Autoimmune Lymphoproliferative Syndrome (ALPS) and ALPS-Related Disorders. Different Bio-Clinical Profile and Similar Response to Treatment: A Single Centre Experience

ALPS is an inherited disorder characterized by lymphoproliferation and autoimmunity that mainly involves blood cells. In the last few years, new disorders other than ALPS have been found to cause lymphoproliferative syndromes, and many patients with similar clinical features but not fitting ALPS diagnostic criteria have been described. In this study we evaluate clinical features and response to the treatment of patients with ALPS and ALPS-related Syndromes (ARS) followed in a single Center.

ALPS was defined according to the revised diagnostic criteria (first international Workshop, 2009). ARS was defined as the presence of cytopenia and/or lymphoproliferation and at least one absolute or primary additional criterion for ALPS. Medical records of patients followed in our Center between 2001 and 2014 for these conditions were evaluated.

Sixty-five patients (35 males), with median age at diagnosis of 10 years (range 0-39) with ALPS (32) (definitive: 21, probable: 11), or ARS (33) entered this study. A positive history of lymphoproliferation was present in 8/32 (25%) and in 3/33 (9%) of ALPS and ARS subjects, respectively. Lymphoproliferation was present in 51/65 (78%) patients and consisted of isolated lymphoadenopathy (10/51, 19%), isolated splenomegaly (26/51, 51%), or both conditions (15/51, 29%). It was present in 32/32 (100%) and in 19/33 (57%) of patients with ALPS or ARS, respectively. In particular, lymphoadenopathy was present in 17/32 (53%) and in 8/33 (24%) of ALPS and ARS patients, respectively (p 0.04). Splenomegaly was found in 27/32 (84%) and in 14/33 (43%) of ALPS and ARS subjects respectively (p < 0.01) Cytopenia was present in 51/65 (78%) of patients and involved one (28/51, 55%) or more cell lineage in (23/51, 45%). Trilinear cytopenia was present in 7 ALPS patients and in no subjects with ARS (p<0.01). Isolated thrombocytopenia was the most frequent occurring in 4/32 (12%) and in 12/33 (36%) ALPS and ARS, respectively (p 0.03). No statistical difference was found on the incidence of other type of cytopenia between the 2 groups. The median percentage of Double Negative T-cells/total lymphocytes was 2.6 (range 1.5-14.8) and 1.8 (range 0.6-9.2) in ALPS and ARS patients, respectively (p<0.01). Autoantibodies were present in 17/32 (53%) and in 20/33 (58%) ALPS and ARS patients, respectively, being ANA the most frequently found marker (9/17 ALPS, 8/19 ARS). Autoimmune symptoms other than cytopenia were present in 13/32 (41%) and in 5/33 (15%) patients with ALPS and ARS, respectively (p<0.02). The most common symptom was arthritis that was present in 8 patients (4 ALPS, 4 ARS). The other issues consisted of tyroiditis, hepatitis, nephrosis syndrome, eczema, cholangitis, celiac disease, colitis, and psoriasis.

Fifty-one/65 (78%) patients required treatment and 10/51 (20%) responded to steroids/Immunoglobulin given as first line therapy. The remaining 41 (80%) patients required further lines of treatment. Thirty-four/41 (83%) received MMF for a median of 314 days with a partial/complete response in 17/25 (68%) evaluable patients, and in particular, in 11/14 (79%) and 6/11 (54%) of ALPS and ARS patients, respectively. Mild side-effects (vomit, gastrointestinal issues, fever, headache) were reported in 5 (15%) patients. Sirolimus was given for a median of 395 days to 18/41 (44%) patients, including 11 patients who had previously failed MMF treatment, and led to a partial/complete response in 12/16 (75%) patients and, in particular, in 5/7 (71%) and 7/9 (78%) of ALPS and ARS patients, respectively. Vomit was reported as side effect in one (6%) patient. Median duration of follow-up was 3.3 years (range 0-12.6)

This study confirms the existence of a group of patients who do not fulfil ALPS diagnostic criteria and display a more attenuated bio-clinical phenotype. The presence of lymphoproliferation and elevated DNT is the main feature differentiating ALPS from ARS patients. Trilinear cytopenia is a typical feature of ALPS patients and isolated thrombocytopenia is more frequent in ARS patients. The presence of autoimmune symptoms other than cytopenia is more frequent in ALPS patients. MMF and Sirolimus, which are reported as safe and effective in ALPS patients, may represent a valid option for the treatment of ALPS-related disorders as well. Further studies are needed to identify the immunological defects underlying ARS patients which may help for a better classification of these disorders.