Renal involvement as a unique manifestation of hemophagocytic syndrome.

Renal-limited hemophagocytic syndrome (HPS) is a rare clinical setting characterized by abnormal activation of the immune system. Fever associated with pancytopenia, hepatosplenomegaly with liver dysfunction, and hypofibrinogenemia are usually observed in HPS. From a histological level, the presence of non-malignant macrophages infiltrating bone marrow and organs represents the hallmark of this condition. Non-malignant macrophages are associated with phagocytizing activities involving other blood cells. While primary HPS is usually associated with inherited dysregulation of the immune system, secondary HPS usually occurs in the context of infection or is linked to a neoplastic process. Clinical presentation varies and can potentially lead to life-threatening settings. While renal involvement has frequently been reported, however, detailed descriptions of the kidney manifestations of HPS are lacking. More critically, the diagnosis of HPS is rarely supported by renal biopsy specimens. We report four rare cases of biopsy-proven renal-limited HPS in patients presenting with acute kidney injury (AKI). The available evidence on this topic is critically discussed in light of the possible emergence of an autonomous entity characterized by an isolated kidney involvement.

Non HCV-Related Mixed Cryoglobulinemic Vasculitis With Biopsy-Proven Renal Involvement: The Effects of Rituximab.

In the countries where HCV infection is still endemic, about 90% of subjects with mixed cryoglobulinemia had previously been infected with HCV and about 80% are RNA positive. Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome. The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p < 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p < 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.

A Prospective Study on Long-Term Clinical Outcomes of Patients With Lupus Nephritis Treated With an Intensified B-Cell Depletion Protocol Without Maintenance Therapy.

BACKGROUND: We aimed to investigate the safety and efficacy of an intensified B-cell depletion induction therapy (IBCDT) without immunosuppressive maintenance regimen compared with standard of care in biopsy-proven lupus nephritis (LN). METHODS: Thirty patients were administered an IBCDT (4 weekly rituximab [RTX] 375 mg/m2 and 2 more doses after 1 and 2 months; 2 infusions of 10 mg/kg cyclophosphamide [CYC], 3 methylprednisolone pulses), followed by oral prednisone (tapered to 5 mg/d by the third month). No immunosuppressive maintenance therapy was given. Thirty patients matched for LN class and age were selected as controls: 20 received 3 methylprednisolone pulses days followed by oral prednisone and mycophenolate mofetil (MMF) 2 to 3 g/d, whereas 10 were given the Euro Lupus CYC. MMF (1-2 g/daily) or azathioprine (AZA, 1-2 mg/kg/day) were given for > 3 years as a maintenance therapy. RESULTS: At 12 months, complete renal remission was observed in 93% of patients on IBCDT, in 62.7% on MMF, and in 75% on CYC (P = 0.03); the dose of oral prednisone was lower in the IBCDT group (mean ± SD 2.9 ± 5.0 mg/dl) than MMF (10.5 ± 8.0 mg/d, P < 0.01) or CYC group (7.5 ± 9.0 mg/d, P < 0.01). Mean follow-up after treatment was 44.5 months (interquartile range [IQR] 36-120 months), 48.6 months (IQR 36-120 months), and 45.3 (IQR 36-120 months) for IBCDT, MMF, and CYC, respectively. At their last follow-up visit, we observed no significant differences in proteinuria and serum creatinine, nor in the frequency of new flares among the 3 groups. CONCLUSION: In biopsy-proven LN, the IBCDT without further immunosuppressive maintenance therapy was shown to be as effective as conventional regimen of MMF or CYC followed by >3-year maintenance either MMF or AZA regimen. Moreover, the use of IBCDT was associated with a marked reduction of glucocorticoid cumulative dose.

An agent-to-agent real life comparison study of tocilizumab versus abatacept in giant cell arteritis.

OBJECTIVES: The present study aimed at evaluating the efficacy of abatacept (ABA) compared to tocilizumab (TCZ), assumed as a gold standard biologic treatment in the management of patients with giant cell arteritis (GCA). METHODS: Thirty-three biospy-proven GCA consecutive patients were prospectively collected. Odd patients (from 1 to 33) were assigned to TCZ, given either intravenously (IV 8 mg/kg/month), #8 cases, or subcutaneously (SC 162 mg/week) #9, based on patient's preference. ABA was administered subcutaneously at the dose of 125 mg/week in 16 even patients (from 2 to 32). Biological therapies were prescribed in addition to oral prednisone. RESULTS: A single biologic agent was administered in 28 patients out of 33 (85%) (8 TCZ IV, 9 TCZ SC and 16 ABA). Five patients (15%) needed a therapeutic switch (one patient from TCZ to ABA, and 4 patients from ABA to TCZ). Among the TCZ IV group, all patients experienced a response (57% complete response and 43% partial response). Among the TCZ SC group, 7 experienced a clinical response (complete in 67% and partial in 16%). Among the ABA group, 10 patients (62%) achieved either complete (5 patients) or partial (5) response, respectively. After 12 months of therapy, 100% of patients in TCZ groups, both IV and SC, and 7 (43%) of ABA group were receiving doses of oral prednisone not exceeding 7.5 mg/day as maintenance. CONCLUSIONS: Both TCZ and ABA can be proposed as an effective therapeutic option in GCA with relevant inflammatory symptoms. ABA can be considered in the patient with absolute or relative or contraindications to TCZ.

Outcome of patients with severe AL amyloidosis and biopsy-proven renal involvement ineligible for bone marrow transplantation.

INTRODUCTION: AL amyloidosis is caused by a clone of plasma cell. Due to the impact of the disease on patient survival, careful evaluation of organ involvement is essential and treatment should be tailored to single patient's risk. AIM: We analyzed the clinical, laboratory and histological characteristics of 21 elderly patients (pts) (mean age 74.7 ± 7.97 years, range 55-81) with AL amyloidosis, including 17 patients (81%) with biopsy-proven renal involvement, who were ineligible for bone marrow transplantation, and evaluated the impact of renal impairment on survival. RESULTS: Cardiac and renal involvement was found in 14 (67%) cases. Among the 17 patients with renal involvement, 12 had renal failure with proteinuria, and one showed isolated renal failure and vascular amyloid deposition. Hematological response occurred in 57.1% after first line therapy (75% after three cycles). In six of the patients with renal involvement, proteinuria decreased from 4.2 to 1.1 g/24 h (range 0.2-3 g/24 h), serum Creatinina (sCr) levels declined or stabilized. Severe renal failure at diagnosis was found to directly influence patient survival, while the Staging System for Renal Outcome in AL Amyloidosis did not associate with outcomes. CONCLUSIONS: To the best of our knowledge this is the first case series in which the whole cohort of patients with urinary or functional abnormalities underwent a histological evaluation. None of the patients were eligible for bone marrow transplantation. Hematologic response was 57.1%, while renal response was much lower (35%). Of note, the Staging System did not completely apply to this peculiar setting of patients in whom renal involvement was not presumptive but biopsy-proven. More aggressive approaches may be needed in these patients to avoid the inexorable progression of the disease.

Pathogenic variants in EP300 and ANKRD11 in patients with phenotypes overlapping Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS), Rubinstein-Taybi syndrome (RSTS), and KBG syndrome are three distinct developmental human disorders. Variants in seven genes belonging to the cohesin pathway, NIPBL, SMC1A, SMC3, HDAC8, RAD21, ANKRD11, and BRD4, were identified in about 80% of patients with CdLS, suggesting that additional causative genes remain to be discovered. Two genes, CREBBP and EP300, have been associated with RSTS, whereas KBG results from variants in ANKRD11. By exome sequencing, a genetic cause was elucidated in two patients with clinical diagnosis of CdLS but without variants in known CdLS genes. In particular, genetic variants in EP300 and ANKRD11 were identified in the two patients with CdLS. EP300 and ANKRD11 pathogenic variants caused the reduction of the respective proteins suggesting that their low levels contribute to CdLS-like phenotype. These findings highlight the clinical overlap between CdLS, RSTS, and KBG and support the notion that these rare disorders are linked to abnormal chromatin remodeling, which in turn affects the transcriptional machinery.

The "4 plus 2" rituximab protocol makes maintenance treatment unneeded in patients with refractory ANCA-associated vasculitis: A 10 years observation study.

BACKGROUND: ANCA associated vasculitides (AAV) often present with a chronic relapsing course. Relapse leads to increased immunosuppressive exposure and consequent toxicity. While two randomized controlled trials have shown rituximab (RTX) to be the most effective induction treatment in patients with relapsing disease, the optimal treatment duration and RTX dose remain debated. Whether to administer a maintenance dose to every patient, at a fixed time interval or on the basis of B cell count and ANCA titre or only when disease manifestations do occur is still debated as well. METHODS: 11 patients (5 with granulomatosis with polyangiitis, 4 with microscopic polyangiitis-MPA-, and 2 with eosinophilic granulomatosis with polyangiitis -EGPA-) intolerant or refractory to conventional therapies including cyclophosphamide were enrolled. All patients received the so called "improved 4+2" RTX scheme as a rescue therapy. Following RTX administration, immunosuppressive drugs were rapidly tapered and no immunosuppressive maintenance therapy had been given. RESULTS: After a mean follow-up of 85 months since the "4+2" RTX protocol: four out of 11 patients (37%, 1 EGPA and 3 MPA, all MPO-positive) remained in remission after one cycle of "4+2" RTX infusion protocol with no relapse for a median 66 months [60-108]). Seven relapsing patients were re-treated once with RTX (again as monotherapy with the same protocol) after a median of 54 months (24-96). Following re-treatment, they again showed complete remission over a median of 32 months (12-96) of observation. CONCLUSION: In one of the longest-term observation (85 months) studies, sustained clinical remission without immunosuppressive maintenance therapy (and a negligible dose of prednisone since the 5thmonth) was obtained by the "4 + 2" RTX infusion protocol in patients with ANCA-associated vasculitis intolerant or refractory to conventional therapy.

High-Dose Rituximab Ineffective for Focal Segmental Glomerulosclerosis: A Long-Term Observation Study.

BACKGROUND: A beneficial effect of rituximab (RTX) on focal segmental glomerulosclerosis (FSGS) in pediatric patients or in transplant recipients has been reported in isolated cases. However, the use of RTX in adult patients with idiopathic FSGS needs further investigation. METHODS: Eight patients who had biopsy-proven FSGS (63.9 ± 14.0, range 40-81 years, 4 women, 4 men) with major risk factors precluding corticosteroids or conventional immunosuppression were treated with a high dose of RTX (8 weekly doses of 375 mg/m2) and prospectively followed up for at least 2 years (29.1 ± 8.8 months, range 24-42 months). RESULTS: RTX failed to improve proteinuria in 7 out of 8 patients, who had persistent nephrotic proteinuria. In one case, a rapidly deteriorating renal function was also observed. Only one patient showed an improvement in renal function and a remarkable reduction in proteinuria. There were no differences in clinical or laboratory characteristics or in the CD20 B lymphocyte count after RTX between the responder and the 7 nonresponder patients. CONCLUSIONS: Only a minority (1 of 8) in our series of adult patients with FSGS showed positive effects of high doses of RTX. Future studies are warranted to investigate more promising therapeutic options in the management of FSGS.

Improved (4 Plus 2) Rituximab Protocol for Severe Cases of Mixed Cryoglobulinemia: A 6-Year Observational Study.

BACKGROUND: In a prospective, single-center open study, we evaluated the very long-term effects of rituximab (RTX) administered to patients with severe mixed cryoglobulinemia (MC). METHODS: RTX was administered to 31 patients with MC (type II in 29 cases and type III in 2) with diffuse membranoproliferative glomerulonephritis (16 cases), peripheral neuropathy (26) and large skin ulcers (7). All but 4 patients had serum anti-hepatitis C virus antibodies. RTX was administered at a dose of 375 mg/m2, according to a '4 + 2' protocol (days 1, 8, 15 and 22 plus 1 dose 1 and 2 months later). No other immunosuppressive drugs were added. Response was evaluated over a very long-term follow-up (mean 72.47 months, range 30-148). RESULTS: Complete remission of pretreatment active manifestations was observed in all cases of purpuric lesions and non-healing vasculitic ulcers, and in 80% of the peripheral neuropathies. Cryoglobulinemic nephropathy significantly improved during follow-up, starting from the 2nd month after RTX (serum creatinine from 2.1 ± 1.7 to 1.5 ± 1.6 mg/dl, p ≤ 0.05; 24-hour proteinuria from 2.3 ± 2.1 to 0.9 ± 1.9 g/24 h, p ≤ 0.05). Improvement of cryoglobulinemic serological hallmarks, such as cryocrit and low complement C4, were observed. No clinically relevant side effects were recorded. Re-induction with RTX was carried out in 9 relapsed patients after a mean of 31.1 months (12-54), again with beneficial effects. The survival rate was 75% at 6 years and the probability of remaining symptom-free for 10 years without any therapy was of about 60% after a single '4 + 2' infusion cycle, while the probability of living symptom-free 5 years after relapsing was 80% if given the same treatment. CONCLUSION: In this open, prospective study, RTX appeared to be very effective and safe in the treatment of the most severe cases of MC.

A 4-year observation in lupus nephritis patients treated with an intensified B-lymphocyte depletion without immunosuppressive maintenance treatment-Clinical response compared to literature and immunological re-assessment.

BACKGROUND: B cells (BC) play a critical role in systemic lupus erythematosus (SLE). BC depletion therapy still remains an attractive option, despite the disappointing results of randomized controlled trials (RTCs). METHODS: Twelve patients with SLE [3 males, mean age 43.8 yrs (25-55)] with severe multiorgan involvement all including kidney (3 patients with Class IV, 4 with Class III/V and 5 with Class V, according to the International Society of Nephrology/Renal Pathology Society glomerulonephritis classification), skin lesions [10], severe polyarthralgias with arthritis [10], polyserositis [2], and lymphadenopathy [5] have been prospectively treated with an intensified B cell depletion therapy (IBCDT) protocol due to their resistance or intolerance to previous therapy (six cases) or as a front line immunosuppressive treatment in 6 women with unsatisfactory therapeutic compliance or as a specific request of a short-time immunosuppression for gestational perspectives. PROTOCOL: Rituximab (RTX) 375 mg/sm on days 1, 8, 15, 22, and 2 more doses after 1 and 2 months, associated with 2 IV administrations of 10mg/kg of cyclophosphamide and 3 methylprednisolone pulses (15mg/kg) followed by oral prednisone (0.8 mg/kg/day, rapidly tapered to 5mg/day by the end of the 3rd month after RTX). No further immunosuppressive maintenance therapy has been given. RESULTS: Patients had been followed-up for a mean of 44.5 (24-93)months. Significant decreases (p<0.05) were found in the levels of ESR (baseline mean value: 55.0mm; 3 months: 36; end of follow-up: 13), anti-dsDNA antibodies (baseline: 185 U; 3 months: 107; end of follow-up: 15), and proteinuria (baseline: 4.9 g/24h; 3 months: 0.97; end of follow-up: 0.22). C4 values (baseline 11 mg/dl) significantly increased (p<0.05) after 3 months (22 mg/dl) and at the end of the follow-up (20mg/dl). Of the 12 patients, 9 (75%) have remained well after one cycle of IBCDT, with no flare (mean 51.6 months [25-93]). Three patients relapsed after 36, 41, and 72 months, respectively. Following re-treatment, they again showed complete remission over 18-48 months of observation. CONCLUSIONS: A promising role of RTX in an intensified protocol of induction therapy can be envisaged in patients for whom avoiding immunosuppressive maintenance therapy and sparing steroids are particularly appealing. Moreover, our data confirm in one of the longest follow-up available, the opportunity to reconsider the regimens of BL depletion in the treatment of the most severe or refractory forms of SLE despite the disappointing results of RCTs.

Canakinumab as rescue therapy in familial Mediterranean fever refractory to conventional treatment.

Familial Mediterranean fever is an autosomal recessive autoinflammatory disorder mainly affecting Mediterranean populations, which is associated with mutations of the MEFV gene that encodes pyrin. Functional studies suggest that pyrin is implicated in the maturation and secretion of interleukin-1 (IL-1). The IL-1 receptor antagonist or anti-IL-1 monoclonal antibody may therefore represent a rational approach for the treatment of the rare patients who are refractory to conventional therapy. We report the case of a young female affected by familial Mediterranean fever who proved to be resistant to colchicine and was successfully treated with canakinumab.

Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann-Pick disease type C.

BACKGROUND: Twenty-five patients with Niemann Pick disease type C (age range: 7 months to 44 years) were enrolled in an Italian independent multicenter trial and treated with miglustat for periods from 48 to 96 months. METHODS: Based on the age at onset of neurological manifestations patients' phenotypes were classified as: adult (n = 6), juvenile (n = 9), late infantile (n = 6), early infantile (n = 2). Two patients had an exclusively visceral phenotype. We clinically evaluated patients' neurological involvement, giving a score of severity ranging from 0 (best) to 3 (worst) for gait abnormalities, dystonia, dysmetria, dysarthria, and developmental delay/cognitive impairment, and from 0 to 4 for dysphagia. We calculated a mean composite severity score transforming the original scores proportionally to range from 0 to 1 to summarize the clinical picture of patients and monitor their clinical course. RESULTS: We compared the results after 24 months of treatment in 23 patients showing neurological manifestations. Stabilization or improvement of all parameters was observed in the majority of patients. With the exception of developmental delay/cognitive impairment, these results persisted after 48-96 months in 41 - 55% of the patients (dystonia: 55%, dysarthria: 50%, gait abnormalities: 43%, dysmetria: 41%, respectively). After 24 months of therapy the majority of the evaluable patients (n = 20), demonstrated a stabilization or improvement in the ability to swallow four substances of different consistency (water: 65%, purée: 58%, little pasta: 60%, biscuit: 55%). These results persisted after 48-96 months in 40-50% of patients, with the exception of water swallowing. Stabilization or improvement of the composite severity score was detected in the majority (57%) of 7 patients who were treated early (within 3.5 years from onset) and rarely in patients who received treatment later. CONCLUSIONS: The results of this study suggest that miglustat treatment can improve or stabilize neurological manifestations, at least for a period of time; the severity of clinical conditions at the beginning of treatment can influence the rate of disease progression. This conclusion applies particularly to patients with juvenile or adult onset of the disease. TRIAL REGISTRATION: EudraCT number 2006-005842-35.

A multidrug, antiproteinuric approach to alport syndrome: a ten-year cohort study.

BACKGROUND/AIMS: Combined ACE inhibitor, angiotensin-receptor-blocker, non-dihydropyridine calcium-channel-blocker, and statin therapy (Remission Clinic) reduced proteinuria and halted progression in non-diabetic nephropathies, but their efficacy in Alport syndrome (AS) nephropathy is unknown. METHODS: From February 2004 to September 2007, we included nine albuminuric AS adults with creatinine clearance >20 ml/min/1.73 m(2) in a single-center, open-label, prospective, off-on-off academic study. After the 1-month wash-out from RAS inhibition (Run-in), patients entered the 4-month, add-on, treatment period with benazepril (10-20 mg/day), valsartan (80-160 mg/day), diltiazem (60-120 mg/day), and fluvastatin (40-80 mg/day) followed by the 1-month wash-out (Recovery). The primary outcome was albuminuria at month 4. After recovery, patients were kept on the Remission Clinic protocol and followed until July 2014 (Extension). RESULTS: The median (IQR) albuminuria progressively declined from 657.7 (292.7-1,089.6) µg/min at baseline to 71.4 (21.7-504.9) µg/min at treatment end (p = 0.009) and raised to 404.3 (167.9-446.8) µg/min after recovery. Albumin and IgG fractional clearances significantly (p ≤ 0.005) decreased from 66.9 (53.6-80.8) to 9.4 (4.6-26.0) and from 5.1 (3.0-8.4) to 1.1 (0.6-3.2), and then recovered toward baseline. Blood pressure and lipids significantly decreased on treatment, without changes in inulin-measured GFR or para-aminohippuric-measured RPF. After recovery, one patient refused to enter the extension, one with severe renal insufficiency at baseline reached ESRD, and seven retained normal serum creatinine until the end of the study. At the final visit, three were microalbuminuric and one was normoalbuminuric. Treatment was well tolerated. CONCLUSION: The Remission Clinic approach safely ameliorated albuminuria, blood pressure, lipids, and glomerular selectivity in AS patients and halted long-term progression in those without renal insufficiency to start with.

Mycophenolate mofetil as steroid-sparing treatment for elderly patients with giant cell arteritis: report of three cases.

BACKGROUND AND AIMS: Glucocorticoids have never been studied in a placebo-controlled manner in giant cell arteritis (GCA), but their effectiveness is well established. However, evidence for the efficacy of immunosuppressant drugs as steroid-sparing agents in this disease is highly desirable, especially in elderly patients. We report the use of mycophenolate mofetil (MMF) as a steroid-sparing agent in three patients (mean age 78 years) with GCA, at high risk of longterm high dose glucocorticoids because of type II diabetes mellitus, obesity, hypertension or osteoporosis. METHODS: clinical monitoring and assessment of laboratory parameters were carried out weekly (first month) and then patients were seen in the clinic every 2 weeks. Vascular lesions were also monitored at the onset and during the follow-up by Doppler ultrasonography (every 3 months). RESULTS: all three patients showed clinical benefit, and were also able to taper steroid use to a more rapid regimen compared with the recently suggested steroid reduction approach. MMF was well tolerated, and no signs of toxicity were observed in a mean of 21.6 months (12-29) of follow-up. CONCLUSION: mycophenolate mofetil may be considered a steroid-sparing agent in elderly patients with GCA but, before results of controlled trials become available, MMF may be considered only for patients who do not improve or stabilize with conventional therapy, or in patients for whom reduced steroid dosage is highly recommended.

Long-term effects of rituximab added to cyclophosphamide in refractory patients with vasculitis.

BACKGROUND: Current therapies have changed systemic vasculitis from a disease with a high rate of mortality to a chronic curable condition. A limited percentage of patients either remains refractory to conventional treatment or experiences dose-limiting side effects. METHODS: 11 patients (4 affected by idiopathic systemic microscopic polyangiitis, 5 by Wegener's granulomatosis, and 2 by Churg-Strauss syndrome) intolerant or refractory to conventional therapies including cyclophosphamide were enrolled. All patients received rituximab as a rescue therapy and were followed for 30-54 months. Following rituximab administration, immunosuppressive drugs were rapidly tapered and no immunosuppressive maintenance therapy was given. RESULTS: Significant decreases in levels of serum creatinine, proteinuria, erythrocyte sedimentation rate, C-reactive protein, and ANCA titers were observed during the follow-up (at least 30 months after rituximab administration). Arthralgia and weakness rapidly disappeared in all patients. Out of 7 patients, 5 reported a decrease in the degree of paresthesia and in the electrophysiologic parameters. Six months after rituximab administration the mean dose of prednisone was 5.5 mg/day. CONCLUSION: In this sample of patients with systemic vasculitis who were refractory or intolerant to more conventional treatment, rituximab proved to be safe and effective in a long-term follow-up, and showed steroid- and immunosuppressive-sparing effects allowing the persistence of long-lasting remissions without maintenance therapy.

Apheresis as rescue therapy in a severe case of sudden hearing loss.

A 23-year-old man complained of progressive left ear hearing loss and tinnitus and was unsuccessfully treated with steroids and mannitol. Four months later he presented with sudden, severe, asymmetrical, bilateral sensorineural hearing loss. The results of the laboratory workup were normal except for antinuclear autoantibodies. Auditory brain stem responses showed absent peak and interpeak latencies on both sides. The combination of plasma exchange with high doses of steroids resulted in a definite improvement. Plasmapheresis combined with steroid administration can be used as second-line therapy in idiopathic, sudden sensorineural hearing loss.

Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy.

BACKGROUND: B cells play a central role in systemic lupus erythematosus (SLE). Rituximab is expected to induce apoptosis of all the CD20-positive B cells. A proportion of patients are refractory or intolerant to standard immunosuppression. These are candidate to new therapeutic options. METHODS: Eight patients [six women, two men, mean age 41-year-old (27-51), with severe multiorgan involvement (kidney, skin, nervous system, polyarthritis, polyserositis, antiphospholipid antibody syndrome)] were considered eligible for an intensive combination therapy including rituximab. Rituximab was administered (dose 375 mg/m(2)) on Days #2, 8, 15 and 22. Two more doses were administered 1 and 2 months following the last weekly infusion. This treatment was combined with two pulses of 750 mg cyclophosphamide (Days #4 and 17) and three pulses of 15 mg/kg (Days #1, 4 and 8) methylprednisolone followed by oral prednisone, 50 mg for 2 weeks rapidly tapered until 5 mg in 2 months. Response was evaluated by assessing the changes in clinical signs and symptoms [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI score)] and laboratory parameters for at least 12 months. RESULTS: Levels of erythrocyte sedimentation rate and anti-double-strand DNA antibodies significantly decreased (P < 0.01 at 12 months), whereas C3 and mainly C4 values increased at 6 months (P < 0.01 for C4). Proteinuria improved in the cases with renal involvement (P < 0.01 at 3, 6 and 12 months). SLEDAI score improved moving from the mean 17.3 (12-27) before therapy to 3.1 (1-5) after rituximab treatment. Constitutional symptoms including arthralgia, weakness and fever disappeared in all the previously affected patients; paresthesia improved in the four patients with polyneuropathy and skin lesions gradually resolved in the patients with necrotizing skin ulcers at presentation. Drug side effects were negligible. CONCLUSIONS: Long-lasting remissions were obtained in patients with severe SLE and major organ involvement by this intensive administration of rituximab combined with low doses of intravenous cyclophosphamide and methylprednisolone pulses followed by a rapid tapering of prednisone to 5 mg/day as a sole maintenance therapy.

Rituximab as a therapeutic tool in severe mixed cryoglobulinemia.

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis, associated in most cases with hepatitis C virus (HCV) infection, sustained by proliferation of oligoclonal cells. Systemic B cell depletion and clinical remission can be achieved in non-Hodgkin lymphoma by human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen (rituximab). Similar effects could be expected in type II MC. Twelve patients, mean age 61.9 years (range 37-76), 11 with HCV infection genotype 2a2c (4 cases) or 1b (6 cases) and 3 (1 case) and symptomatic type II MC with systemic manifestations, including renal involvement, marrow clonal restriction, large necrotizing ulcers, and polyneuropathy, were considered eligible for rituximab therapy because of resistance or intolerance to conventional therapy or important bone marrow infiltration. Rituximab was administered intravenously at a dose of 375 mg/m2 on days 1, 8, 15, and 22. Two more doses were administered 1 and 2 months later. No other immunosuppressive drugs were added. Response was evaluated by assessing the changes in clinical signs, symptoms, and laboratory parameters. Levels of proteinuria, hematuria, erythrocyte sedimentation rate, cryocrit, rheumatoid factor, and IgM decreased while C4 values increased and HCV viral load remained stable during short- and medium-term observation. Bone marrow abnormalities were found to reverse to normal. Constitutional symptoms disappeared or ameliorated. No acute or delayed side effects were seen. Based on this experience and a number of reports published in the last 5 years, Rituximab appears to be a safe and effective therapeutic option in symptomatic patients with HCV-associated MC with signs of systemic vasculitis.

Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial.

BACKGROUND: In chronic nephropathies, inhibition of angiotensin-converting enzyme (ACE) is renoprotective, but can further renoprotection be achieved by reduction of blood pressure to lower than usual targets? We aimed to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease. METHODS: We undertook a multicentre, randomised controlled trial of patients with non-diabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril (2.5-5 mg/day). We randomly assigned participants either conventional (diastolic <90 mm Hg; n=169) or intensified (systolic/diastolic <130/80 mm Hg; n=169) blood-pressure control. To achieve the intensified blood-pressure level, patients received add-on therapy with the dihydropyridine calcium-channel blocker felodipine (5-10 mg/day). The primary outcome measure was time to end-stage renal disease over 36 months' follow-up, and analysis was by intention to treat. FINDINGS: Of 338 patients who were randomised, three (two assigned intensified and one allocated conventional blood-pressure control) never took study drugs and they were excluded. Over a median follow-up of 19 months (IQR 12-35), 38/167 (23%) patients assigned to intensified blood-pressure control and 34/168 (20%) allocated conventional control progressed to end-stage renal disease (hazard ratio 1.00 [95% CI 0.61-1.64]; p=0.99). INTERPRETATION: In patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown.

Thin glomerular basement membrane disease: clinical significance of a morphological diagnosis--a collaborative study of the Italian Renal Immunopathology Group.

BACKGROUND: Thin glomerular basement membrane disease (TBMD) is a nephropathy defined by diffuse thinning of the glomerular basement membrane (GBM) at electron microscopy examination, without the alterations of Alport's syndrome (ATS). It is known that many patients with TBMD have a type IV collagen disorder and that the disease occasionally may be progressive. This study investigated 51 patients with the morphological diagnosis of TBMD lacking any sign of ATS, with the aim of defining the prevalence of type IV collagen mutations and the course of the disease. METHODS: Patients were investigated as follows: (a) clinical picture and family investigation; (b) renal biopsy findings; (c) immunohistochemical study of renal tissue for collagen IV alpha-chains; (d) pedigree reconstruction and molecular investigations in genes encoding type IV collagen chains, when DNA samples were available; and (e) follow-up data. RESULTS: Renal biopsy analysis revealed no light microscopy changes in 27 patients and minimal abnormalities in the remainder. Global glomerular sclerosis was found in seven cases and superimposed mesangial immunoglobulin-A deposits in four. Normal staining of GBM for alpha(IV) chains was observed in all but one patient, where alpha5(IV) was absent and molecular investigation revealed a COL4A5 mutation. Five out of 25 cases had a mutation in the COL4A3/COL4A4 genes. Eight out of 38 patients followed up for 12-240 months (21%) showed signs of disease progression or hypertension. CONCLUSIONS: This study confirms that a considerable proportion of patients with TBMD have a type IV collagen disorder and that this lesion is not always benign. Thus, families should be investigated carefully whenever possible and patients and affected relatives should be examined periodically for signs of disease progression.