Disease severity of proliferative lupus nephritis in Maghrebians.

Objective To study the influence of Maghrebian ethnicity on lupus nephritis. Methods We retrospectively reviewed the files of a cohort of 194 patients with proliferative lupus nephritis followed in seven lupus centres belonging to three groups: Europeans living in Belgium/France (E; n = 111); Maghrebians living in Europe, in casu Belgium/France (ME; n = 43); and Maghrebians living in Morocco (MM; n = 40). Baseline presentation was compared between these three groups but complete long-term outcome data were available only for E and ME patients. Results At presentation, the clinical and pathological characteristics of lupus nephritis did not differ between E, ME and MM patients. Renal relapses were more common in ME patients (54%) than in E patients (29%) ( P < 0.01). Time to renal flare and to end-stage renal disease was shorter in ME patients compared to E patients ( P < 0.0001 and P < 0.05, respectively). While proteinuria measured at month 12 accurately predicted a serum creatinine value of less than 1 mg/dl at 7 years in E patients, this was not the case in the ME group, in whom serum creatinine at month 12 performed better. Conclusion Despite a similar disease profile at onset, the prognosis of lupus nephritis is more severe in Maghrebians living in Europe compared to native Europeans, with a higher relapse rate.

Unusual case of tetraparesis in a patient with systemic lupus erythematosus.

We describe the case of a 67-year-old Asian female patient suffering from severe systemic lupus erythematosus (SLE), including biopsy-proven glomerulonephritis, since the age of 40 who was admitted for tetraparesis. Neurological examination confirmed proximal muscular weakness, hypoesthesia and diminished tendon reflexes. The patient suffered from extremely severe Jaccoud's arthropathy. Magnetic resonance imaging (MRI) demonstrated severe narrowing of the upper spinal canal due to a soft tissue mass surrounding the odontoid process, assumed to be a synovial pannus, causing myelopathy. The patient was treated with three intravenous pulses of methylprednisolone with prompt and full clinical recovery. Follow-up MRI confirmed considerable regression of the pannus. Inflammatory transverse myelopathy is the most common explanation for para/tetraparesis in SLE. However, in this case, the symptoms were caused by atlantoaxial synovitis, which is more typical for rheumatoid arthritis.

Prognosis of proliferative lupus nephritis subsets in the Louvain Lupus Nephritis inception Cohort.

OBJECTIVE: The objective of this paper is to evaluate whether the different International Society of Nephrology/Renal Pathology Society (ISN/RPS) classes of proliferative lupus nephritis (LN) have a distinct baseline presentation, short-term response to immunosuppression (IS) and long-term prognosis. METHODS: Ninety-eight patients with new onset (first renal biopsy) ISN/RPS proliferative LN (Class III: n=24; IV-S: n=23; IV-G: n=51) were diagnosed at our institution between 1995 and 2012 (Louvain Lupus Nephritis inception Cohort). Their baseline renal parameters, primary response to IS at one year, survival and long-term renal outcome (mean follow-up: 77 months) were compared. RESULTS: At baseline, serum creatinine and 24-hour proteinuria were higher in Class IV-G, as was activity index on renal biopsy in Class IV-S and IV-G compared to III. Upon treatment, renal parameters improved with the same kinetics and to the same extent in the three pathological classes. On repeat renal biopsies (n=43), activity indices dropped similarly. Poor outcomes (death, end-stage renal disease, renal impairment defined by an eGFR <60 ml/min/1.73 m(2)) did not statistically differ between groups, although there was a trend toward more renal impairment at follow-up in Class IV-G compared to IV-S and III. Finally, the presence of even mild chronic lesions on baseline biopsy was clearly predictive of late renal outcome. CONCLUSION: Subsetting proliferative LN into Class III, IV-S and IV-G provides less clinically discriminant prognostic information than baseline chronicity index.

Rituximab treatment induces the expression of genes involved in healing processes in the rheumatoid arthritis synovium.

OBJECTIVE: Rituximab displays therapeutic benefits in the treatment of patients with rheumatoid arthritis (RA) resistant to tumor necrosis factor (TNF) blockade. However, the precise role of B cells in the pathogenesis of RA is still unknown. We undertook this study to investigate the global molecular effects of rituximab in synovial biopsy samples obtained from anti-TNF-resistant RA patients before and after administration of the drug. METHODS: Paired synovial biopsy samples were obtained from the affected knee of anti-TNF-resistant RA patients before (time 0) and 12 weeks after (time 12) initiation of rituximab therapy. Total RNA was extracted, labeled according to standard Affymetrix procedures, and hybridized on GeneChip HGU133 Plus 2.0 slides. Immunohistochemistry and quantitative real-time reverse transcriptase-polymerase chain reaction experiments were performed to confirm the differential expression of selected transcripts. RESULTS: According to Student's paired t-tests, 549 of 54,675 investigated probe sets were differentially expressed between time 0 and time 12. Pathway analysis revealed that genes down-regulated between time 0 and time 12 were significantly enriched in immunoglobulin genes and genes involved in chemotaxis, leukocyte activation, and immune responses (Gene Ontology annotations). In contrast, genes up-regulated between time 0 and time 12 were significantly enriched in transcripts involved in cell development (Gene Ontology annotation) and wound healing (Gene Set Enrichment Analysis). At baseline, higher synovial expression of immunoglobulin genes was associated with response to therapy. CONCLUSION: Rituximab displays unique effects on global gene expression profiles in the synovial tissue of RA patients. These observations open new perspectives in the understanding of the biologic effects of the drug and in the selection of patients likely to benefit from this therapy.

Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines.

We previously demonstrated that baseline synovial overexpression of the interleukin-7 receptor α-chain (IL-7R) is associated with poor response to tumour necrosis factor (TNF) blockade in rheumatoid arthritis (RA). We found that IL-7R gene expression is induced in fibroblast-like synovial cells (FLS) by the addition of TNF-α, IL-1ß and combinations of TNF-α+ IL-1ß or TNF-α+ IL-17, thereby suggesting that these cytokines play a role in the resistance to TNF blockade in RA. Because FLS and CD4 T cells also produce a soluble form of IL-7R (sIL-7R), resulting from an alternative splicing of the full-length transcript, we wondered whether expression of sIL-7R is similarly regulated by pro-inflammatory cytokines. We also investigated whether sIL-7R is detectable in the serum of RA patients and associated with response to TNF blockade. RA FLS were cultured in the presence of pro-inflammatory cytokines and sIL-7R concentrations were measured in culture supernatants. Similarly, sIL-7R titres were measured in sera obtained from healthy individuals, early untreated RA patients with active disease and disease-modifying anti-rheumatic drug (DMARD)-resistant RA patients prior to initiation of TNF-blockade. Baseline serum sIL-7R titres were correlated with validated clinical measurements of disease activity. We found that exposure of RA FLS to pro-inflammatory cytokines (TNF-α, IL-1ß and combinations of TNF-α and IL-1ß or TNF-α and IL-17) induces sIL-7R secretion. Activated CD4 T cells also produce sIL-7R. sIL-7R serum levels are higher in RA patients as compared to controls. In DMARD-resistant patients, high sIL-7R serum concentrations are strongly associated with poor response to TNF-blockade. In conclusion, sIL-7R is induced by pro-inflammatory cytokines in RA FLS. sIL-7R could qualify as a new biomarker of response to therapy in RA.

The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.

OBJECTIVE: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. PATIENTS AND METHODS: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. RESULTS: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. CONCLUSION: The data confirm that a LD IVCY regimen followed by AZA-the "Euro-Lupus regimen"-achieves good clinical results in the very long term.

A pilot study of mycophenolate mofetil combined to intravenous methylprednisolone pulses and oral low-dose glucocorticoids in severe early systemic sclerosis.

OBJECTIVE: This pilot study was aimed at evaluating the efficacy and safety of a protocol-based treatment strategy combining mycophenolate mofetil (MMF), intravenous (IV) methylprednisolone (MP) pulses and low-dose glucocorticoids (GC) in early systemic sclerosis (SSc) patients suffering from either active interstitial lung disease (ILD) or extensive skin disease. PATIENTS AND METHODS: Sixteen SSc patients were recruited in the study, 9 based on the severity of their skin involvement (modified Rodnan total skin score [TSS] >or= 15) and 7 based on the presence of active ILD. Patients received 3 consecutive daily IV MP pulses, followed by 5 additional monthly IV MP pulses. MMF (0.5 g bid for one week; then, 1 g bid) and low-dose (5-10 mg/day) oral prednisolone were prescribed for one year. Patients were assessed at baseline, month 6 and 12. Statistics were by ANOVA. RESULTS: TSS and Health Assessment Questionnaire significantly improved over time. In ILD patients, the vital capacity, forced expiratory volume in one second and carbon monoxide diffusing capacity significantly improved. Although the difference was not statistically significant, ground glass lesions decreased, based on semi-quantitative planimetry analyses performed on chest high-resolution computerized tomography. Toxicity was low and none of the patients suffered from renal crisis. CONCLUSION: The results of this pilot study suggest that the combination of MMF, IV MP and low-dose GC might achieve good clinical, functional and radiological results in patients suffering from severe early SSc.

[Disseminated lupus erythematosis: current therapies and future hopes]. / Le lupus érythémateux disséminé: des progrès thérapeutiques aujourd'hui, des espoirs pour demain.

The author summarizes his recent scientific achievements in the field of systemic lupus erythematosus, with special emphasis on the role of certain cytokines in the pathophysiology of the disease, the treatment of kidney involvement and glucocorticoid-induced bone manifestations.

Lupus nephritis: the significance of serological tests at the time of biopsy.

We reviewed the initial serological data of 50 patients with biopsy-proven lupus nephritis. As compared with a group of lupus patients without nephritis, patients with nephritis had lower serum complement C3 (p less than 0.05) and C4 (p less than 0.005) levels and higher serum DNA binding activity (p less than 0.001). The frequency of rheumatoid factor, antiphospholipid, anti-ENA, and fluorescent antinuclear antibodies was similar in both groups. We correlated the serological data of the patients with nephritis with the clinical severity of their disease. Using a functional staging system based on the serum albumin and creatinine levels at the time of biopsy, we found that patients with functionally milder disease (proteinuria without nephrotic syndrome or renal failure) had higher C3 (p less than 0.05) and lower DNA binding (p less than 0.005) than patients in the more severe functional classes (nephrotic syndrome with or without renal failure). In contrast, C4 levels were always very low, irrespective of functional severity. We also correlated the serological data with the pathological findings. Patients suffering from diffuse proliferative nephritis had higher DNA binding values than patients with focal proliferative (p less than 0.01) or membranous (p less than 0.001) nephritis. By contrast, complement levels were not correlated with the severity of biopsy changes. Taken together, the data presented here suggest that C3 and DNA binding, but not C4, correlate with the clinical severity of lupus nephritis at presentation whereas DNA binding, but not complement levels, correlates with the severity of pathological changes.

Malignant lymphoma in systemic rheumatic diseases. A report of five cases.

We describe five patients suffering from systemic rheumatic diseases who developed a malignant lymphoma. Two patients, one with systemic lupus erythematosus and another with systemic necrotizing vasculitis, suffered from Hodgkin's disease and three other patients, one with lupus and two with Sjögren's syndrome, developed non-Hodgkin's lymphoma. Only one of these patients had been treated with immunosuppressive drugs before the onset of the lymphoproliferative malignancy. Four patients were given combination chemotherapy and complete remission was achieved in the three patients for whom follow-up data were available. We discuss the relationships between systemic rheumatic diseases and lymphoma.

Functional outcome of myositis patients: can a low-dose glucocorticoid regimen achieve good functional results?

OBJECTIVE: During the last few years, in an attempt to reduce the side effects of glucocorticoid (GC) therapy, we have been treating polymyositis-dermatomyositis (PM-DM) patients with a lower starting dose of GC than is classically recommended. In order to validate this approach, we performed a functional re-evaluation of these PM-DM patients. METHODS: A comprehensive protocol evaluating muscle strength, muscle function, CK levels, persistence of spontaneous activity on electromyography, disability in daily life activities and degree of dependence was applied in 25 non-cancer-associated biopsy-proven PM-DM patients, 15 of whom had been treated with a high-dose regimen (i.e. > 0.5 mg prednisolone/kg/day) and 10 with a low-dose regimen (i.e. < or = 0.5 mg prednisolone/kg/day). RESULTS: Our results indicate that the functional outcome of PM-DM patients given a low-dose starting regimen of GC does not differ from that observed in patients given higher doses. Interestingly, vertebral fractures were less common in patients treated with lower GC doses. CONCLUSIONS: Although our analysis has certain shortcomings, including the small number of patients investigated and their uncontrolled assignment to a low-dose or a high-dose GC regimen, the results of this retrospective study suggest that a low-dose starting regimen of GC can achieve a good functional outcome in PM-DM patients, with a reduction of treatment-related disability. This approach would be welcome as a step forward should it be validated by a longitudinal study.

Cytokines in rheumatoid arthritis.

An ever-growing number of cytokines that play a critical role as soluble mediators of immune and inflammatory responses are being described. Not surprisingly, most of them have been detected in SF or serum of patients with RA. However, given the numerous interactions within the cytokine network--e.g., agonistic and antagonistic properties and natural inhibitors--one should beware of over-simplistic views, the most so as extrapolation from in vitro and animal models is always a challenge. From a clinical viewpoint, more work is required before measurements of cytokines in RA be used as activity indices and--more importantly--as prognostic marker.

Neonatal lupus erythematosus with congenital heart block associated with maternal systemic lupus erythematosus.

We report the presence of complete heart block in a girl whose mother has anti-Ro antibodies and is suffering from systemic lupus erythematosus with Sjögren's syndrome. HLA antigens studies in the two patients support the hypothesis described recently that HLA DR3 is responsible for the production of anti-Ro antibodies and not for the phenotypic expression of the tissue injury.

Persistent pneumomediastinum and dermatomyositis: a case report and review of the literature.

We describe a 42-year-old man with dermatomyositis and interstitial lung disease who presented with anterior neck pain and dyspnoea. Chest radiographs showed subcutaneous emphysema, pneumomediastinum and diffuse reticulonodular infiltration in both lungs. After the administration of high doses of prednisolone, an improvement of pulmonary function and respiratory symptoms was observed but the pneumomediastinum persists 12 months after diagnosis, and without any complication. We review the cases that have been reported thus far of pneumomediastinum associated with dermatomyositis and discuss the possible mechanisms involved. We conclude that pneumomediastinum is not an uncommon complication of dermatomyositis and that its aetiopathogenesis remains very unclear.

A rare case of primary skeletal muscle lymphoma: the value of octreotide scintigraphy.

We report a case of non-Hodgkin lymphoma presenting as a painless mass of the quadriceps femoris muscle that was detected by a somatostatin analogue (octreotide) scintigraphy. We review the few reported cases of primary muscular lymphoma and discuss the potential value of octreotide imaging as a new diagnostic tool.

Clinical significance of antiproteinase 3 antibody positivity in cANCA-positive patients.

We addressed the clinical significance of antiproteinase 3 (anti-PR3) antibody (Ab) positivity by reviewing the files of 79 patients whose serum contained antineutrophil cytoplasmic antibodies with a cytoplasmic staining pattern (cANCA) and had been tested for anti-PR3 reactivity. Vasculitis was present in most (22/35) cANCA+ PR3+ patients but in only a few (5/44) cANCA+ PR3- patients, thereby suggesting that anti-PR3 Ab positivity in cANCA+ patients is more indicative of vasculitis than cANCA positivity alone. Noteworthy, one-third of cANCA+ PR3+ patients -- those with anti-PR3 Ab titres lower than 100 U/ml -- did not suffer from vasculitis. Anti-PR3 reactivity in vasculitis patients was only weakly associated with Wegener's granulomatosis (WG), as nine out of 22 cANCA+ PR3+ vasculitis patients (41%) did not fulfil the ACR classification criteria for WG. There was no correlation between anti-PR3 Ab titres and disease activity at diagnosis. However, titres measured when patients were in remission were much lower than initial values. Taken together, our results indicate that anti-PR3 Ab positivity should be interpreted in its clinical context.

[Lupus erythematosus: from clinical aspects to immunopathology]. / Le lupus erythémateux: de la clinique a l'immunopathologie.

The author highlights some of the clinical and serological signs associated with systemic lupus erythematosus and use them as keys to enter into the most recent advances in the immunopathology of the disease, in particular the mechanisms underlying the production of pathogenic autoantibodies. He stresses that a better knowledge of the pathophysiology of the disease, combined to the progresses in basic immunology and biotechnology, has raised hopes for a more targeted immunointervention.

sIL7R concentrations in the serum reflect disease activity in the lupus kidney.

OBJECTIVES: Evaluation of disease activity in systemic lupus erythematosus (SLE) nephritis is a challenge, and repeated renal biopsies are usually needed in order to confirm a suspicion of flare. In a previous cross-sectional study, we reported that serum soluble form of the interleukin-7 receptor (sIL7R) levels is strongly associated with nephritis in SLE patients. In the present study, we wanted to confirm the association between changes in serum sIL7R concentrations and renal disease activity in a large longitudinal cohort of SLE nephritis patients. METHODS: Sera were harvested longitudinally in 105 SLE nephritis patients. Serum sIL7R cut-off value for the detection of SLE nephritis activity was determined as the mean sIL7R concentration in non-nephritis SLE patients + 2 SDs using data collected in our previous study. Patients with glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) (n=17) were excluded from the study due to persistently elevated serum sIL7R values. RESULTS: Serum sIL7R concentrations above the renal cut-off value were observed in 25 (out of 88) patients with a normal GFR. These patients had significantly higher serum double-stranded DNA (dsDNA) Ab and urinary protein to creatinine (UPC) ratio. Strikingly, 12 of them developed a renal British Isles Lupus Assessment Group index (BILAG) A within the next 3 months, while this was only the case in four out of the 63 other patients (p<0.0001). The test had 75.0% sensitivity and 81.9% specificity for the detection of a renal BILAG A. Combination of serum sIL7R with any of the classical tests (anti-dsDNA Ab titres, UPC ratio, serum C3) resulted in an increased specificity for the detection of a renal flare. Administration of immunosuppressive therapy resulted in a significant decrease in serum sIL7R concentrations. CONCLUSIONS: Serum sIL7R is a sensitive and specific marker of renal disease activity in SLE. Elevated serum sIL7R values in SLE patients are associated with or predict the occurrence of an SLE nephritis flare.