Successful rituximab treatment of refractory hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia associated with systemic lupus erythematosus

Abstract

High-dose steroids, immunosuppressants such as cyclophosphamide and cyclosporine, and high-dose intravenous immunoglobulin have all been used to control hemophagocytic lymphohistiocytosis (HLH) or autoimmune hemolytic anemia (AIHA) associated with systemic lupus erythematosus (SLE); however, some patients are refractory to treatment. Rituximab has successfully resolved many of the refractory manifestations of SLE. Here, we report a case of HLH and AIHA associated with SLE that was refractory or intolerable to conventional therapy, but was successfully treated with rituximab.     

Fatal hemophagocytic syndrome in a patient with a previously well-controlled asymptomatic HIV infection after EBV reactivation

We present a rare case of hemophagocytic lymphohistiocytosis (HLH) in a 70 year-old male patient with previously well-controlled HIV infection. We could confirm HLH in different organs post mortem. Since the diagnosis of HLH was delayed, the patient died despite initiation of chemotherapy. As cause for HLH, an EBV reactivation could be confirmed. In HIV infection, HLH may be the first HIV manifestation, often triggered by an opportunistic infection or immune reconstitution syndrome, but it is uncommon in the state of a well-controlled or aviremic HIV infection.     

The role of infections in primary hemophagocytic lymphohistiocytosis: a case series and review of the literature.

There is a paucity of literature addressing infection-related morbidity and mortality in children with primary hemophagocytic lymphohistiocytosis (HLH), a rare condition characterized by abnormal proliferation of macrophages, hypercytokinemia, and T cell immunosuppression. Therefore, a retrospective chart review was done of patients diagnosed with primary HLH over a 15-year period. Significant infections present at diagnosis, during the course of illness, and just prior to death or at autopsy were noted. Of the 18 children identified with primary HLH, an infectious agent was documented at the initial presentation of HLH in 5. Significant infections occurred during therapy in 10 (56%) of 18. Of the 12 fatal cases, invasive infection was the cause of death in 8 children, and 6 of these deaths were directly attributable to invasive fungal infection. Significant infections were common during therapy in children with primary HLH, and fungal infections were an important cause of mortality in this group.     

Foetal loss, liver necrosis and acute lupus erythematosus in a patient with antiphospholipid antibody syndrome.

The antiphospholipid antibody syndrome (APS) is characterized by arterial or venous thromboses and recurrent foetal loss. It occurs as primary disease, but also in the context of systemic lupus erythematosus (SLE). Whereas primary APS induces a thrombotic microangiopathy without significant inflammatory reaction, secondary APS in SLE is usually associated with vasculitis. Here we report a patient with APS who presented with acute diarrhoea and then developed a HELLP-like syndrome characterized by a spontaneous abortion, multifocal hepatic necroses and thrombocytopenia. Thereafter an acute flare of SLE with arthralgias, pleuritis, skin rash and glomerulitis occurred. Clinical amelioration was only achieved by combining curettage, anticoagulation and immunosuppression, a treatment taking into account the pathogenesis of HELLP-like disease, APS and SLE. To our knowledge this is the first reported case of APS associated with combined acute manifestations of these three syndromes triggered by a presumable intestinal infection.     

High-dose immunosuppression with autologous stem cell transplantation in severe refractory systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an immune-mediated disease that is responsive to suppression or modulation of the immune system. Patients with SLE who experience persistent multiorgan dysfunction, despite standard doses of intravenous cyclophosphamide (Cy), represent a subset of patients at high risk of early death. We investigated the efficacy and toxicity of high-dose immunosuppression and autologous hematopoietic stem cell transplantation (SCT) to treat such patients. Six patients (all female, age 15-29 years) with severe refractory SLE were enrolled in the clinic of our institution from 1998 to 2003. All patients were seriously ill, with SLE disease activity indices (SLEDAI) of 6-30, including two cases with central nervous system lupus, one case with lung vasculitis, and three cases with nephritis and nephrotic syndrome. All patients were registered in the European Group for Blood and Marrow Transplantation (EBMT)/European League Against Rheumatism (EULAR) database. Previous immunosuppression included pulse Cy intravenous, prednisolone (standard doses and pulse therapy), oral Cy and azathioprine, with little or no effect on disease progression. Autologous hemopoietic stem cells were collected from bone marrow (n = 4) or mobilized from peripheral blood with Cy and granulocyte colony-stimulating factor (G-CSF) (n = 2). Pre-transplant conditioning regimens included BEAM +/- ATG (n = 2), melphalan 140 mg/m2 + etoposid 1600 mg/m2 (n = 2) and Cy 200 mg/kg +/- ATG (n = 2). Median time to an absolute neutrophil count (ANC) greater than 0.5 x 10(9)/L and platelet count greater than 50 x 10(9)/L was 13 and 15 days, respectively. Three patients died on days 11, 22 and 63 due to transplant-related complications. The follow-up is now 60 and six months for two patients (complete remission), and 42 months for one other patient (partial response). All patients had experienced multiple and severe episodes of infections pre-SCT and long-term history of corticosteroid therapy (3-14 years). We conclude that achievement of prolonged, corticosteroid-free remissions is a reality. Judicious selection of patients earlier in disease or in remission, but with a high risk of relapse or further progression, will diminish transplantation-related mortality.     

Multiple avascular necrosis of bone and polyarticular septic arthritis in patients with systemic lupus erythematosus

Objective Avascular necrosis of bone (AVN) and osteoarticular infection share similar risk factors in systemic lupus erythematosus (SLE) patients. However, their coincidental development in SLE has rarely been described. We describe four cases of AVN complicated by Staphylococcus aureus infection in SLE.Methods Patients were identified by retrospectively reviewing an SLE cohort followed between 1979 and 2003. A review of the literature from 1960 until 2003 was also done.Results Among 315 SLE patients, four developed joint infection by S. aureus following or coincidentally with AVN. All presented multifocal disease with severe or relapsing course, resulting in severe incapacity. The clinical course suggests that AVN developed first in active SLE patients with positive antiphospholipid (aPL) antibodies treated with high-dose corticosteroids (CS), and subsequent bone infarcts favor infection. Our patients often required prolonged antibiotic therapy and surgical treatment.Conclusions Active SLE patients with aPL antibodies on high-dose CS seem at high risk of developing multiple AVN complicated by infection. Avascular necrosis and bone or joint infection by S. aureus in these patients is a major complication that leads to severe joint destruction and disability.     

Scleroderma renal crisis precipitated by steroid treatment in systemic lupus erythematosus and scleroderma overlap syndrome

Introduction: Connective tissue disorders can overlap in various ways. Patients may present with features of more than one specific disease without satisfying the diagnostic criteria and thereafter evolve into a specific disease entity. Occasionally, patients may fulfil simultaneously the diagnostic criteria of two or more diseases. Several cases of systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) overlap syndrome have been reported. SLE patients often develop lupus nephritis, the treatment of which is based on immunosuppression with corticosteroids (CS) and cytotoxic drugs. However, the use of high dose of CS has been associated with scleroderma renal crisis (SRC) in patient with SSc. Case report: a 43-year-old woman presented to the nephrology department of the Military hospital in Rabat, Morocco, in August 2011 with progressive dyspnea and oliguria. She was diagnosed as SLE and scleroderma overlap syndrome based on clinical and serological markers. Renal biopsy showed lupus nephritis. Immunosuppression consisting of high-dose steroid and cyclophosphamide pulses was given. There was response to treatment but 15 days later the course of the disease was complicated by scleroderma renal crisis evidenced by elevated blood pressure, deteriorating kidney function, hemolysis and thrombocytopenia. The patient was treated with perindopril and rapid reduction of steroid doses. This was followed by correction of hemolysis and thrombocytopenia. Two months later, the patient was off dialysis, but had chronic renal insufficiency with an estimated GFR of 25 ml/minute. Conclusion: This report describes the occurrence of SRC in a patient with lupus nephritis and SSc/ SLE overlap syndrome who was treated by CS and cyclophosphamide. Key words: Systemic Sclerosis; Lupus Erythematosus; Overlap Syndrome; Scleroderma Renal Crisis; Corticosteroids.     

Syngeneic peripheral blood stem cell transplantation with brief immunosuppression for severe aplastic anemia

We report the cases of two severe aplastic anemia (SAA) patients who were successfully treated with syngeneic peripheral blood stem cell transplantation (PBSCT) using immunosuppression without high-dose chemotherapy or irradiation for conditioning. A 21-year-old woman with SAA of 6 years duration had been transfused heavily before transplantation and had developed refractory thrombocytopenia, chronic hepatitis and secondary hematochromatosis. Syngeneic PBSCT with immunosuppression using ATG, methylprednisolone, and cyclosporin-A was eventually performed without high-dose chemotherapy in September 1997. The second syngeneic PBSCT with the same immunosuppression was successfully performed in a 35-year-old male patient who had had SAA for 3 months in November 1998. Haemopoietic engraftment was rapid and sustained. There was no infection or mucositis during the syngeneic PBSCT. The patients are currently 9 to 22 months post-PBSCT without rejection. Our experience suggests that syngeneic PBSCT with brief immunosuppression is an effective alternative to pretransplant high-dose chemotherapy conditioning for SAA patients having syngeneic transplantation. Bone Marrow Transplantation (2000) 25, 337-339.     

Mycobacterium avium complex infection in kidney transplant patients

Mycobacterium avium complex (MAC) infections have been reported rarely in renal transplant patients. Consequently the clinical course and optimal treatment of these patients are not well understood. We present 3 patients with MAC infections after receiving a renal transplant (2 with generalized and 1 with localized infection). All patients were treated with combination antibiotic therapy and reduction of immunosuppression. One patient experienced clinical control of disease but a mild cellular rejection that was successfully treated with high-dose corticosteroids. One patient died of disseminated MAC infection. The patient with localized infection died of unrelated causes. In summary, MAC infection, although rare in renal transplant patients, may respond to combination antimicrobial therapy and reduction of immunosuppression.     

Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial,a randomized trial of low-dose versus high-dose intravenous cyclophosphamide

OBJECTIVE: Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment. METHODS: In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed. RESULTS: Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant. CONCLUSION: The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen.     

Control of severe systemic lupus erythematosus after high-dose immunusuppressive therapy and transplantation of CD34+ purified autologous stem cells from peripheral blood.

A 35 y old woman with severe and progressive systemic lupus erythematosus (SLE) received high-dose chemotherapy followed by a T cell depleted autologous stem cell transplantation. Peripheral blood stem cell were mobilised with Cyclophosphamide 4.5 g/m2 followed by Granulocyte-Colony Stimulating Factor (G-CSF). A CD34 positive selection provided a 3 log T cell depletion. High-dose immunosuppression consisted of the BEAM regimen. The purified autograft was reinfused on day 0. In the post transplant period, hemopoietic growth factors, G-CSF, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Erythropoietin, were administered, engraftment was rapid. Both the mobilisation and the transplant procedures were easily performed and well tolerated. One year later, the patient is in clinical remission. The ANA and anti-SSA-antibodies were undetectable at 1 and 6 months after intensification, but reappeared at low levels at 9 months. Corticosteroid requirement has gradually decreased. In conclusion, we report here the favourable evolution of a patient with a severe SLE, who clinically improved with high-dose immunosuppressive therapy and autologous stem cell transplantation, and showed a 9 month serological remission.     

Infection à cytomégalovirus au cours du lupus érythémateux systémique. Série de 12 cas cliniques et revue de la littérature

IntroductionPatients with systemic lupus erythematosus (SLE) are at risk of cytomegalovirus (CMV) infection, due to the disease itself or to drug-induced immunosuppression. Also, active CMV infection may trigger or worsen SLE flare-up.MethodsIn this retrospective single-centre cohort study, we reported all adult inpatients with a diagnosis of SLE, presenting with active and confirmed CMV infection. The goal was to describe their characteristics and outcomes (evolution of CMV infection, secondary infections and SLE flare-up), and to review the existing literature.ResultsWe identified 400 patients with confirmed SLE, including 12 who presented with active CMV infection. Severe CMV manifestations were present in 7 patients treated with immunosuppressive regimen out of 10, and in one patient out of two without immunosuppressive therapy. Six patients developed other infections, and 3 showed characterised SLE flare-up over the 3-month follow-up. All patients were alive at end of follow-up.DiscussionAmong patients with SLE, CMV infection affected more frequently those treated with immunosuppressive drugs, but treatment-free patients were sometimes severely affected. CMV infection was associated with an increased incidence of SLE flare-up and infectious complications. Our results suggest that early anti-viral chemotherapy may be beneficial in these patients.     

Human immunodeficiency virus infection and systemic lupus erythematosus. An unusual case and a review of the literature

Systemic lupus erythematosus (SLE) and infection with the human immunodeficiency virus (HIV) are rarely seen in the same patient. Both diseases share clinical and serological features and the differential diagnosis is difficult, with renal manifestations being of special interest. To date, 29 cases of association between the two diseases have been reported, but the diagnosis was simultaneous in just two of these and only 18 fulfilled the ARA criteria for the diagnosis of SLE. Most patients experienced an improvement in their SLE after development of their HIV associated immunosuppression and a reactivation of lupus manifestations has also been noted after immunological recovery secondary to antiretroviral therapy. We present the case of a woman in whom HIV and SLE with renal involvement were diagnosed simultaneously.     

Nocardia infection in SLE: A case series of three patients

ObjectivesNocardia infections have been described in immunosuppressed patient including patients with systemic lupus erythematosus (SLE). There are only a few case series in patients with SLE. Thus we studied the clinical presentations, organ involvement, treatment and outcome of cases of nocardial infection in the SLE patients.MethodsRecords of SLE patients who attended our rheumatology clinic in the last 25 years were reviewed and cases of nocardial infection were identified and data was collected from case records.ResultsThree cases of nocardiosis were found in our lupus series, giving a prevalence of 0.2%. Brain involvement was seen in all 3, whereas pulmonary and subcutaneous abscess was found in two patients each. All patients were managed with antibiotics and one patient required surgical drainage. All recovered without any morbidity.ConclusionNocardial infection, though rare in SLE has a good outcome. Involvement of brain, skin and lung together in a patient with background of immunosuppression should raise a suspicion of nocardial infection.     

Management of therapy-resistant systemic lupus erythematosus with rituximab: report of a case and review of the literature

Therapy of systemic lupus erythematosus (SLE) with major organ involvement consists of aggressive immunosuppression with glucocorticoids and cytotoxic agents. When remission is achieved, maintenance therapy is begun to reduce the risk of relapse while minimizing toxicity. Remission with standard therapy is, however, not always achieved. We discribe a women with SLE and microangiopathic haemolytic anaemia and thrombocytopenia, pneumonitis and nephritis refractory to high-dose steroids, pulse cyclophosphamide, plasmapheresis and intravenous immunoglobulins. The anti-CD20 monoclonal antibody rituximab was administered, resulting in major clinical and biochemical improvement. Therapy-resistant SLE generally has an ominous prognosis. A few anecdotal reports and small open studies describe beneficial effects of rituximab in these cases. Rituximab may be a promising new approach to improve the dismal outcome of therapy-resistant SLE.     

Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus: association with human papillomavirus infection

OBJECTIVE: To compare the prevalence of abnormal Pap smears in patients with systemic lupus erythematosus (SLE) with that in a large group of healthy controls, and to determine whether SLE itself is an independent risk factor. The association of human papillomavirus (HPV) infection and the use of immunosuppressive agents with abnormal Pap smears in SLE was also assessed. METHODS: Eighty-five SLE patients participated in this cross-sectional study. A sample of cervical cells was collected from each patient for routine cytologic examination. HPV was typed by restriction and sequencing analysis. A structured questionnaire was administered to the subjects to ascertain the possible behavioral and biologic risk factors associated with cervical atypia. Data on 2,080 healthy female subjects were retrieved for comparison. RESULTS: The mean (+/-SD) age of SLE patients and controls was 42 +/- 9 years and 44 +/- 10 years, respectively. The prevalence of abnormal Pap smears was significantly increased in SLE patients compared with controls (16.5% versus 5.7%). The prevalence of squamous intraepithelial lesions was increased approximately 6-fold in SLE patients (11.8%) compared with controls (2.0%). SLE itself remained an independent risk factor for abnormal Pap smears (odds ratio 3.5, 95% confidence interval 1.8-6.9). The overall prevalence of HPV infection in SLE patients and controls was 11.8% and 7.3%, respectively. However, 10.6% of SLE patients were infected with at least 1 high-risk type of HPV, compared with 4.2% of controls. Multiple infections were also more common in SLE patients than in controls (4.7% versus 1.1%). There were no significant differences in the use of immunosuppressive agents between SLE patients with normal Pap smears and those with abnormal Pap smears. CONCLUSION: Abnormal Pap smears were more common among SLE patients than controls, even after adjusting for HPV status. SLE-associated immunosuppression increases susceptibility to high-risk HPV infection and multiple HPV infections. The use of immunosuppressant agents was not associated with abnormal Pap smears.     

'Sustained remission' in a case of SLE following megadose cyclophosphamide

Cytotoxic therapy, especially with cyclophosphamide in the dose 8-20 mg/kg used as intermittent pulses, has been shown to improve both patient and renal survival in systematic lupus erythematosus (SLE), but to date there is no cure for the disease. Owing to the paucity of recognisable clones, the rationale and goal of cytotoxic immunosuppressive therapy in the treatment of immune-mediated diseases as against malignancies is to suppress the aberrant inflammation and immune-mediated reactions responsible for tissue damage, without dangerously suppressing the normal host defence mechanism(s). We report the case of a patient suffering from SLE with nephritis who has remained in sustained remission over the past 8 years without any maintenance therapy following an accidental administration of a single dose of 5000 mg of intravenous cyclophosphamide (44.2 mg/kg body weight). The patient recovered fully from pancytopenia following the injection. Presently, she is asymptomatic and working gainfully. Her laboratory parameters including blood counts, urine analysis, FANA and anti-dsDNA have reverted to normal. Cyclophosphamide in the dose of 30-160 mg/kg has been safely and effectively used in various neoplastic conditions with the aim of destroying every possible tumour cell. The experience of the present case suggests that such an approach may be applicable to SLE.     

Meningococcal purpura fulminans in a patient with systemic lupus erythematosus: a mimic for catastrophic antiphospholipid antibody syndrome?

Purpura fulminans (PF) is a life-threatening disorder characterized by acute onset of progressive cutaneous hemorrhage, necrosis, and disseminated intravascular coagulation. Acute infectious PF occurs most commonly in the setting of meningococcal sepsis. When PF occurs in the setting of systemic lupus erythematosus (SLE), the catastrophic antiphospholipid antibody syndrome (CAPS) must be ruled out because urgent therapy is required. Plasmapheresis is effective in both cases, but immunosuppression (high-dose corticosteroids plus cyclophosphamide), although beneficial in patients with CAPS, could be harmful in patients with meningococcal PF. The authors report here a patient with SLE who presented to the intensive care unit with meningococcal PF, acute renal failure, and acute respiratory distress syndrome and discuss clinical similarities and laboratory differences from CAPS.     

In vivo evidence for apoptosis in the bone marrow in systemic lupus erythematosus

An increase in leucocyte apoptosis and impaired clearance of apoptotic cells has been observed in patients with systemic lupus erythematosus (SLE). Apoptotic cells are likely to be a key source of autoantigens in SLE as they express many of the nuclear autoantigens (in surface blebs and apoptotic bodies) that are relevant to this disease. The clearance of apoptotic cells is usually a rapid process, such that few cells are usually seen in the extracellular environment in vivo. We report a case in which multiple apoptotic bodies were observed in the bone marrow of a patient with SLE that was complicated by an immune-mediated pancytopenia. We have subsequently examined the frequency of apoptotic cells, identified morphologically, and by caspase-3 staining in bone-marrow trephine samples taken from patients with SLE over a 10-year period of follow-up. A high proportion of bone marrows contained apoptotic debris. The novel demonstration of apoptotic bodies in vivo in patients with SLE is unusual and supports the notion that the marrow may be a target organ in the disease. Their abundance is also consistent with the hypothesis that normal clearance mechanisms are defective and/or overwhelmed in SLE.