Prevalence and outcome of pulmonary fibrosis in microscopic polyangiitis.

We sought to determine the type of pulmonary involvement in microscopic polyangiitis (MPA), primarily focusing on pulmonary fibrosis (PF), its prevalence, temporal relationship with other disease manifestations and outcome. 33 patients (16 males) with biopsy proven perinuclear anti-neutrophilic cytoplasmic antibody-positive MPA (age 63.5 yrs) participated in the study. Pulmonary involvement was assessed using standard methods, including radiographic imaging (chest radiographs and high-resolution computed tomography), pulmonary function testing, bronchoscopy and bronchoalveolar lavage, and, if indicated, lung biopsy. All-cause mortality was analysed by the Kaplan-Meier method and was compared between MPA patients with and without PF. At the time of diagnosis, renal involvement was detected in all patients, with renal biopsies being consistent with segmental necrotising glomerulonephritis in all patients. The most common respiratory symptom was haemoptysis, which was found in nine (27%) patients. PF was present in 12 (36%) patients at the time of diagnosis, whereas one patient developed PF while on therapy approximately 10 yrs after disease diagnosis. In seven patients with PF, respiratory symptoms related to fibrosis preceded other disease manifestations by a median (range) period of 13 (5-120) months. Patients were followed up for a period of 38+/-30 months. Presence of PF was associated with increased mortality (p = 0.02), with six deaths occurring in the fibrotic group and one in the nonfibrotic group. In the fibrotic group most deaths were related to PF. PF occurs frequently in MPA, may precede other disease manifestations by a variable length of time and has a poor prognosis.

Myocardial performance and aortic elasticity are impaired in patients with ankylosing spondylitis.

OBJECTIVE: To measure aortic stiffness and global left ventricular (LV) function in patients with ankylosing spondylitis (AS) and no clinical evidence of heart disease. METHODS: Fifty-seven consecutive patients with AS (54 males, three females, mean age 41.78+/-10.02 years) without clinical evidence of cardiac involvement and 78 healthy subjects (73 males, five females, mean age 39.92+/-9.11 years) underwent complete echocardiographic study. Aortic stiffness was determined non-invasively by aortic distensibility (AoD) and the global LV function was evaluated by the myocardial performance index (the Tei index). RESULTS: AoD in patients with AS [(2.21+/-0.24)x10(-6) cm(2) dyn(-1)] was decreased compared to controls [(2.58+/-0.19) )x10(-6) cm(2) dyn(-1), p<0.01], confirming that aortic stiffness is increased in AS. The LV Tei index was significantly increased in the patient group compared to the control group (0.392+/-0.031 vs. 0.370+/-0.034, p<0.01). The ejection fraction (EF) did not differ between the two groups (p>0.05). In multivariate linear regression analysis, AoD was significantly associated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and LV isovolumic relaxation time (IVRT) whereas the LV Tei index was associated with BASDAI and the LV mass index. CONCLUSIONS: Patients with AS and no clinical evidence of cardiac disease have increased stiffness of the aorta and decreased global myocardial performance and both of these abnormal measurements correlate with disease activity. The abnormal Tei index may reflect an early manifestation of cardiac dysfunction in these patients.

Thoracoabdominal motion in ankylosing spondylitis: association with standardised clinical measures and response to therapy.

OBJECTIVES: To assess the relationship between thoracoabdominal motion during quiet breathing and standardised indices of disease severity in patients with ankylosing spondylitis (AS); also to evaluate whether thoracoabdominal motion improves after institution of biological agents in these patients. METHODS: Displacement of the rib cage (RC) and abdomen (Abd) during quiet breathing in the sitting, standing and supine position were recorded by impedance plethysmography in 60 patients (mean (SD) age 41 (10) years, 56 men) and 21 healthy men (mean (SD) 36 (7) years). x-y plots of RC versus Abd displacement during quiet breathing were constructed, and the angle of the slope of the RC-Abd loop was calculated and averaged for five consecutive breaths. In 13 patients treated with anti-tumour necrosis factor alpha (TNFalpha), measurements were made before and at 3, 6 and 12 months after the start of treatment. RESULTS: In the entire AS group, the angle of the slope of the RC-Abd loop correlated with Bath Ankylosing Spondylitis Functional Index (BASFI) in the sitting (R = -0.50, p<0.0001), standing (R = -0.36, p = 0.004) and supine (R = -0.47, p = 0.0001) position, but not with Bath Ankylosing Spondylitis Disease Activity (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI) or the modified Schober's test. In 13 patients treated with anti-TNFalpha, the angle of the RC-Abd slope improved significantly (35-69% over baseline at 3 months) in all body positions and in a nearly parallel fashion with the improvements in standardised clinical measurements. CONCLUSIONS: The pattern of thoracoabdominal motion during quiet breathing correlates with BASFI, and its response to anti-TNFalpha treatment is large. This variable may be an appropriate target for evaluating potential usefulness in monitoring thoracic spine involvement and response to treatment in AS.

Evidence-based recommendations for the management of ankylosing spondylitis: results of the Hellenic working group of the 3E Initiative in Rheumatology.

OBJECTIVE: The 3E (Evidence, Experts and Exchange) Initiative is a multi-national effort that involves a large number of experts and practicing rheumatologists addressing specific questions relevant to everyday clinical practice, concerning the management of Ankylosing Spondylitis. Within this multinational group, the Hellenic working group, addressed specific issues complementary to the international ones, and formulated evidence-based recommendations, in order to improve everyday clinical practice for patients with Ankylosing Spondylitis. METHODS: A scientific committee of rheumatologists specializing in AS formulated a set of 7 questions in three domains: diagnosis, monitoring and treatment. Literature search in MedLine for papers published up to August 2006 was conducted. The evidence to support each proposition was evaluated and scored. To avoid any conflict of interest with the sponsor issues related to the use of biologics were not discussed. After extensive discussion among 50 rheumatologists and one Delphi round of votes, the final recommendations were formulated. RESULTS: A literature search resulted in a total of 320 relevant papers of which 29 were evaluated. A total of seven recommendations were formulated: two concerning diagnosis (role of HLA-B27 and MRI) and prognosis, one concerning monitoring for extra-articular manifestations and four concerning treatment (analgesics, disease modifying agents and physical therapy) were made. The level of evidence and the strength of recommendation were reported. The compiled agreement among experts ranged from 90% up to 100%. CONCLUSION: Recommendations for the management of AS were developed using an evidence-based approach followed by physicians' consensus with high level of agreement. These are complementary to existing ones, and address specific domains of everyday clinical practice.

Is the heart affected in primary Sjögren's syndrome? An echocardiographic study.

OBJECTIVE: To evaluate whether patients with primary Sjögren's syndrome without overt cardiac disease have echocardiographic abnormalities and their relation with clinical and laboratory data. METHODS: One hundred and seven consecutive patients with primary Sjögren's syndrome and 112 healthy controls, matched for age and gender, underwent complete echocardiographic study. RESULTS: Thirty-two patients had mitral valve regurgitation (p<0.001) whereas tricuspid and aortic valve regurgitation were, also, more frequent in the patient group (p=0.022 and p=0.007 respectively). In multivariate analyses, low C4 levels of complement and age were strong predictors of mitral valve regurgitation whereas age was predictor of aortic valve regurgitation. Tricuspid valve regurgitation was associated with pulmonary hypertension. Clinically silent pericardial effusion, found in 9 patients (p=0.008), was associated with cryoglobulinemia and primary biliary cirrhosis. Twenty-four patients had pulmonary hypertension (p<0.001) whereas hypocomplementemia and cryoglobulinemia were strong predictors of pulmonary artery systolic pressure. The analyses reveal that easy fatigability was associated with pulmonary hypertension and low C4 levels. The patients' left ventricular mass index differed significantly from the controls (108.9+/-17.21 gm(-2) vs. 85.8+/-6.73 gm(-2), p<0.001) and was associated with palpaple purpura and anti-Ro/SSA. From the diastolic function indices only the left ventricular isovolumic relaxation time differed significantly among patients and controls. CONCLUSION: Valvular regurgitation, pericardial effusion, pulmonary hypertension and increased left ventricular mass index occur with disproportionately high frequency in patients with primary Sjögren's syndrome and no clinically apparent heart disease. Thus echocardiographic studies may need to be performed in these patients especially when palpable purpura, antibody reactivity and low C4 levels are present.

Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the "Euro-Lupus Project".

The "Euro-Lupus Cohort" is composed by 1000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium--the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

Lupus nephritis: treatment with mycophenolate mofetil.

OBJECTIVE: To evaluate the safety and efficacy of mycophenolate mofetil (MMF) treatment in patients with lupus nephritis. METHODS: Eighteen patients with biopsy-proven lupus nephritis (17 females, one male; mean age 31.6 yr; mean lupus duration 92 months; mean duration of nephritis 57 months; nine with focal proliferative glomerulonephritis, three with diffuse proliferative glomerulonephritis, six with membranous nephropathy) were included. With five exceptions, all patients had been treated previously with cyclophosphamide and were selected because of either toxicity or inadequate clinical response to treatment. MMF was given at 2 g daily in combination with steroids for up to 31 months (mean 15.3 months). The side-effects of MMF were recorded and efficacy was assessed as the renal function profile. RESULTS: Complete remission was observed in 10/18 patients and another 4/18 went into partial remission. Both creatinine clearance and proteinuria were significantly improved during MMF treatment in patients with the proliferative forms of nephritis. MMF demonstrated a steroid-sparing effect in the whole population. Treatment failure was recorded in 4/18 patients, all with membranous nephropathy. Two patients developed gastrointestinal complaints and infectious meningitis occurred in one patient. CONCLUSION: MMF appears to be an efficacious and safe treatment in patients with proliferative forms of lupus nephritis who do not respond to or cannot tolerate conventional treatment. The efficacy of MMF in lupus membranous nephropathy remains unclear.

Infliximab Therapy for Patients With Active and Refractory Spondyloarthropathies at the Dose of 3 mg/kg: A 20-Month Open Treatment.

BACKGROUND: : Infliximab at the dose of 5 mg/kg per infusion has been shown effective for the treatment of active spondyloarthropathies. It is not clear if the 5 mg/kg is required in most patients. OBJECTIVE: : To evaluate the long-term efficacy and safety of infliximab at the lower dose of 3 mg/kg in patients with active and refractory ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: : Thirty patients were enrolled in a 78-week, single-center, prospective, open-label pilot study, including 16 patients with severe and active AS and 14 patients with active and refractory PsA. Infliximab (3 mg/kg, in combination with a stable dose of methotrexate was administered intravenously at 0, 2 and 6 weeks, and q8 weeks thereafter (schedule-A) and the improvement of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; for AS patients) and Patient Global Assessment of Disease Activity (PDA; for PsA patients) was monitored at baseline and at every visit (primary variables). Patients who did not respond sufficiently at 14 weeks, as well as patients who relapsed at any time during follow-up, received infliximab every 4 weeks (treatment schedule-B). Three different statistical approaches (per-protocol, last observation carried forward and by intention-to-treat) were applied. RESULTS: : Ten patients discontinued treatment for various reasons, including 3 (10.0%) because of allergic reactions. Twenty patients (66.7%, 9 with AS and 11 with PsA) had completed 78 weeks of treatment (schedule-A, 11 patients; schedule-B, 9 patients). Of these patients, 18 (90.0%) showed optimal response (improvement >/=50%), including 13 (65.0%) with improvement >/=70%. ASsessments in AS (ASAS) 50% was attained by 7/9 AS patients (77.8%). At 78 weeks of treatment, statistically significant improvement of indices of disease activity, function and quality of life was observed by all statistical approaches applied. CONCLUSIONS: : Infliximab at 3 mg/kg every 8 weeks or, if needed, every 4 weeks appears to be an effective and rather safe treatment of patients with active and refractory AS and PsA after 78 weeks of treatment.

Lessons from the "Euro-Lupus Cohort".

The "Euro-Lupus Cohort" is composed by 1,000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium - the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

How significant is sensorineural hearing loss in primary Sjögren's syndrome? An individually matched case-control study.

OBJECTIVE: We evaluated whether sensorineural loss and vestibular abnormalities are common in patients with primary Sjögren's syndrome (pSS) and whether such abnormalities are clinically significant. METHODS: In an individually matched case-control design, 48 patients with pSS underwent complete audiovestibular evaluation along with 48 age and sex matched individuals without otologic problems. Differences of > 20 dB between patient and control ears at any frequency tested were considered to be significant. RESULTS: Significant differences in hearing loss were seen at 4,000 Hz (6 vs 0 ears; p = 0.03) and at 8,000 Hz (9 vs 0 ears; p = 0.003). Small differences in hearing acuity were also observed in the lower frequencies, but the absolute mean difference was < 3 dB. A decrease of at least 60 dB in hearing acuity at any frequency up to 4,000 Hz was seen only in 3 elderly pSS patients. Abnormal brainstem auditory evoked responses were recorded in 7 patients and 5 controls, but no patient had retrocochlear lesions identified on magnetic resonance imaging. Four patients in each group had abnormalities on electronystagmography. CONCLUSION: pSS is associated with sensorineural hearing loss affecting preferentially the high frequencies, but clinically significant defects are not common. There is no evidence of retrocochlear disease or increased vestibular involvement in pSS.

Right ventricular diastolic dysfunction in patients with anticardiolipin antibodies and antiphospholipid syndrome.

OBJECTIVE: To evaluate the prevalence of diastolic dysfunction in patients with anticardiolipin antibodies (aCL) and to examine whether the antiphospholipid syndrome (APS) is associated with diastolic dysfunction independently of valvular abnormalities and systolic dysfunction. METHODS: Pulsed, continuous, colour Doppler echocardiography was performed in 179 subjects, of whom 15 were excluded from the analysis because of systolic dysfunction or severe valvular disease. The remaining 164 subjects included 29 patients with primary APS, 26 patients with secondary APS (APS in the presence of systemic lupus erythematosus (SLE)), and 30 patients with SLE and aCL but without APS; 43 patients with SLE without aCL and 36 normal volunteers served as control groups. RESULTS: The groups compared differed significantly in all measures of right ventricular function. There was a gradation of increasing diastolic function impairment as manifested by prolonged deceleration time (DT) and isovolumic relaxation time (IVRT) across the groups of patients with SLE without aCL, SLE with aCL, secondary APS, and primary APS. Differences in left ventricular diastolic function measures were less prominent. In regression analysis, DT increased by 19.6 ms (p=0.002) in the presence of primary APS and by 20.1 ms (p=0.038) in the presence of pulmonary hypertension. The titre of IgG aCL was the strongest predictor of a prolonged IVRT. CONCLUSION: Diastolic dysfunction, in particular of the right ventricle-that is, independent of valvular disease and systolic dysfunction, is a prominent feature of APS and may be related to the pathogenesis of the syndrome.

Predictors of clinical outcome and radiologic progression in patients with neuropsychiatric manifestations of systemic lupus erythematosus.

PURPOSE: We sought to identify the predictors of clinical outcome and of the evolution of cerebral abnormalities in patients with neuropsychiatric systemic lupus erythematosus (SLE). SUBJECTS AND METHODS: Thirty-two patients with SLE (including 14 with the antiphospholipid syndrome) who had been hospitalized with primary neuropsychiatric disease were observed prospectively for at least 2 years. Laboratory and clinical characteristics and data from magnetic resonance imaging (MRI) studies obtained during the hospitalization and 2 years later were evaluated. We ascertained nonreversible or new MRI changes and clinical outcomes, including neuropsychiatric events, during follow-up. RESULTS: Cranial MRI scans on admission were abnormal in 26 (81%) of the 32 patients. Patients with the antiphospholipid syndrome were more likely to have focal cerebral white matter lesions (odds ratio [OR] = 12, 95% confidence interval [CI]: 2.0 to 72). After 2 years, neuropsychiatric deficits substantially improved in 22 (69%) of the patients, stabilized in 6 (19%), and deteriorated in 4 (12%). The number of prior neuropsychiatric events was associated with persistent MRI lesions (OR = 4.8 per each event, 95% CI: 1.1 to 21) and unfavorable clinical outcome (OR = 4.3 per each event, 95% CI: 1.4 to 13) at 2 years. The antiphospholipid syndrome also predicted an unfavorable clinical outcome at 2 years (OR = 11, 95% CI: 1.7 to 65). CONCLUSIONS: Among patients with SLE who have neuropsychiatric disease, prior neuropsychiatric events and the antiphospholipid syndrome increase the risk of adverse outcomes.

Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome.

We assessed whether initial clinical presentations suggestive of antiphospholipid syndrome (APS) predicted the subsequent rate and type of serious clinical outcomes. Eighty-two consecutive patients with anticardiolipin antibodies or lupus anticoagulant were followed for 814 person-years after a first event suggestive of APS (livedo reticularis, thrombocytopenia, autoimmune haemolysis, thrombosis, central nervous system manifestations, recurrent abortions). The hazard of developing a second event was largest in patients with antibodies recognizing beta2 glycoprotein I who had autoimmune haemolysis as the first event (hazard ratio HR 2.70, p=0.018) and smallest in patients without such antibodies who had recurrent abortions as their first event (HR 0.37, p=0.028). Subsequent serious events in patients with venous and arterial thromboses, recurrent abortions, central nervous system manifestations and autoimmune haemolytic anaemia were likely to be of the same type as the presenting event (odds ratio (OR) 3.76, 5.90, 77.7, 6.92, and 7.13, respectively. Adjusting for therapy, the rate of subsequent serious events was 6.86-fold higher (p=0.0001) in patients presenting with two events, 1.56-fold higher (p=0.038) in autoimmune haemolysis presentations, 1.69-fold higher (p=0.004) in patients with anti-beta2-glycoprotein-I antibodies, and 46% (p=0.063) lower in thrombocytopenia presentations. Initial clinical features determine the long-term evolution of APS, and specific types of clinical manifestations cluster during the course of the disease.

Takayasu's arteritis-associated aneurysm formation without steno-occlusive lesions.

The authors report a case of a 20-year-old woman with Takayasu's arteritis (TA) presenting with recurrent erythema nodosum-like lesions, elevated acute-phase proteins and aortographic findings of multiple aneurysmal dilatations of the aorta without the coexistence of steno-occlusive lesions. This finding indicates that aneurysms could be an early manifestation of TA and not necessarily a change secondary to stenotic lesions.

Risk factors for central nervous system involvement in systemic lupus erythematosus.

We investigated risk factors for central nervous system (CNS) involvement in systemic lupus erythematosus (SLE), in 32 such patients individually matched 1 : 3 to 96 control SLE patients without CNS events. Univariate analysis showed that CNS involvement was significantly associated with the antiphospholipid syndrome (APS) as well as its features: arterial thrombosis, recurrent fetal loss, livedo reticularis and IgG anticardiolipin (aCL) antibodies in high titres. Other potential associations included cutaneous vasculitic lesions, thrombocytopenia, positive ANA, anti-SS-B/La and low serum levels of C(3) and C(4) complement components, while articular manifestations and discoid rash were significantly less common in patients with neuropsychiatric (NP) disease. In multivariate modeling, CNS involvement was strongly associated with cutaneous vasculitic lesions OR 33, 95% CI 1.5-720) and arterial thromboses (OR 13, 95%CI 0.82-220), and negatively related to the presence of articular manifestations (OR 0.015, 95%CI 0.00-0.17) and discoid rash (OR 0.004, 95%CI 0.00-0.35). Associations with APS-related arterial thromboses and vasculitis point to the importance of arterial vascular pathophysiology in the pathogenesis of NP disease in SLE. Patients with articular manifestations and discoid rash are at very low risk of NP events. Patients with an adverse SLE disease profile may require closer observation and may be the target group for studying pre-emptive interventions.

The clinical relevance of antibodies to ribosomal-P common epitope in two targeted systemic lupus erythematosus populations: a large cohort of consecutive patients and patients with active central nervous system disease.

OBJECTIVES: To develop an enzyme linked immunosorbent assay (ELISA) using as substrate a synthetic 22-aminoacid peptide, corresponding to the ribosomal P0, P1 and P2 common epitope. To study the specificity and sensitivity of the method and evaluate the frequency and clinical associations of anti-P antibodies in two groups of systemic lupus erythematosus (SLE) patients: (a) unselected SLE patients and (b) SLE patients with central nervous system (CNS) involvement. PATIENTS AND METHODS: The C-terminal 22 aminoacid peptide of the ribosomal P proteins (Lys-Lys-Glu-Glu-Lys-Lys-Glu-Glu-Lys-Ser-Glu-Glu-Glu-Asp-Glu-Asp-Met- Gly-Phe-Gly-Leu-Phe-Asp) was synthesised according to Merrifield's solid phase procedure. Purification of the peptide was performed by preparative high performance liquid chromatography and confirmed by amino acid analysis. Using this peptide, in a concentration 5 microg/ml, an ELISA was developed. The presence of anti-P antibodies was evaluated by western blot using purified ribosomal proteins from rat liver. Sera from 178 consecutive patients with SLE and 28 patients with SLE and CNS manifestations were tested. Sera from 58 patients with rheumatoid arthritis and 57 patients with primary Sjögren's syndrome were used as controls. The cut off point of the assay was defined using 124 normal sera. RESULTS: The specificity of the assay was evaluated by homologous inhibition. Pretreatment of positive sera with soluble 22mer peptide of the ribosomal P proteins resulted in 88% inhibition. The concordance between the peptide assay and western blot was found to be 83%. Thirty three of 178 (18. 6%) of the unselected SLE patients had antibodies to P-protein common epitope. Their presence was associated with more active disease (European Consensus Lupus Activity Measurement, ECLAM scoring system) (p<0.001), higher levels of anti-ds DNA antibodies (p<0.05) and lower levels of the C4 component of complement (p<0.01). Eleven of 28 (39.3%) patients with SLE and active CNS involvement had antibodies to P-protein. The overall prevalence of anti-P antibodies in active CNS disease patients was statistically significantly higher, as compared with unselected SLE patients (chi(2)=6.04, p<0.05). These antibodies were found in a high proportion of patients without anticardiolipin antibodies (52.4%) and they were associated with diffuse CNS involvement (psychiatric disorders (71%) and epilepsy (75%)). CONCLUSIONS: A synthetic analogue of the common epitope of ribosomal P-proteins can be use as an antigen for the detection of anti-P antibodies. These antibodies are associated with active SLE and CNS involvement particularly in patients without anticardiolipin antibodies.

Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide.

UNLABELLED: Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide. BACKGROUND: Long-term intravenous cyclophosphamide (IVC) in combination with corticosteroids is standard therapy for proliferative lupus nephritis, but it has limitations. There are few data on long-term remission rates, predictors of relapse, and the ability to achieve a second remission with currently recommended IVC regimens. METHODS: A cohort of 85 patients with proliferative lupus glomerulonephritis (focal N = 33, diffuse N = 52) treated with IVC was assembled in three institutions. Timing and predictors of remission, relapse, and re-remission were evaluated with Kaplan-Meier analyses and Cox models. RESULTS: The median time to remission was 10 months, whereas an estimated 22% of patients had not remitted after 2 years. The median time to relapse among 63 patients who had achieved remission was 79 months. In multivariate models, adverse predictors of remission were a delay in the initiation of therapy from the time nephritis was clinically diagnosed [hazard ratio (HR) 0.58, P = 0. 063] and a higher amount of proteinuria (HR 0.86 per 1 g/24 hours, P = 0.014). Predictors of earlier relapse for patients entering remission included a longer time to remission (HR 1.029 per month, P = 0.025), a history of central nervous system involvement (HR 8.41, P = 0.002), and World Health Organization histology (P = 0.01). Among the 23 patients who relapsed during follow-up, the median time to re-remission was 32 months, and with three exceptions, all patients took substantially longer time to remit the second time compared with their first remission (P = 0.01). The time to re-remission was longer in patients who had taken longer to remit the first time (HR 0.979 per month, P = 0.16), in patients who had relapsed earlier after the first remission (HR 1.071 per month, P = 0.002), and in those with evidence of chronicity in the original kidney biopsy (P = 0.015). CONCLUSIONS: Prolonged courses with a cumulative risk of toxicity are needed to achieve remission in many first-treated patients and in most patients treated for a second time. The optimal management of patients with identified adverse predictors of response needs further study.