Autoimmune lymphoproliferative syndrome

Synonym: Canale-Smith syndrome

What is autoimmune lymphoproliferative syndrome?¹

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited non-malignant lymphoproliferative disorder characterised by heterozygous mutations within the first apoptosis signal receptor (FAS) signalling pathway. Defects in FAS-mediated apoptosis cause an expansion and accumulation of autoreactive CD4- and CD8- (double-negative) T cells, leading to cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and a greatly increased lifetime risk of lymphoma.²

The majority of patients with ALPS have heterozygous germline mutations in the gene for the TNF receptor-family member FAS (CD 95, Apo-1) which are inherited in an autosomal dominant fashion. Somatic FAS mutations are the second most common genetic cause of ALPS.³

It can present in children or adults but usually presents in early childhood. ALPS should be considered in all children with unexplained lymphadenopathy, organomegaly, or autoimmune cytopenias.

Autoimmune lymphoproliferative syndrome aetiology²

ALPS is caused by genetic defects in the genes controlling apoptosis (programmed cell death):

• The defective pathway is FAS-mediated apoptosis, which is part of the normal downregulation of the immune system involving T and B lymphocytes.

• This leads to chronic lymphoproliferation, autoimmunity and an increased risk of malignancies.

• Approximately 70% of patients have an identifiable genetic mutation.

ALPS symptoms (presentation)²

ALPS-associated mutations show an incomplete penetrance that varies by both the affected gene and the mutation type, with the most common FAS mutations showing a reported progression to ALPS of approximately 60%.

Affected patients develop disease at a median age of 11.5 months, and demonstrate a spectrum of clinical findings as a consequence of non-malignant lymphoid hyperplasia and the progressive accumulation of autoreactive B and T lymphocytes.

The classic presentation is an adolescent with non-infectious, non-malignant lymphadenopathy and splenomegaly. Splenomegaly may be profound (greater than 10 times normal size) with a risk of splenic rupture. Hepatomegaly is present in up to 50% of cases.

The accumulation of autoreactive T-cells triggers a constellation of variable autoimmune symptoms. Immune-mediated cytopenias are the most common and may affect any lineage. The most frequent of these is autoimmune haemolytic anaemia which can be severe. Also common are idiopathic thrombocytopenic purpura (ITP) resulting in excessive bruising and bleeding, and autoimmune neutropenia which can persist even after splenectomy.

Cytopenias are often accompanied by an increase or decrease in serum IgG levels (70% of patients). New cytopenias in ALPS patients have been reported in patients as old as 54 years.
Autoimmune syndromes involving solid organs are much less common, but reported sites of involvement include: kidneys (glomerulonephritis), liver (autoimmune hepatitis), connective tissue (systemic lupus erythematosus), eyes (uveitis), thyroid (thyroiditis), skin (urticarial rash), and nervous system (Guillain-Barre syndrome).

ALPS patients also have a greatly increased risk for the development of secondary malignancies which does not reduce with age, extends across mutation types, and represents a significant cause of morbidity and mortality. There is a 150-fold increased risk for Hodgkin lymphomas and a 14-fold increased risk for non-Hodgkin lymphomas.

Investigations⁴

General investigations

Blood tests
These may show:

• Autoimmune-type haemolytic anaemia, thrombocytopenia, neutropenia and hypergammaglobulinaemia.

• T- and B-cell lymphocytosis.

• Positive direct Coombs' test - direct antiglobulin test (DAT).

• Positive autoantibodies (antiplatelet and antineutrophil and antinuclear).

• Raised IgG levels, possibly also raised IgA or IgM; but some patients have hypogammaglobulinaemia.

• Raised serum B12.

• Raised interleukin-10 (IL-10).

Biopsy

• Most patients merit tissue biopsy (bone marrow or lymph nodes) initially to rule out malignancy, infections and other lymphoproliferative disorders.

• Histology of lymph nodes shows marked paracortical expansion of T cells, and other characteristic features.

Radiology

• Imaging of the liver, spleen or lymph nodes cannot accurately distinguish benign from malignant lymphoproliferation in the context of ALPS.

Diagnostic tests

In addition to clinical findings, the diagnosis based on:⁵

• Abnormal biomarker testing (soluble interleukin-10 [IL-10], Fas ligand [FasL], IL-18, and vitamin B12).

• Defective in vitro tumour necrosis factor receptor superfamily member 6 (Fas)-mediated apoptosis.

• T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called "α/β-DNT cells").

• Identification of pathogenic variants in genes relevant for the Fas pathway of apoptosis. These genes include FAS (either germline or somatic pathogenic variants), CASP10, and FASGL. Up to 20% of those with clinical ALPS have not had a genetic aetiology identified.

Diagnostic criteria²

Required criteria

1. Chronic (> 6 months), non-malignant, non-infectious lymphadenopathy and/or splenomegaly

2. Elevated CD3+ TCRαβ+CD4−CD8− DNT cells (>1.5% of total lymphocytes or >2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts

Additional criteria

• Primary:

1. 1. Defective lymphocyte apoptosis in two separate assays.

   2. Somatic or germline pathogenic mutation in FAS, FASLG, or CASP10.

• Secondary:

1. 1. Elevated plasma sFASL levels (>200 pg/mL), plasma IL-10 levels (>20 pg/mL), serum or plasma vitamin B12 levels (>1500 ng/L) or plasma IL-18 levels >500 pg/mL.

   2. Typical immunohistological findings.

   3. Autoimmune cytopenias (haemolytic anaemia, thrombocytopenia, or neutropenia) with elevated IgG levels (polyclonal hypergammaglobulinaemia)

   4. Family history of a non-malignant/non-infectious lymphoproliferation with or without autoimmunity.

• Definitive diagnosis: both required criteria plus one primary accessory criterion.

• Probable diagnosis: both required criteria plus one secondary accessory criterion.

Differential diagnosis

The differential diagnosis includes infection, other inherited immunodeficiency disorders, primary and secondary autoimmune syndromes, and lymphoma.²

Autoimmune lymphoproliferative syndrome treatment and management²

• Up to 50% of ALPS patients require immunosuppression for treatment of their autoimmune manifestations.

• Short duration treatment with high dose corticosteroids is successful in the acute setting and patients are transitioned to steroid-sparing immunosuppressive regimens to avoid the side effects of prolonged corticosteroid therapy.

• Mycophenolate mofetil leads to improved outcome. Rituximab is also useful in ALPS, but should be avoided if possible due to the risk of prolonged hypogammaglobulinaemia which appears to be unique to ALPS patients.

• Both steroid and steroid-sparing treatment may be supplemented with intravenous immunoglobulin (IVIG), if necessary. Recombinant granulocyte-colony stimulating factor (GCSF) may be useful in the management of isolated neutropenia.

• Work up to rule out lymphoma is needed for those who develop constitutional signs and symptoms or unusual change to disease course.

• Splenectomy should be avoided if possible, as it leads to significantly worse outcomes. Regimens used to treat cytopenias are usually successful in resolving hypersplenism. However, splenectomy may be necessary in cases of uncontrolled hypersplenism that fails medical treatment. It is recommended that such patients remain on long-term antibiotic prophylaxis and maintain their vaccinations.

• The mTOR inhibitor sirolimus was shown to be effective in the amelioration of ALPS-related refractory cytopenias in a small multicenter clinical trial.

• Currently, the only known cure for ALPS is haematopoietic stem cell transplant, but this is reserved for severe cases refractory to immunosuppressive regimens.

Complications⁴

Increased risk of malignancy

• Lymphoma (Hodgkin's or non-Hodgkin's) is the most common.

• Relatives who inherit the same genetic mutation may have an increased malignancy risk.

• FAS gene mutations have been reported in tumour cells from T-cell leukaemia, multiple myeloma, melanoma, non-small cell lung cancer and transitional cell carcinoma of the bladder. However, the relevance of these findings to ALPS patients is not clear.

Infections

• Increased risk of postsplenectomy pneumococcal sepsis, even with vaccination and antibiotic prophylaxis.

• The autoimmune neutropenia itself does not usually confer an increased risk of infection, as there is usually a neutrophil response to infection. However, immunosuppressive medication (if used) may increase infection risk.

• Some patients develop common variable immunodeficiency (5-10%).

Prognosis²

• Long-term prognostic data are lacking, because this is a rare and recently identified disease. ALPS patients can live into adulthood.

• The major causes of morbidity and mortality are splenectomy-related sepsis and the development of lymphomas.

• Many ALPS patients can ultimately control their disease and with long-term treatment, are likely to experience a decrease or complete resolution of their lymphadenopathy, splenomegaly, and autoimmune symptoms.

• Patients with certain mutations in the intracellular domain of FAS may have a worse prognosis, while those with mutations in the extracellular domain may experience more mild disease.