohort of patients with PAH related to connective tissue diseases. MATERIALS AND METHODS: In the present prospective, noncontrolled study, 13 patients (nine with systemic sclerosis, two with systemic lupus erythematosus, one with mixed connective tissue disease and one with overlap syndrome including scleroderma and myositis), mostly nonresponders to prostanoids therapy, were treated for 1 year with bosentan. Cardiac haemodynamics and the diagnosis of PAH were performed by Doppler ultrasound examination. Exercise capacity was assessed by 6-min walking test at baseline and at 3, 6 and 12 months of therapy. RESULTS: During bosentan treatment, progressive improvement of exercise capacity was observed. Walk distance increased in seven patients, remained unchanged in three and slightly decreased in three patients. A progressive significant decrease of right ventricular systolic pressure was also observed, whereas pulmonary artery mean pressure remained unchanged. Adverse effects related to bosentan (elevation of hepatic aminotransferases) were noted in two patients. CONCLUSION: Long-term treatment with bosentan was effective in improving exercise capacity and pulmonary haemodynamics in patients with PAH related to connective tissue diseases.

[Antinuclear, anti-dsDNA and anti-ENA antibodies in patients affected with rheumatoid arthritis or ankylosing spondylitis during treatment with infliximab]. / Gli autoanticorpi antinucleo, anti-dsDNA anti-ENA nei pazienti con artrite reumatoide o spondilite anchilosante in trattamento con infliximab.

OBJECTIVE: We evaluated the induction and clinical significance of ANA, anti-dsDNA and anti-ENA during infliximab therapy in patients with Rheumatoid Arthritis (RA) or Ankylosing Spondylitis (AS). METHODS: We tested sera from 30 RA and 30 AS patients before and during treatment with infliximab. ANA and antidsDNA were determined by indirect immunofluorescence and anti-ENA by an "in house" counterimmunoelectrophoresis. Statistical analysis was performed by X2 and McNemar's tests and U-test of Mann-Whitney. RESULTS: Eight of the 30 RA patients and 1 of the 30 AS patients were positive for ANA before treatment with infliximab. Eighteen of the 22 (81.8%) negative patients with RA and 11 of the 29 (37.9%) negative patients with AS became positive for ANA during infliximab treatment. No ANA positive patients became negative during the therapy. The difference between ANA before and after treatment resulted significant in both RA and AS patients (p=0.001). The frequency of anti-dsDNA and anti-ENA did not change significantly from baseline, in both RA and AS patients. Acquired ANA positivity was not associated with clinical signs of lupus syndrome and was not correlated with adverse events. The mean values of ESR and CRP in RA patients who became positive for ANA were significantly decreased (p=0.01 and p=0.02 respectively). CONCLUSIONS: Infliximab treatment induced a significant increase in the frequency of ANA in RA and AS patients. The significance of ANA development in these diseases is at present unknown. The significant decrease of ESR and CRP in RA patients who became positive for ANA after treatment should be investigated in a larger number of patients.

Clinical implications of autoantibody screening in patients with autoimmune myositis.

OBJECTIVE: To evaluate the clinical usefulness of serum autoantibody profiling in patients with autoimmune myositis. METHODS: We retrospectively studied 74 consecutive patients: 68 had definite or probable myositis according to Bohan-Peter criteria, six suffered from antisynthetase syndrome with subclinical myopathy. Myositis specific antibodies (MSA) (anti-ARS, -SRP, -Mi-2) were determined by RNA immunoprecipitation or immunoblot, myositis associated antibodies (MAA) (anti-RoRNP, -U1RNP, -PM/Scl, -Ku) by immunoblot. RESULTS: Forty-three patients (58%) were positive for MSA: anti-Jo-1 in 15/27 polymyositis (PM) (55%), 4/33 dermatomyositis (DM) (12%), 1/8 overlap (12%) and 2/6 antisynthetase syndrome (33%); anti-ARS non-Jo-1 in 1/27 PM (4%), 2/33 DM (6%) and 4/6 antisynthetase syndrome (67%); anti-Mi-2 in 1/27 PM (4%) and 11/33 DM (33%); anti-SRP in 3/27 PM (11%) and 1/33 DM (3%). One patient was anti-Jo-1/Mi-2 positive, one anti-Jo-1/SRP positive. Moreover, 27 patients (36%) were positive for MAA: anti-Ro/SSA in 8/27 PM (30%), 7/33 DM (21%), 1/8 overlap (12%), and 3/6 antisynthetase syndrome (50%); anti-U1RNP in 1/27 PM (3.7%), 1/33 DM (3%), and 2/8 overlap (25%); anti-PM/Scl in 2/8 overlap (25%), anti-Ku in 2/8 overlap (25%). Anti-Jo-1 was predominantly associated with PM, anti-Mi-2 was almost exclusively found in DM patients. Anti-ARS antibodies were closely associated with interstitial lung disease and polyarthritis; notably, anti-ARS non-Jo-1 was more frequent in patients without overt muscle alterations. Anti-Ro/SSA antibody was not associated with any disease subset, but significantly more frequent in antisynthetase syndrome. CONCLUSIONS: Searching for MSA and MAA in patients with autoimmmune myositis is recommended because of its diagnostic and clinical value. Anti-ARS non-Jo-1 antibodies seem to preferentially target patients with pulmonary fibrosis without overt myopathy.

[Rare autoimmune rheumatic illnesses during pregnancy. Systemic sclerosis, polymyositis/dermatomyositis and vasculitis]. / Seltene autoimmune rheumatische Erkrankungen in der Schwangerschaft. Systemische Sklerose, Polymyositis/Dermatomyositis und Vaskulitiden.

Autoimmune rheumatic diseases (ARD) affect young females during childbearing age. Over the last decades, improvements in survival as well as quality of life in patients affected with ARD have led to an increased number of pregnancies observed during the course of such diseases. Systemic lupus erythematosus (SLE) is the most frequently observed ARD during pregnancy, and the immunoendocrine changes occurring during pregnancy may influence the course of this disease. Pregnancy can also occur in patients with rare ARD, namely systemic sclerosis, polymyositis/dermatomyositis, systemic vasculitis including Wegener's granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyangiitis, Takayasu arteritis and Behçet disease. This review focuses on the complications during pregnancy caused by these rare ARD, and we briefly discuss the data published on these disorders. Some guidelines for the management of these conditions during pregnancy will also be provided. However, it is important to note that data on pregnancy outcome are very limited and, in the absence of prospective studies, most of the information derives from case reports and retrospective studies.

[Intra-articular treatment with the TNF-alpha antagonist, etanercept, in severe diffuse pigmented villonodular synovitis of the knee]. / Trattamento intra-articolare con l'antagonista del TNFalpha etanercept nella sinovite villo-nodulare pigmentosa diffusa del ginocchio.

Pigmented villonodular synovitis (PVNS) is a rare pre-malignant disease that require aggressive treatment as surgical synovectomy, eventually followed by radiosynovectomy. Nevertheless, the disease often reoccurs after these treatments. To determine the safety and efficacy of intra-articular (IA) TNFalpha blockade with etanercept (ETN), before extended arthroscopic synovectomy, in severe PVNS of the knee, two patients, (a 26-year-old man with B27+ undifferentiated spondylarthropathy and a 32-year-old femal with seronegative oligoarthritis), affected by diffuse knee PVNS (diagnosis made by histological examination), resistant to IA corticosteroid injections and to repeated arthroscopic synovectomy, were submitted, after protocol approval by human research committee and patient's written informed consent to intra-articular etanercept (IA-ETN) treatment with a different dosage schedule: 12.5 mg weekly IA-ETN injection for 4 weeks, followed by extended arthroscopic synovectomy and of 25 mg IA-ETN injection for 4 weeks, respectively. Previous DMARDs treatment was continued in stable appropriate doses. Any adverse events were recorded throughout the study. The following parameters were considered as clinical endpoints: 1) Knee Joint Index (KJI: range 0-14); 2) Thompson index (THI: range 0-9) At the study entry and at the end of follow-up, high frequency ultrasound grey scale synovial thickening (US-ST) was also assessed. No adverse events were observed due to IA-ETN and to arthroscopic synovectomy. Marked improvement of knee disease activity over time and sustained functional recover was obtained. US-ST evaluation before treatment initiation and at the end of follow-up confirmed the regression of knee joint synovial proliferation.

[Primary antiphospholipid syndrome and hyperhomocysteinemia: a study of a group of 29 patients]. / Sindrome da anticorpi antifosfolipidi primaria e iperomocisteinemia: studio di un gruppo di 29 pazienti.

OBJECTIVE: In order to investigate the potential role of hyperhomocysteinemia as an additional risk factor for thrombotic events, we studied its prevalence in patients with primary antiphospholipid syndrome (APS) and evaluated its association with different clinical features. METHODS: We enrolled 29 patients without any current evidence of underlying connective tissue disorder and fulfilling the Sapporo preliminary classification criteria for APS. RESULTS: Ten (34,4%) patients showed mild hyperhomocysteinemia (18,34 micromol/L +/- 2,04 DS). Nine had history of cerebrovascular disease, isolated (3 cases) or more often (6 cases) in association with other APS features. All patients, but one, showed multiple ischemic cerebral lesions. Seven of the 10 patients with hyperhomocysteinemia had multiple antiphospholipid antibody positivity and presented more frequently (6 cases) multi-site vascular involvement. CONCLUSIONS: The frequency of hyperhomocysteinemia in patients with primary APS is not negligible and appears to be associated with cerebral microangiopathic disease, multiple antiphospholipid antibody positivity and the simultaneous involvement of different vascular districts. For this reason and because hyperhomocysteinemia can be easily corrected with safe and relatively inexpensive therapeutic interventions, we advocate the measurement of homocysteinemia in every patient affected by APS and possibly in subjects with positive antiphospholipid antibody without a history of thrombosis.

[Sensibility and specificity for pregnancy morbidity of anti-ß2-glycoprotein I antibodies in antiphospholipid syndrome]. / Sensibilità e specificità degli anticorpi anti-β2-glicoproteina I per l'impegno ostetrico della sindrome da anticorpi antifosfolipidi.

OBJECTIVE: This study aimed to evaluate the sensitivity and specificity of the anti-β2-glycoprotein I (GPI) antibodies for pregnancy morbidity in the antiphosoplipid syndrome (APS). METHODS: 335 women were recruited and on the basis of their clinical features were subdivided into 2 groups homogenous for number and age. The first (study) group contained the women whose pregnancy complications satisfied the classification criteria for APS. The second (control) group was made up of women with pregnancy complications not included in the classification criteria for APS. Anti-β2-GPI, anticardiolipin antibodies (aCL) and lupus anticoagulants (LA) were determined in all of these women. RESULTS: The only antiphospholipid antibodies occurring with a significant frequency (p=0,00) in the women with pregnancy criteria for APS were the IgG anti-β2-GPI and the IgG aCL present respectively in 23,92% and in 27,60% of the women. Its association was found to be significant (p=0,000). The distribution of the different levels of positivity of the IgG and IgM anti-β2-GPI in the patients of the study and control groups was not significantly different. The highest sensitivity for pregnancy complications was that of the IgG aCL and of the IgG anti-β2-GPI whose difference was not statistically significant. The comparison of the specificity of the IgG and IgM anti-β2-GPI with that of the IgG and IGM aCL was not statistically significant. CONCLUSIONS: The importance of determining the IgG anti-β2-GPI as part of routine laboratory testing of women with pregnancy complications typical of APS was confirmed. Together with IgG aCL these antibodies have proved to be the most sensitive and specific markers of pregnancy complications in APS.

[Tenosynovitis of the ankles as onset of sarcoidosis in a patient with ulcerative colitis]. / Tenosinovite delle caviglie come segno d'esordio di sarcoidosi in un paziente con rettocolite ulcerosa.

Arthritis and tenosynovitis are frequently reported as complications of inflammatory bowel diseases. About 10% of patients with ulcerative colitis presents articular inflammation, usually in the phases of activity of intestinal disease. Tenosynovitis is also a frequent complication of ulcerative colitis. We describe here a case of tenosynovitis of both ankles occurring in a patient affected by ulcerative colitis not in active phase. Chest X-ray and TC showed hilar lymph node enlargement and transbronchial biopsy confirmed the diagnosis of sarcoidosis. In this disease tenosynovitis is very rare, unlike arthritis that is rather common. In conclusion we observed a case of ankle bilateral tenosynovitis as onset manifestation of sarcoidosis.

[Isolated congenital heart block in undifferentiated connective tissue disease and in primary Sjögren's syndrome: a clinical study of 81 pregnancies in 41 patients]. / Il blocco cardiaco congenito nella connettivite indifferenziata e nella sindrome di Sjögren primitiva. Studio di 81 gravidanze in 41 pazienti.

OBJECTIVE: To study the incidence and the features of congenital heart block (CHB) in patients with undifferentiated connective tissue disease (UCTD) and primary Sjögren's syndrome (pSS). METHODS: We studied 81 pregnancies of 41 women attending the Outpatients' Clinic of the Rheumatology Unit of University Hospital of Padova from July 1989 to March 2004. Twenty five of these (61%) were affected with UCTD and 16 (39%) with pSS. Serologic inclusion criteria was anti-Ro/La positivity, assessed by counterimmunoelectrophoresis and ELISA. RESULTS: CHB was found in 2 out of the 46 (4.3%) pregnancies followed by our Staff and in 2 out of the 35 (5.7%) included in the retrospective part of the study. In 3 cases CHB was a 3rd degree block, causing pregnancy termination in 2. The only 2nd degree block was identified in one patient at the 22nd week of gestation and treated with dexamethasone and plasma-exchange. All of the women were positive to 52 kd and 60 kd Ro autoantibodies. CHB mothers had higher titer antibodies to 52 kd Ro protein than did the mothers with healthy infants (P = 0.026). Electrocardiographic abnormalities at birth were found in 3 out of 29 asymptomatic infants. One presented sinus bradycardia, the second abnormalities of ventricular repolarization, both regressed spontaneously, while the third ventricular extrasystoles which continue even now at 5 months. CONCLUSIONS: These results showed that in UCTD and pSS there is a higher incidence of CHB than that reported in Systemic Lupus Erythematosus. Electrocardiographic screening in all infants born to mothers with anti-Ro/La antibodies would seem an important measure to identify those with irreversible heart conduction abnormalities.

Value of C reactive protein in the assessment of erosive osteoarthritis of the hand.

OBJECTIVE: To investigate the value of serum C reactive protein (CRP) as a marker of erosive osteoarthritis (EOA) of the hand. METHODS: Ninety eight patients, 67 with EOA and 31 with non-EOA of the hand, were included in the study and analysed for radiographic score (RS), number of erosions, and joint count (JC) at clinical observation and at bone scintigraphy. CRP was assayed in a serum sample by a highly sensitive immunonephelometric method. RESULTS: The median (interquartile range) CRP level was 4.7 (2.4-6.9) mg/l in the EOA and 2.1 (0.5-4.9) mg/l in the non-EOA group (p = 0.001). In all patients, CRP correlated with RS (r(s) = 0.43, p<0.001), and mainly with JC at clinical observation (r(s) = 0.72, p<0.001) and at bone scintigraphy (r(s) = 0.47, p<0.001). The correlation of CRP with RS and JC was confirmed at clinical observation and at bone scintigraphy in the EOA subgroup, but only with JC at clinical observation in the non-EOA subgroup. CONCLUSIONS: CRP levels are higher in EOA than in non-EOA patients. These levels probably reflect the disease activity of EOA, as suggested by correlations between CRP and JC at clinical observation and at bone scintigraphy.

[Incidence and management of infusion reactions to infliximab in 186 italian patients with rheumatoid arthritis: the Padua experience]. / Frequenza e trattamento delle reazioni all'infusione di infliximab in 186 pazienti con artrite reumatoide: esperienza di Padova.

OBJECTIVE: We report the incidence and treatment of infusion reactions to infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor alpha, in a large cohort of patients with rheumatoid arthritis. PATIENTS AND METHODS: One hundred eighty six patients with rheumatoid arthritis treated with infliximab for a total of 216.6 patient years were retrospectively evaluated. Patients received 2160 infliximab infusions at the Division of Rheumatology at the University Hospital of Padua from May, 2000 to April, 2004. Specific treatment protocols for initial and subsequent acute infusion reactions were followed and the outcomes documented. RESULTS: The overall incidence of infusion reactions to infliximab was 0.8% (19 out of 2160 of infusions), affecting 10.2% of patients (19 out of 186). Mild, moderate, or severe acute reactions occurred in 0.1% (3 of 2160), 0.6% (13 of 2160), and 0.04% (1 of 2160) of infliximab infusions, respectively. Delayed infusion reactions occurred in 0.09% (2 of 2160) of infusions. Use of specific treatment protocols resulted in rapid resolution of all acute reactions to infliximab. With a prophylaxis protocol, all patients who experienced an initial mild acute reaction were able to receive additional infusions. CONCLUSIONS: Using appropriate treatment protocols, infliximab infusion reactions were effectively treated and prevented in patients with mild acute reactions upon retreatment. In the case of moderate to severe infusion reactions, the risks and the benefits of the continuation of infliximab therapy need to be carefully considered.

Efficacy and safety of nadroparin in the treatment of pregnant women with antiphospholipid syndrome: a prospective cohort study.

The optimal therapeutic management of patients with antiphospholipid syndrome (APS) during pregnancy is debatable. In the present prospective cohort study the use of a low molecular weight heparin (LMWH) (nadroparin), administered alone twice daily in 30 pregnant women who were diagnosed with APS on the basis of the current classification criteria, is evaluated. Dosage was adjusted according to anti-Xa levels in the patients as the pregnancies progressed. Three women, in whom an important gradual fall in platelet count in the first trimester did not respond to increased nadroparin doses, were shifted to a second-line treatment protocol. Fetal loss occurred in two of the 27 remaining women (7.40%), while 25 (92.59%) delivered 25 live infants, between the 32nd and 40th weeks of gestation. No fetal problems were registered during pregnancies, while maternal complications occurred in two of the 25 patients (8%). Moreover, there were no thrombotic events in any of the women during the study. Patient compliance was good and only minor side-effects were reported. The results of this study indicate that nadroparin alone is useful and safe in the management of pregnant patients with APS. However, in consideration of the good pregnancy outcome obtained in patients with only pregnancy morbidity when heparin and aspirin were used together, other studies comparing nadroparin twice daily with once daily plus Aspirin would be useful to ascertain which is more effective in these patients.