scholarly journals Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome

2015 ◽  
Vol 3 ◽  
Author(s):  
V. Koneti Rao
Keyword(s):  
Autoimmune Lymphoproliferative Syndrome ◽  
Immunological Disorders ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias

Using the Genetics of the Autoimmune Lymphoproliferative Syndrome to Guide Therapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-7-SCI-7
Author(s):  
David T. Teachey
Keyword(s):  
Mycophenolate Mofetil ◽  
T Cell ◽  
Autoimmune Disease ◽  
Mtor Signaling ◽  
Cell Phenotype ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Second Line ◽  
Evans Syndrome ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias

Abstract Abstract SCI-7 Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis. Patients with ALPS may present with lymphoproliferation (lymphadenopathy and hepatosplenomegaly), autoimmune disease (most commonly autoimmune cytopenias), and secondary malignancies (typically EBER+ non-Hodgkin lymphoma). Eighty percent of ALPS patients have an identifiable genetic mutation in FAS (TNFRSF6), FASL (TNFSF6), or CASP10. These mutations can be germline or somatic with localization to the double negative T cell (DNT) compartment. DNTs (cell phenotype TCRα/β+, CD3+, CD4−, CD8−) are an atypical T cell population found in elevated quantities in peripheral blood and lymphoid tissue in ALPS patients. The diagnostic criteria for ALPS were modified in 2010 based on the results of an international consensus conference and include meeting a constellation of clinical findings, elevated DNTs, abnormal biomarkers (elevated vitamin B12, IL-10, and sFasL), in vitro evidence of defective Fas-mediated apoptosis, and mutations (somatic or germline) in Fas pathway genes. Patients with idiopathic autoimmune cytopenia syndromes (ITP, AIHA, and Evans Syndrome) and rheumatologic conditions (SLE) may have similar clinical presentations as ALPS. Our group demonstrated that approximately 45% of children diagnosed with Evans syndrome may in fact have a forme fruste of ALPS as confirmed by genetic and functional testing. Diagnosing ALPS with genetic confirmation is extremely important, because patients with idiopathic immune cytopenias should receive different treatment than ALPS patients. While first line therapy for both uses IVIgG and corticosteroids, two second-line treatments routinely used for refractory and/or chronic idiopathic autoimmune cytopenias are relatively contradicted in ALPS patients. Splenectomy has been associated with pneumococcal sepsis despite appropriate vaccination and antibiotic prophylaxis in ALPS patients. It is hypothesized that ALPS patients have increased difficulty fighting encapsulated organisms and splenectomy should be avoided. Rituximab (anti-CD20 monoclonal antibody) has been shown to cause profound and potentially life-long hypogammaglobulinemia similar to common variable immunodeficiency when used in ALPS patients and should also be avoided. In contrast, other agents used less commonly in idiopathic autoimmune cytopenias have demonstrated remarkable success in ALPS. Mycophenolate mofetil (MMF) improves autoimmune cytopenias in some refractory ALPS patients and is often used as second line treatment. Recently, we demonstrated that the mTOR inhibitor sirolimus (rapamycin) is extremely effective in ALPS both in preclinical models and in children. We have found complete responses in most patients treated with sirolimus to date. Unlike other agents, we found that sirolimus improved both autoimmune disease and lymphoproliferation, as well as specifically targeting the abnormal DNTs. No other agent, including corticosteroids, has been demonstrated to eliminate DNTs. Our preliminary data suggest that the DNTs have intrinsic abnormalities in mTOR signaling, potentially driving the autoimmune disease; and, therefore, we have a possible biologic explanation for the profound effects. Ongoing work will determine if the mTOR signaling abnormalities are specific to FAS-mutant ALPS or whether they are also found in other genetic ALPS variants that result in abnormal Fas-mediated apoptosis. Disclosures: Off Label Use: Sirolimus and mycophenolate mofetil are medications used to treat refractory autoimmune disease in patients with ALPS.

Complete Responses in Patients with Autoimmune Lymphoproliferative Syndrome (ALPS) Using the mTOR Inhibitor Sirolimus (rapamycin)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2569-2569
Author(s):  
Davi d T. Teachey ◽  
Robert J Greiner ◽  
Dirk Schwabe ◽  
Jack Bleesing ◽  
Catherine Scott Manno ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mycophenolate Mofetil ◽  
T Cell ◽  
Complete Resolution ◽  
Mtor Inhibitor ◽  
Autoimmune Arthritis ◽  
High Dose ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis. Patients with ALPS develop lymphadenopathy, hepatosplenomegaly, and increased number of a T cell population normally found in low numbers in peripheral blood called double negative T cells (DNTs, T cell phenotype CD3+/4−/8−, TCRalpha/beta +). Patients frequently develop severe autoimmune disease, primarily manifested as autoimmune cytopenias. Some patients with ALPS need long-term treatment and these patients have limited therapeutic options. Sirolimus, an mTOR inhibitor, has been shown to induce apoptosis in normal and malignant lymphocytes. Because ALPS is caused by defective lymphocyte apoptosis, we hypothesized that sirolimus would be effective by inducing apoptosis in these abnormal cells, controlling the lymphoproliferation that is the hallmark of the disease. We previously tested this hypothesis using murine models of ALPS, and have now opened a phase I/II clinical trial testing sirolimus in patients with ALPS. Six children with ALPS (2 type IA; 4 type III) were started on treatment with sirolimus, targeting a serum trough level of 5–15ng/ml. 4 patients were treated for clinically significant autoimmune cytopenias that either failed standard therapies or in whom these therapies, including high dose corticosteroids, were not tolerated. The two other patients also had autoimmune cytopenias; however, the indication for treatment was autoimmune arthritis and colitis with steroid intolerance. Four of the patients had previously failed treatment with mycophenolate mofetil and not all six could tolerate corticosteroids. One patient had failed treatment with rituximab, methotrexate, cyclosporine, tacrolimus, anti-TNFalpha agents, and cyclophosphamide. Another patient had failed treatment with mercaptopurine and plaquenil. Five of 6 patients had complete resolution of autoimmune cytopenias and normalization of blood counts within 4 weeks of initiating therapy with sirolimus. One of six patients had persistent Grade 1 thrombocytopenia (plt count >100,000/mm3 but less than 150,000/mm3). Four patients had resolution of lymphadenopathy and splenomegaly (3 complete; 1 partial with a greater than 90% reduction). Patients have been treated for 3, 3, 4, 15, 26, and 36 months, respectively. The two patients with co-morbid autoimmune arthritis and colitis showed response in these symptoms as well. All six patients had a greater than 50% reduction in DNTs. Serial PET/CTs were performed on one patient that demonstrated a complete resolution of diffuse PET-avid disease after 3 months. No patient developed any significant toxicity. One patient had developed EBV reactivation while being treated with a combination of high dose steroids, mycophenolate mofetil, and plaquenil-the EBV load went to zero after conversion to sirolimus, which may represent the effect of an mTOR inhibitor on EBV-transformed B cells. We found sirolimus significantly reduced the lymphoproliferative state and improved autoimmunity in patients with ALPS who had failed other therapies. We will continue to test sirolimus in a clinical trial; however, based on the significant improvement we found with this series we would argue that sirolimus be considered as second line therapy for patients with steroid-refractory or steroid-intolerant disease.

scholarly journals Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1928 ◽  
Author(s):  
Karen Bride ◽  
David Teachey
Keyword(s):  
Clinical Manifestations ◽  
Lymphocyte Activation ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Regulatory Pathways ◽  
Diagnosis And Management ◽  
Disease Biology ◽  
Autoimmune Pathology ◽  
Lymphocyte Homeostasis ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited syndrome characterized by abnormal lymphocyte survival caused by failure of apoptotic mechanisms to maintain lymphocyte homeostasis. This failure leads to the clinical manifestations of non-infectious and non-malignant lymphadenopathy, splenomegaly, and autoimmune pathology, most commonly, autoimmune cytopenias. Since ALPS was first characterized in the early 1990s, insights in disease biology have improved both diagnosis and management of this syndrome. Sirolimus is the best-studied and most effective corticosteroid-sparing therapy for ALPS and should be considered first-line for patients in need of chronic treatment. This review highlights practical clinical considerations for the diagnosis and management of ALPS. Further studies could reveal new proteins and regulatory pathways that are critical for lymphocyte activation and apoptosis.

Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study

Blood ◽  
2010 ◽  
Vol 115 (11) ◽  
pp. 2142-2145 ◽  
Author(s):  
Alix E. Seif ◽  
Catherine S. Manno ◽  
Cecilia Sheen ◽  
Stephan A. Grupp ◽  
David T. Teachey
Keyword(s):  
Strong Predictor ◽  
Clinical Manifestations ◽  
High Rate ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Evans Syndrome ◽  
Apoptotic Pathway ◽  
Abnormal Lymphocyte ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias ◽  
Immunoglobulin Levels

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and lymphadenopathy. These findings overlap with Evans syndrome (ES), defined by presence of at least 2 autoimmune cytopenias. We hypothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measuring peripheral blood double-negative T cells (DNTs) and Fas-mediated apoptosis. ALPS was diagnosed in 47% of patients tested. Markedly elevated DNTs (≥ 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patients with DNTs less than 2.5% had ALPS on apoptosis testing. Severity of cytopenias and elevated immunoglobulin levels also predicted ALPS. This is the largest published series describing children with ES and documents a high rate of ALPS among pediatric ES patients. These data suggest that children with ES should be screened for ALPS with DNTs.

Erythematous Rash Following Romiplostim Administration in a Patient with Autoimmune Lymphoproliferative Syndrome

2013 ◽  
Vol 47 (1) ◽  
pp. e7-e7 ◽  
Author(s):  
Lisa Biondo ◽  
Megan Bodge ◽  
Stephan R Paul
Keyword(s):  
Treatment Options ◽  
Autoimmune Disorder ◽  
Maculopapular Rash ◽  
Drug Manufacturer ◽  
Punch Biopsy ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Erythematous Rash ◽  
Lymphoproliferative Syndrome ◽  
Grade 3 ◽  
Autoimmune Cytopenias

OBJECTIVE To report a case of erythematous rash induced by romiplostim administration in a patient with autoimmune lymphoproliferative syndrome (ALPS). CASE SUMMARY A 19-year-old female with ALPS-related thrombocytopenia (platelet count 4 × 10 3 /μL) successfully treated with romiplostim 500 μg weekly for 9 months presented with a grade 3 maculopapular rash. Symptoms on presentation included purpuric, erythematous pustules confined to the trunk following romiplostim administration the previous day. A punch biopsy of skin from the patient's right lower abdomen revealed perivascular chronic inflammation with numerous eosinophils consistent with drug reaction. The patient had received romiplostim 500 μg weekly with no other reports of rash until this time. Romiplostim was discontinued, the patient was monitored, and the rash resolved within 1 week. Romiplostim was then restarted at 200 μg weekly. The patient has achieved platelet normalization at a current romiplostim dose of 250 μg weekly with no further adverse reactions. DISCUSSION ALPS is a rare autoimmune disorder with approximately 500 known cases worldwide. Pharmacotherapy for ALPS patients generally targets autoimmune cytopenias associated with the disorder. When standard therapies for ALPS-related cytopenias fail, clinicians are often forced to consider novel treatment options. Our patient had ALPS-related thrombocytopenia that was treated with romiplostim, which resulted in grade 3 maculopapular rash after almost 1 year of treatment. The likelihood that this patient's erythematous rash was due to romiplostim administration was determined to be possible based on the Naranjo probability scale. The reaction was reported to the drug manufacturer and to the Food and Drug Administration's MedWatch program. CONCLUSIONS This is the first documented case, to our knowledge, of severe maculopapular rash occurring less than 24 hours after romiplostim administration for treatment of ALPS-related chronic thrombocytopenia. Rash has been reported as an adverse event of romiplostim therapy at higher doses (750 μg), but not at a dose of 500 μg. This report also describes successful rechallenge of romiplostim after resolution of the rash.

scholarly journals Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5164-5169 ◽  
Author(s):  
Kennichi C. Dowdell ◽  
Julie E. Niemela ◽  
Susan Price ◽  
Joie Davis ◽  
Ronald L. Hornung ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Serum Vitamin ◽  
Interleukin 10 ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Increased Risk ◽  
Type Ia ◽  
Fas Signaling ◽  
Adults And Children ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin B12, interleukin-10, and sFAS-L. These data support testing for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a similar clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children.

scholarly journals Autoimmune Cytopenias in Nonmalignant Lymphoproliferative Disorders: Thinking Beyond ALPS(Autoimmune Lymphoproliferative Syndrome)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-48
Author(s):  
Elaine Kulm ◽  
Sharon Webster ◽  
Kate Howe ◽  
Amy Rump ◽  
Gulbu Uzel ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
T Cell ◽  
Genetic Diagnosis ◽  
Immune Dysregulation ◽  
Lymphoproliferative Disorders ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
History Of ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias ◽  
Lrba Deficiency

The ALPS Clinic at NIH has studied autoimmune lymphoproliferative disorders for over 30 years elucidating the genetic underpinnings and natural history of Autoimmune Lymphoproliferative Syndrome (ALPS) due to FAS gene defects (Blood 2014). Over the years, we continue to receive and work-up numerous referrals for diseases that masquerade like ALPS-FAS, presenting with multi-lineage cytopenias due to autoimmune peripheral destruction and splenic sequestration in the setting of non-malignant lymphoproliferation. In a review of 259 cases evaluated by our team, there were 150 ALPS-FAS, 54 Activated PI3K-delta Syndrome (APDS), 31 CTLA-4 Haploinsufficiency (CTLA4), 7 LRBA deficiency (LRBA), and 17 MAGT-1 deficiency (XMEN) patients. Non-malignant lymphadenopathy and splenomegaly occurred on average in 83% and 71% of all patients, respectively. Anemia, thrombocytopenia, and neutropenia were seen in 65%, 58%, and 46%, respectively. Thus, autoimmune cytopenias in the setting of non-malignant lymphoproliferation in themselves are not adequate to rule in or rule out a presumptive diagnosis of ALPS-FAS. Timely and accurate genetic diagnosis of ALPS-like conditions will improve the morbidity and mortality associated with these disease processes. Rapamycin, an m-TOR inhibitor provides salutary benefits for many of these conditions by restoring the TREG function and reversing immune-dysregulation. For example, in addition to lymphadenopathy and splenomegaly associated with an increased risk of malignant lymphoma like ALPS-FAS patients, APDS patients usually present with recurrent sinopulmonary and ear infections. Their serum IgM tends to be elevated with low IgG levels. Unlike for ALPS-FAS patients, a potential targeted treatment for APDS exists: Leniolisib, a targeted PI3Kinase p-110 delta inhibitor is currently undergoing clinical trials (Blood 2016). CTLA-4 is critical for T-cell activation and immune check-point regulation by tempering regulatory T cell function. Patients affected by CTLA4 and LRBA variants present with symptoms of lymphocytic infiltration of the bone marrow (often leading to hypoplastic anemia), gut (colitis, bowel obstruction), lungs (bronchiectasis, restrictive airway disease), and central nervous system (seizures and neurological deficits due to brain and spinal cord lesions). They also tend to have B cell lymphopenia, low IgG and IgM levels. CTLA4 and LRBA patients share pathophysiology as well as clinical phenotype because LRBA gene regulates intracellular lysosomal trafficking and recycling of CTLA-4 protein. Hence CTLA-4 haploinsufficiency or LRBA deficiency renders both patient types CTLA-4 deficient. This can be directly addressed with abatacept infusions, a CTLA-4 hybridized immunoglobulin given as a combination immunosuppressive therapy with rapamycin. Abatacept replaces the CTLA-4 molecule and reverses some of the immune dysregulation and thus morbidity associated with both CTLA4 and LRBA deficiency. Like APDS patients, XMEN patients are also prone to recurrent ear and sinopulmonary infection, but key differentiating features of this X-linked disorder are that only males are affected, these patients are unable to clear Epstein-Barr virus (EBV) once exposed, and they have a propensity to develop EBV-driven lymphomas. These patients also usually have a strong family history of multiple lymphomas in males. Even though a targeted treatment does not yet exist, steroid-sparing measures such as rituximab, rapamycin and mycophenolate mofetil are the first-line treatments often used in managing their refractory autoimmune cytopenias. Hence accurate early genetic diagnosis is key to accessing the appropriate treatment, thus decreasing the morbidity and mortality associated with these childhood onset ALPS-like rare inherited disorders (table). Table Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Rapamycin, Abatacept, Mycophenolate Mofetil.

scholarly journals A Girl with Autoimmune Cytopenias, Nonmalignant Lymphadenopathy, and Recurrent Infections

2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Marjolein A. C. Mattheij ◽  
Ellen J. H. Schatorjé ◽  
Eugenie F. A. Gemen ◽  
Lisette van de Corput ◽  
Peet T. G. A. Nooijen ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Healthy Controls ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Recurrent Infections ◽  
Chronic Idiopathic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
The Alps ◽  
Lymphoproliferative Syndrome ◽  
Autoimmune Cytopenias ◽  
Common Variable

We describe a girl, now 9 years of age, with chronic idiopathic thrombocytopenic purpura, persistent nonmalignant lymphadenopathy, splenomegaly, recurrent infections, and autoimmune hemolytic anemia. Her symptoms partly fit the definitions of both autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency disorders (CVIDs). Genetic analysis showed no abnormalities in the ALPS-genesFAS, FASLG, andCASP10. The CVID-associatedTACIgene showed a homozygous polymorphism (Pro251Leu), which is found also in healthy controls.

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