Autoimmune Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder of lymphocyte homeostasis. It is defined as a chronic (>6 months) non-malignancy and non-infectious uncontrolled proliferation of lymphocytes commonly accompanied by autoimmune manifestations, lymphadenopathy, splenomegaly, and susceptibility to malignancies.[1] ALPS is the first disease known to be caused by a primary defect in programmed cell death and the first description of a monogenic cause of autoimmune disease. The first genetic defect was described in 1995 by the discovery of the FAS gene mutation.[2] Other ALPS-associated genetic defects in the apoptotic pathway and ALPS-like disorders (ALPS-related syndromes) have subsequently been identified.

An illustrative case of ALPS is as follows:

• A 10-year-old male presented with a history of lymphadenopathy, splenomegaly, and onset of multilineage cytopenias as an infant, with subsequent splenectomy at age 13 months

• After undergoing the splenectomy, the patient developed pneumococcal meningitis, which led to hearing loss that required a cochlear implant

• Subsequently, the patient experienced several episodes of pneumococcal sepsis, chronic osteomyelitis, profound neutropenia, vasculitis, autoimmune hemolytic anemia, and thrombocytopenia, with many hospitalizations and intensive care unit (ICU) admissions for treatment of these complications

This patient’s repeated infections with encapsulated organisms highlight the importance of maintaining the spleen in ALPS patients, if possible. The constellation of lymphadenopathy, splenomegaly, and autoimmune cytopenias necessitating long-term immunosuppressive treatment with mycophenolate mofetil makes diagnosis and management of these patients quite challenging.

Apoptosis is a genetically regulated form of nonimmunogenic cell death. Its roles in biologic processes, including embryogenesis, aging, and many diseases, are crucial. It may be activated via death receptors (extrinsic pathway) or mitochondrial (intrinsic pathway). A failure of apoptosis leads to inappropriate cell survival and diseases associated with excessive accumulations of cells such as cancer, chronic inflammatory conditions, and autoimmune diseases.[3]

Apoptosis is most often mediated by extrinsic pathway via FAS or CD95 or apoptosis antigen 1 (APO-1) or tumor necrosis factor receptor superfamily 6 (TNFRSF6), a cell surface death receptor. Under physiologic conditions, lymphocyte activation is followed by apoptosis when FAS ligand (FASL) interacts with FAS; this results in cytoplasmic recruitment of a protein known as the FAS-associated death domain (FADD), followed by recruitment of procaspase 8 and procaspase 10 and resultant cellular apoptosis.

The essential role of FAS plays in maintaining lymphocyte homeostasis and peripheral immune tolerance to prevent autoimmunity was first demonstrated by studying FAS-deficient MRL/lpr-/- mice. Mice homozygous for FAS mutations develop hypergammaglobulinemia, glomerulonephritis, massive lymphadenopathy, and expansion of an otherwise rare population of T-cell receptor (TCR) α/β cells that lack expression of both CD4 and CD8 (double-negative T [DNT] cells).[4] This provided insights into the pathophysiology of a similar syndrome seen in humans.[5]

ALPS, as this disorder was subsequently named in humans[2] , is caused by a failure of apoptotic mechanisms to maintain lymphocyte homeostasis leading to abnormal lymphocyte survival. Most cases of ALPS are caused by loss-of-function mutations in components of the FAS apoptotic pathway or extrinsic pathway. The most common genetically defined ALPS is the autosomal dominant transmission of heterozygous germline mutations in FAS (70%), and the second common is somatic FAS mutations (10–15%). Other autosomal recessive transmissions in FAS-mediated apoptotic pathway causing ALPS are genes encoding CASP10 (< 1%) and FASL (< 1%).[6] Some patients may have a compound heterozygous mutation or more than one mutation, such as FAS mutation and CASP10 mutation.[7] Approximately 20% of ALPS does not have an identifiable mutation.

ALPS is rarely caused by a defect of mitochondrial apoptosis or intrinsic pathway. A heterozygous germline gain of function mutation encoding NRAS, an oncogene, leading to a failure of apoptosis in response to interleukin-2 withdrawal was identified as the first intrinsic pathway defect causing ALPS.[8]

The extrinsic pathway of apoptosis. Mutations have been identified in each of the genes coding for Fas, Fas-ligand (FasL), caspase-8, and caspase-10. This figure was previously published in Rao VK, Straus SE. Autoimmune Lymphoproliferative Syndrome. Clinical Hematology. 58;759. 2006: Elsevier.

The defective apoptosis results in lymphoproliferation with appropriate persistence and accumulation of autoreactive or potentially oncogenic lymphocytes, leading to splenomegaly and lymphadenopathy with an increased risk of Hodgkin and non-Hodgkin lymphoma.

The lymphoproliferation is mainly characterized by the accumulation of CD3+TCRα/β + CD4-CD8- or DNT cells in the peripheral blood (>2.5% of T cells) and lymphoid tissues. These DNT cells likely derive from CD8+ T cells since the DNT cells from ALPS patients share a CDR3 sequence with CD8+ T cell across several TCRVβ families.[9] The DNT cells in ALPS are unique since they do proliferate, produce high IL-10, and display other surface markers including, B220, CD27, CD28, CD57, and CD45RA. The significance of these DNT cells in ALPS is not fully understood. However, the number of DNT cells correlates with the presence of autoantibodies in ALPS.[10]

The number of DNT cells in normal individuals are less than 2% of T cells. Mildly elevated DNT cells can be detected in other autoimmune/ inflammatory conditions[11] and hemophagocytic syndromes.[12] The positive CD57, CD45RA markers can distinguish between DNT cells from ALPS and DNT cells from other conditions.[1]

It is unknown whether B cell development is normal in ALPS. Normal B cell numbers with elevated IgG, IgA are common.[13] Abnormal B cell functions related to disorganized splenic marginal zone but not an intrinsic B cell defect are reported including low serum IgM, low blood memory B cells and poor anti-polysaccharide antibody production with a higher risk of pneumococcal septicemia.[14]

Other immune cells, including gdT cells, NK-T cells, and NK cells, are not affected by ALPS.

Investigation of family members of ALPS patients has revealed a population with identical genetic mutations and same apoptosis defects but can be asymptomatic without elevated DNT cells, IL-10 or soluble FASLG. Additionally, some of the healthy mutation-positive controls had biomarker evidence of disease but are asymptomatic, whereas other family members had very mild disease. These findings suggest that FAS mutations causing cellular apoptosis abnormalities alone are not sufficient to cause clinical APS; and the pathophysiology of ALPS is multifactorial, with an autosomal dominant inheritance pattern and variable penetrance.[15, 16]  

Autoimmune lymphoproliferative syndrome (ALPS) classification and ALPS-related syndrome (ALPS-like disorder)

The nomenclature for the various types of ALPS is determined based on the genetic mutation present in an individual. Patients meeting diagnostic criteria for ALPS in whom no genetic mutation can be identified and classified as ALPS–undetermined.

ALPS-like disorders or ALPS-related syndromes are diseases which have similar features of those with ALPS but are missing required diagnostic features such as elevated DNT cells or have additional manifestations such as immunodeficiency features (Table 1). ALPS-like disorders should be considered and evaluated in any patients with clinical features of ALPS.

Table 1. ALPS-like disorders or ALPS-related syndromes ^{[6, 17]} (Open Table in a new window)

For most cases of ALPS, the genetic mutation has been identified in the extrinsic apoptosis pathway. The mutation in the intrinsic pathway is extremely rare.[1, 8] Although 20% of ALPS patients have no identifiable mutation that leads to their defective lymphocyte apoptosis, they may still meet the diagnostic criteria for ALPS or an ALPS-related disorder (see Workup).

In patients with ALPS, the disease process can often be explained by the failure to eliminate redundant lymphocyte populations properly. As noted (see above), lymphocytes that are potentially autoreactive or oncogenic predispose these patients to the development of autoimmune diseases and lymphoma.

The initial presentations of ALPS include persistent lymphadenopathy (>95%) or splenomegaly (>90%) followed by autoimmune cytopenias (>70%) such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), and hepatomegaly (50%) in an otherwise healthy child.[15, 16] To meet the case definition of ALPS, a patient must have chronic, nonmalignant lymphadenopathy or splenomegaly that lasts for 6 months or longer.

Associated multilineage cytopenias due to autoantibodies or splenic sequestration can lead to petechiae, bleeding, pallor, icterus, fatigue, and recurrent infections; the latter are mostly due to neutropenia. A family history of similar disorders may be noted; these are usually inherited in an autosomal dominant fashion. A thorough review of a patient’s extended family for a history of adenopathy, cytopenias, splenectomies, or lymphoma can provide clues in diagnosing ALPS.

Careful attention to the development of systemic B symptoms (eg, fever, drenching night sweats, pruritus, and weight loss) is important for cancer surveillance in those at high-risk for B cell lymphoma. Some of the patients may develop other specific organ autoimmunity or systemic autoimmune diseases such as autoimmune hepatitis, glomerulonephritis, uveitis, and Guillain-Barre syndrome.

The mortality and morbidity of ALPS vary widely. The major determinants of prognosis in patients diagnosed with ALPS include the following:

• The severity of autoimmune disease (particularly autoimmune cytopenias)

• Hypersplenism

• Asplenia-related sepsis

• Development of lymphoma

Addressing these serious conditions with proper surveillance and education is vital for an optimal prognosis. Patients with mutations of the intracellular region of the Fas protein have a significantly increased risk of developing lymphoma and warrant the most diligent long-term surveillance. Despite the numerous potentially serious complications, the overall prognosis for patients with ALPS is good.

Many patients are expected to live a normal lifespan, with few clinical complications.[6]  However, a significant number of patients develop childhood-onset life-threatening cytopenias, which necessitate interventions such as hospitalization, immunosuppressive therapy, blood transfusion, antibiotic therapy, or splenectomy. These cytopenias are often chronic and refractory.

As pediatric ALPS patients develop into adolescents and young adults, the degree of adenopathy (particularly visible adenopathy) tends to decrease. The natural course of the adenopathy should be discussed with the patients and their families, particularly during adolescence, when visible adenopathy can be particularly distressing.

As with all chronic diseases, appropriate management of ALPS requires continual reinforcement and education regarding matters of adequate nutrition and control of potential adverse effects of medications. Also, as with many chronic diseases with an onset in childhood, adolescence and early adulthood may provide the additional treatment challenge of poor compliance with prescribed medications. Individual responsibility should be encouraged and emphasized by the treatment team.

The initial presentations of ALPS are often that of persistent lymphadenopathy (>95%) or splenomegaly (>90%) followed by autoimmunity (>70%) and hepatomegaly (50%) in an otherwise healthy child.[15, 16] Patients with germline FAS mutations typically present earlier than somatic FAS mutations; however, both mutations have the same clinical manifestations.[40]

The majority of patients develop lymphoproliferation at a young age (median age of 11.5 months) without associated constitutional symptoms. To meet the case definition of ALPS, a patient must have chronic, nonmalignant lymphadenopathy, or splenomegaly that lasts for 6 months or longer. The lymphoproliferation can wax and wane randomly before resolving in most patients after 20 years of age.[6]

Autoimmunity is the second most common clinical presentation, especially autoimmune cytopenias in one or more cell lineages. Autoimmune hemolytic anemia and autoimmune thrombocytopenia are more common than autoimmune neutropenia. The multilineage cytopenias often noticed in ALPS result from splenic sequestration, as well as from underlying autoimmune processes.[1] The symptoms related to cytopenia are pallor, petechiae, bleeding, icterus, fatigue, and recurrent infections. A family history of similar disorders may be noted; these are usually inherited in an autosomal dominant fashion. A thorough review of a patient’s extended family for a history of adenopathy, cytopenias, splenectomies, or lymphoma can provide clues in diagnosing ALPS.

Other autoimmune diseases occur in 10–20% of ALPS and can affect any organ system. The most common are skin rashes, immune-mediated pulmonary fibrosis, autoimmune thyroiditis, uveitis, Guillain-Barre syndrome, autoimmune hepatitis, nephristis, gastritis, pancreatitis, colitis, transverse myelitis, cerebellar ataxia, myocarditis, and arthritis.[6]

Careful attention to the development of systemic B symptoms (e.g., fever, drenching night sweats, pruritus, and weight loss) is essential for cancer surveillance in those at high-risk for B cell lymphoma.

The lymphadenopathy and hepatosplenomegaly seen in patients with ALPS can often be remarkable, sometimes visibly distorting anatomic landmarks (see the image below). These findings can wax and wane.

Examples of an autoimmune lymphoproliferative syndrome (ALPS) in a patient with grade IV (visible) lymphadenopathy.

Areas most commonly affected by lymphadenopathy include the neck and axillary regions, but careful assessment of epitrochlear, femoral, inguinal, and other lymph node chains is essential in the assessment. Petechiae, pallor, icterus, and evidence of infections may be found in patients with characteristic cytopenias. Ongoing surveillance in these patients should include careful attention to the development of changes in lymph node size or the appearance of new focal or generalized lymphadenopathy and worsening splenomegaly.

Complications of ALPS include the development of lymphoma or other malignancy and the development of pneumococcal sepsis or other serious systemic infection (secondary to splenectomy, autoimmune neutropenia, or both; see the image below).

A patient with autoimmune lymphoproliferative syndrome (ALPS) who developed pneumococcal sepsis, a serious complication secondary to neutropenia and asplenia. Note the patient's cochlear implant; he has neurosensory hearing loss from prior episode of pneumococcal meningitis.

Patients with genetic mutations that affect the intracellular domain of the FAS protein have a more severe clinical manifestation from early childhood and are found to have a 51-fold higher risk of Hodgkin lymphoma and a 14-fold increased risk of non-Hodgkin lymphoma. A report on the largest cohort of ALPS patients worldwide showed an approximate 6% incidence of lymphoma in patients with ALPS overall, with a median age at presentation of 17 years.[41]

Lymphadenopathy in ALPS patients with lymphoma can be especially difficult to discern because persistent lymphadenopathy is common even as the patient progresses into adulthood. Like any sporadic lymphomas, however, ALPS-associated lymphomas are amenable to chemotherapy and should be managed accordingly. ALPS-associated lymphadenopathy and splenomegaly tend to become less prominent with age. In patients who have undergone splenectomy, asplenia-related sepsis is a significant lifelong cause of morbidity and mortality.[16]  Long-term management with steroid-sparing medication and avoiding splenectomy are strongly recommended to preserve some antipolysaccharide response.

In evaluating a child with chronic lymphadenopathy or splenomegaly with or without cytopenias, one must evaluate for and rule out numerous diagnoses, including malignancies and chronic infection. A history of constitutional symptoms (eg, weight loss, anorexia, pallor, early fatigue, easy bruising, or frequent ear and throat infection) in conjunction with the physical findings previously mentioned (see Presentation) warrants an evaluation to exclude these conditions.

Depending on the patient’s history and risk factors, the initial evaluation may include a complete blood count (CBC) with differential, as well as immunoglobulin, serum lactate dehydrogenase (LDH), and uric acid levels. Additionally, in a highly suspected case of ALPS, the DNT cell count and levels of vitamin B12, IL-10, and soluble FASLG should be obtained.

Pediatric patients who have acute lymphadenopathy with concerning or atypical features (including fixed or hard nodes or massive lymphadenopathy) or chronic lymphadenopathy without an identified cause should be referred to a pediatric hematologist for consideration of lymph node biopsy and further evaluation.

Lymph node biopsy findings are unique in autoimmune lymphoproliferative syndrome (ALPS), and hematologists, surgeons, and pathologists involved in performing and interpreting biopsy results should be familiar with these findings and include the diagnosis of ALPS if these findings are present on biopsy.

To meet the criteria for a definitive diagnosis of ALPS, both of the 2 required criteria and at least 1 of the primary accessory criteria must be present (see the image below). A probable diagnosis of ALPS includes the required criteria with one secondary accessory. Some patients with probable ALPS have an ALPS-like disorder and should be tested for these conditions (Table 1).

The 2 required diagnostic criteria for ALPS are as follows:

• Chronic, nonmalignant, noninfectious lymphadenopathy or splenomegaly lasting at least 6 months

• Elevated T-cell receptor (TCR) α/β CD3+ CD4–/CD8– T cells, or double-negative T (DNT) cells (≥1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes), in the setting of normal or elevated lymphocyte counts

The primary accessory criteria are as follows:

• Defective lymphocyte apoptosis in 2 separate assays

• A somatic or germline pathogenic mutation in FAS, FASLG, or CASP10

The secondary accessory criteria are as follows:

• An elevated plasma level (>200 pg/mL) of soluble Fas ligand (FasL), elevated plasma interleukin (IL)–10 levels (>20 pg/mL), elevated plasma IL-18 levels (>500 pg/mL), or elevated serum or plasma vitamin B12 levels (>1500 ng/L)

• Typical immunohistochemical findings as reviewed by an experienced hematopathologist

• Autoimmune cytopenia (hemolytic anemia, neutropenia, or thrombocytopenia) plus elevated immunoglobulin G (IgG) levels (polyclonal)

• Family history of a nonmalignant, noninfectious lymphoproliferation, with or without autoimmunity

Although no single laboratory study is diagnostic of ALPS, several laboratory tests should be obtained.

Autoantibodies are frequently found in patients with ALPS. A study of 79 ALPS patients detected autoantibodies in 81%.[15] The common autoantibodies detected in patients with ALPS is a positive Coombs direct antiglobulin test (DAT) and antiplatelet antibodies. Autoimmune neutropenia with antineutrophil antibody is less common.[42]

A CBC with differential may reveal lymphocytosis, reticulocytosis, thrombocytopenia, anemia, neutropenia, monocytosis, or eosinophilia. A quantitative immunoglobulin panel should be obtained if a diagnosis of ALPS is suspected or confirmed. Hypergammaglobulinemia with high IgG and IgA is a common feature in ALPS. Low IgM can be seen resulting from exacerbated class switching.[1]   

Patients with ALPS characteristically demonstrate elevated DNT cells in the peripheral circulation, bone marrow, spleen, or lymphoid tissues. These lymphocytes may be detected by flow cytometric immunophenotyping of samples from any of these sites.[41]

Most patients with ALPS exhibit defective lymphocyte apoptosis. Although the defect of lymphocyte apoptosis in vitro is one of accessory criteria, the test is not routinely used since it is available at specialized laboratories and somatic FAS mutations can have normal result.[40]

Other abnormal laboratory findings that are commonly found in ALPS patients include elevated soluble FasL levels, elevated transaminases (in the subset of patients with autoimmune hepatitis), elevated plasma IL-10 or IL-18 levels, proteinuria (in patients with glomerulonephritis), and elevated serum levels of vitamin B-12.[43]

Molecular genetic testing should also be obtained in patients with clinical or laboratory features consistent with a diagnosis of ALPS. Specifically, genetic analysis of the FAS receptor gene (TNFRSF6), the FasL gene (TNFSF6) and the caspase 10 gene (CASP-10) is warranted. Mutations of the FAS gene have been identified as the cause of most cases of ALPS. If mutation of FAS is not detected, an analysis of the other genes of ALPS or ALPS-like disorders mutations should be considered. 

This genetic testing is important for the following 2 reasons:

• If a mutation is identified, genetic counseling must be provided to the family, and other family members must be invited for screening evaluations.
• The location of the specific gene mutation is important for the prognosis because certain mutation loci are associated with a higher risk of complications, including lymphoma; patients with a mutation of the intracellular domain of FAS have a 14-fold higher risk of non-Hodgkin lymphoma and a 51-fold higher risk of Hodgkin lymphoma. ^[41]

Although imaging studies are not used in establishing a diagnosis of ALPS, once the diagnosis has been made, it is important to obtain baseline and periodic computed tomography (CT) scans. CT of the neck, chest, abdomen and pelvis at the time of diagnosis help establish the extent and location of the patient’s lymphadenopathy.

Because of the increased risk of lymphoma in patients with ALPS, frequent surveillance with serial CT scans is an important part of the long-term management of these patients. As a consequence of the chronic fluctuating nature of their lymphadenopathy, ALPS patients may undergo repeated lymph node biopsies to help rule out lymphoma if they develop systemic symptoms in addition to focal changes of adenopathy.

Positron emission tomography (PET) using18 fluoro-2-deoxy-D-glucose (FDG), or FDG-PET, is the standard for staging and follow-up evaluations of cancers, including lymphomas. FDG-PET can be used as a screening tool for malignancy in ALPS to minimize LN biopsies; however, it can not accurately distinguish benign from malignant lymphoproliferation as ALPS lymphadenopathy is PET-avid.[6]

Positron emission tomography (PET) superimposed over a CT scan from a patient with autoimmune lymphoproliferative syndrome (ALPS). Note the massive cervical adenopathy. PET scans may be used as a screening tool in patients with autoimmune lymphoproliferative syndrome to decrease the number of lymph node biopsies used in screening for malignancy.

Lymph node biopsies are typically performed in ALPS patients. Such biopsies reveal findings unique to ALPS (see Histologic Findings). If the biopsy findings obtained in a patient with lymphadenopathy are consistent with a diagnosis of ALPS, further laboratory testing, including flow cytometric immunophenotyping and genetic testing, is warranted.

At the time of diagnosis, biopsy is used to look for histology suggestive of ALPS, as well as to rule out lymphoma. ALPS is associated with both chronic lymphadenopathy and a significant increase in the risk for lymphoma. In view of these 2 associations, lymph node biopsy may be required if a sudden or dramatic change in a node is noted, particularly if these changes are associated with concerning constitutional symptoms, such as weight loss, fever, and night sweats.[44]

Serial CT and PET may be used as tools to mitigate the tendency to perform repeated lymph node biopsies while still effectively monitoring these patients for malignancy.

The elevated percentage of TCR α/β DNT cells caused by the lymphocyte dysregulation seen in ALPS results in fairly characteristic histopathologic findings on lymph node biopsy. These findings include follicular hyperplasia and paracortical expansion with a mixed infiltrate containing the DNT cells. This specific histologic pattern can help distinguish ALPS from other benign and malignant lymphoproliferative lesions.

Evaluation of lymph node tissue for clonality by means of immunoglobulin and TCR gene rearrangements and cytogenetic analysis for chromosomal aneuploidy are also important for helping to rule out the diagnosis of lymphoma in ALPS patients who have chronic lymphadenopathy.[41]

A specific staging system that can be used to establish a prognosis in patients with ALPS has not been established. However, the degree of generalized lymphadenopathy can be documented longitudinally in a consistent fashion by using the following guidelines:

• Grade 1 - Few shotty nodes

• Grade 2 - Multiple 1-2 cm nodes

• Grade 3 - Multiple nodes, some larger than 2 cm

• Grade 4 - Extensive visible adenopathy

This grading is best performed by using physical examination and CT scanning in the clinical setting.[45]

The treatment key of ALPS depends upon the patient’s manifestations and the disease complications. Upon confirmation of a diagnosis of ALPS, patients should undergo counseling aimed at specifically addressing the natural history, the disease manifestations, and the risks and complications associated with ALPS and its treatment.

The patient and the family should be educated on the risks associated with significant cytopenias (anemia, thrombocytopenia, neutropenia) and other autoimmune diseases that can develop and require immediate medical attention, such as systemic constitutional symptoms, petechiae, or mucosal bleeding. The increased risk of lymphomas and other malignancies should be addressed, especially in ALPS with FAS mutations, and patients should be encouraged to seek further evaluation for any severe or sudden fluctuations in a lymph node or spleen size. The increased risk of severe infections, especially pneumococcal sepsis associated with splenectomy, which is compounded by lack of memory B cells and autoimmune neutropenia, should be discussed.

The massive lymphadenopathy seen in children with ALPS can evoke considerable anxiety in patients and families, and as a result, clinicians may feel inclined to treat these patients for cosmetic purposes alone. However, corticosteroids or immunosuppressive drugs (e.g., azathioprine, cyclosporine, or mycophenolate mofetil) do not consistently shrink the lymph nodes and spleens of ALPS patients, and their use to treat these patients for solely cosmetic purposes is not indicated.[45]

The surgical role in ALPS is limited to lymph node biopsies. Splenectomy for chronic refractory cytopenias should be avoided since it increases significant risk of sepsis and is often ineffective and rarely leads to permanent remission. Hematopoietic stem cell transplantation (HSCT), the only curative treatment, is considered only in severe clinical phenotypes with no response to immune suppressive medications.[6]   

Patients with ALPS are admitted to the hospital on a limited basis—generally, only to treat a critical care emergency (e.g., fever, sepsis, mucocutaneous bleeding, profound anemia, or thrombocytopenia or systemic autoimmune diseases). Conditions associated with ALPS, such as Hodgkin lymphoma and non-Hodgkin lymphoma, may require more extensive hospitalization. Other treatments are usually provided in an outpatient or home setting.

Outpatient care must be individualized. A team approach with appropriate consultants (see Consultations) should emphasize activities of daily living (to include school attendance), proper nutrition, and a healthy and positive attitude. Treatment teams should monitor medications used, as well as medication compliance, and admit patients to the hospital only for definitive medical or surgical treatment. Patients who have undergone splenectomy should wear medical alert bracelets or necklaces or carry wallet cards outlining their risk for sepsis.

An important aspect of caring for ALPS patients is the medical treatment of the chronic and refractory autoimmune cytopenias that frequently cause morbidity and even mortality in these patients.

Initial management of ALPS-related autoimmune cytopenias is corticosteroid therapy with or without high dose IVIG. Many patients often respond well to oral corticosteroids (1–2 mg/kg), and some require high-dose methylprednisolone (5–30 mg/kg/day for 1-3 days) followed by lower-dose prednisone (1–2 mg/kg/day) tapered slowly over months. High-dose (1–2 g/kg) intravenous immunoglobulin (IVIG) may be considered for concomitant use with pulse-dose steroids in those with severe AIHA. The IVIG treatment alone is less effective except ALPS with single-lineage autoimmune thrombocytopenia. However, the effect of IVIG is short-lived and requiries repeated infusion. A low-dose granulocyte colony-stimulating factor (G-CSF) 1–2 µg/kg subcutaneously 2–3 times weekly may be indicated in some patients with autoimmune neutropenia who experience significant infections.

MMF, an inosine-5’-monophosphate dehydrogenase reducing guanosine nucleotides in T and B cells, has been proven to be an effective steroid-sparing agent in 80% of ALPS. It does not require therapeutic drug monitoring, and it is a well-tolerated agent without significant drug-drug interaction. However, MMF does not affect lymphoproliferation or DNT cell depletion since it does not change the differentiation or mitotic activity of DNT cells. Some patients have partial responses and require prolonged corticosteroid therapy.[46]

Sirolimus or rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has recently been successfully studied in ALPS. The evidence of hyperactive mTOR signaling of DNT cells and the abolished survival and proliferation of DNT cells in ALPS by sirolimus have supported the therapeutic role of sirolimus.[47] Sirolimus monotherapy has shown to be a safe and effective steroid-sparing agent with rapid improvement of autoimmune cytopenias, lymphadenopathy, splenomegaly, and undetectable DNT cells within 1 to 3 months[48] as well as normalization of Vit B12, IL-10, and soluble FASLG.[49] Since it is an extremely effective agent, sirolimus has been proposed to be the first-line therapy.[6] The primary drawback of sirolimus is the need for therapeutic drug monitoring (trough level of 5–15ng/ml). The well-known side effects are oral mucositis, hyperlipidemia, decreased renal function, myelosuppression, and drug-drug interaction.

Early use of MMF and sirolimus to minimize corticosteroid exposure is encouraged. A proposed treatment algorithm of ALPS with mild to moderate and moderate to severe autoimmune disease with or without clinically significant lymphoproliferation has been published.[6]

A small retrospective study that looked at the use of rituximab for the treatment of autoimmune cytopenias in ALPS found that whereas some ALPS patients with ITP showed improvement, ALPS patients with AIHA failed to show a significant improvement.[50] Furthermore, the use of rituximab in patients with ALPS-associated cytopenias led to significant toxicities, including hypogammaglobulinemia and neutropenia. Given the preexisting increased risk of infection in these patients, particularly those who are asplenic, rituximab should be avoided in this setting until all other immunosuppressive medication options have been exhausted.[45]

Other reported medications with limited use for refractory cytopenia in ALPS and ALPS-like disorders are pentostatin, bortezomib, the combination of methotrexate and sirolimus, and the combination of vincristine, methotrexate, and mercaptopurine.

All ALPS patients who are asplenic should be treated with long-term antibiotic (e.g., penicillin V) prophylaxis against pneumococcal sepsis. These patients are often unable to produce or maintain protective antibodies against polysaccharide antigens after vaccination because of deficient memory B-cell function. Nevertheless, they should be vaccinated against encapsulated organisms such as pneumococcus, meningococcus, and Haemophilus influenzae type B (HIB) and should wear an appropriate alert bracelet citing their increased risk of infection.

For reasons that remain unclear, the cytopenias in most patients with ALPS improve with age. Nevertheless, hematopoietic stem cell transplantation (HSCT) has been successful in ALPS patients and can be considered a treatment option for those with severe, recalcitrant disease and a matched donor. Sibling donors should be screened for and should be free of a mutation in the apoptosis pathway.

The mortality of a matched unrelated donor-derived allogeneic bone marrow transplant is too high to warrant the procedure in most ALPS patients, many of whom have a near-normal life expectancy. Most patients with cytopenias secondary to ALPS can be managed with immunosuppressive agents. Few patients with recalcitrant autoimmune cytopenias are sick enough as a result of their cytopenias to justify the risks and mortality associated with allogeneic bone marrow transplantation.[45]

As with many chronic illnesses in pediatric or adult medicine, a team approach is required to serve the patient best. A pediatric hematologist and immunologist experienced in diagnosing and treating patients with ALPS and associated cytopenias should act as the treatment team leader. The team should also include a geneticist, a rheumatologist, an occupational therapist, a general pediatrician or internist, and a social worker.

School attendance, compliance with prescribed medications, and plans of action for febrile episodes in asplenic individuals should be discussed and reinforced. Telemedicine may play a role in long-distance consultation and treatment of patients with ALPS who reside at greater distances from full-service institutions.

No specific diets, dietary supplements, or dietary avoidances have been shown to have a significant effect on the course of ALPS.

Physical activity is encouraged in patients with ALPS. Patients with associated splenomegaly should avoid contact sports (eg, football, ice hockey) because of the increased risk of splenic rupture.

To help reduce the risk of traumatic splenic rupture, spleen guards made of fiberglass by an occupational therapist familiar with making such devices for children should be considered in ALPS patients who have massive splenomegaly. This is particularly important for those who are physically active (ie, nearly every toddler) and for children involved in competitive sports.

Although specific mutations that cause ALPS have been identified, no environmental exposures or risk factors have yet been associated with an increased prevalence of the disease. Certainly, any patient with a personal or family history of ALPS should be encouraged to undergo genetic counseling and testing by a geneticist. No other preventive recommendations are currently available for patients with ALPS, except for diligent adherence to care plans in patients who have undergone splenectomy.

Agents used to treat autoimmune lymphoproliferative syndrome (ALPS) include immunosuppressants and immune globulins.

Class Summary

Initial therapy for autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) includes corticosteroids. In refractory autoimmune cytopenias necessitating long-term steroid therapy, mycophenolate mofetil and tacrolimus have been shown to be effective steroid-sparing agents.

Prednisone (Deltasone, Rayos)

Prednisone is useful for treating inflammatory and allergic reactions; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It is the drug of choice for all adult patients with platelet counts below 50,000/µL. Asymptomatic patients with platelet counts higher than 20,000/µL or patients with counts of 30,000-50,000/µL with only minor purpura may not need therapy; withholding medical therapy may be appropriate for asymptomatic patients, regardless of platelet count.

Methylprednisolone (Solu-Medrol, Depo-Medrol, Medrol)

Methylprednisolone decreases inflammation by suppressing migration of PMNs and reversing increased permeability. It is used as the alternative glucocorticoid of choice for all patients with severe life-threatening bleeding or children with platelet counts below 30,000/µL. Careful observation without medical treatment may be appropriate in some asymptomatic children.

Prednisolone (Orapred, Pediapred, Millipred)

Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosage. It is used in all patients with severe life-threatening bleeding or children with platelet counts below 30,000/µL. Careful observation without medical treatment may be appropriate in some asymptomatic children.

Mycophenolate (CellCept, Myfortic)

Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. It inhibits antibody production. Two formulations are available; they are not interchangeable. The original formulation, mycophenolate mofetil (CellCept) is a prodrug that, once hydrolyzed in vivo, releases the active moiety, mycophenolic acid. A newer formulation, mycophenolic acid (Myfortic), is an enteric-coated product that delivers the active moiety.

Sirolimus (Rapamune)

Sirolimus inhibits a mammalian target of rapamycin (mTOR), a kinase that play a fundamental role in regulating the progression of the cell cycle and disrupts proliferation of T cells. Sirolimus monotherapy is a safe and effective steroid-sparing agent with rapid improvement of lymphoproliferation, autoimmunity and normalized biomarkers including Vit B12, IL-10, and soluble FASLG. A dose of 2.5mg/m2 daily can achieve a trough level of 5-15ng/ml. The well-known side effects are oral mucositis, hyperlipidemia, decreased renal function, myelosuppression, and drug-drug interaction.

Class Summary

High-dose (1-2 g/kg IV) immune globulin may be considered for concomitant use with pulse-dose corticosteroids in those with severe AIHA.

Immune globulin intravenous (Bivigam, Carimune NF, Octagam, Gammaplex, Gammagard, Privigen, Panzyga, Gamunex-C)

Immune globulin intravenous is given as a temporary measure to increase platelets. It neutralize circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including interferon gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells while augmenting suppressor T cells; blocks the complement cascade; promotes remyelination; and may increase immunoglobulin G (IgG) in cerebrospinal fluid (10% of cases).