Introduction 1 2 3 22 23 24 25 29 19 26 4 30 33 34 35 6 36 37 39 40 41 42 26 In this study, we present new data on the prevalence of polyclonal and monoclonal gammopathies from a large adult GD I cohort and review the currently available literature. Second, we studied whether age, disease severity, and exposure time are risk factors for the development of monoclonal gammopathies, and if this risk is subsequently decreased by the administration of ERT. In addition, for the first time, we investigated the role of FLC as a predictor of the development of monoclonal gammopathies in GD I. Finally, the pathogenesis of immunoglobulin abnormalities in GD patients was studied by means of pro- and anti-inflammatory cytokine, chemokine, and growth factor levels and is discussed in relation to previous literature. Materials and methods Patients and study design N 43 44 45 46 47 48 We investigated whether levels of FLC could be predictive for the development of MGUS and whether these levels were related to disease severity. Therefore, we measured FLC levels in serum before start of enzyme replacement therapy in ten patients with mild GD (SSI ≤ 8) and ten patients with severe GD (SSI ≥ 9), all without a monoclonal gammopathy. In addition, we studied whether changes in cytokine levels and in FLC and immunoglobulins at baseline and during ERT were related to the presence or absence of a monoclonal gammopathy. Therefore, the group of patients with a monoclonal gammopathy was matched for age, sex, spleen status, SSI, and the use of ERT to a control group of GD patients without a monoclonal gammopathy. Serial measurements of levels of IL-6, IL-10, and PARC at baseline and after 12, 24, and a median of 114 months of ERT (range 40–143, whatever was the last determination) were performed. These were related to changes in immunoglobulins and free light chains. Hepatocyte growth factor (HGF) was measured only at baseline. One patient did not receive therapy; the first hospital visit was used as T0. Assays 49 37 39 Statistics U χ ρ P Search strategy To compare the prevalence of poly- and monoclonal gammopathies in our cohort with earlier case series and to study the relative risk of MM, we performed a MEDLINE search combining the MESH terms Gaucher disease with either hypergammaglobulinemia, paraproteinemias, and/or multiple myeloma. Literature on cytokines, chemokines, and growth factors in relation to the development of immunoglobulin abnormalities in GD were searched combining the MESH terms Gaucher disease with cytokines and/or chemokines. Case reports were excluded and only studies that included at least ten patients were selected. Results Patients The 63 patients had a median age of 53 years (range 25–83). Thirty-two of patients (51%) were men, and 23 (37%) were splenectomized. At baseline, median SSI was 8 (range 3–19). The majority of patients had a genotype containing N370S (95%), with N370S/L444P being the most common combination (40%). All patients had creatinine and urea values within the normal range. 1 Table 1 Characteristics of Gaucher disease type I patients with a monoclonal gammopathy Patient no. Sex Sx Age in 2007 or at death Therapy MG type Ig type 1 M N 55 ERT MGUS, progression to amyloidosis and MM Free κ 2 M Y 71 ERT MM IgGκ 3 F N 46 ERT MGUS, progression to amyloidosis IgGλ 4 M Y 60 ERT MGUS IgGκ 5 M Y 67 ERT MGUS IgGλ 6 M Y 59 ERT MGUS IgAλ, IgGκ 7 F N 67 ERT MGUS IgAκ 8 M N 56 ERT MGUS IgGλ 9 M Y 65 ERT MGUS IgGκ, IgGλ, IgAκ 10 M N 56 ERT MGUS IgMκ, IgMλ 11 F N 63 No MGUS IgGλ, IgMκ 12 F Y 75 ERT MGUS IgGκ 13 M N 51 ERT MGUS IgGλ M F Sx ERT MG MM MGUS Ig Of the 12 patients with MGUS, two developed MM and/or amyloidosis after approximately 2 years of ERT (#1 and 3). Patient #1 was diagnosed with MM and amyloidosis 25 months after start of ERT. Pulse therapy with dexamethasone was started. Three months after the diagnosis the patient died from cardiac failure. At 24 months after start of ERT, patient #3 was diagnosed with amyloidosis. She received melphalan and prednisone, but died 12 months later from cardiac failure. Patient #2 was diagnosed with MM stage IA before start of ERT. During follow-up, IgG levels gradually increased. After 7 years of ERT, treatment with reduced dose melphalan and prednisone was started, which resulted in unacceptable cytopenia. Subsequently, thalidomide, 100 mg daily, was started with beneficial effect and stable disease parameters for the last 3 years. 1 26 2 Table 2 Baseline characteristics of Gaucher type I patients with a monoclonal gammopathy vs patients without a monoclonal gammopathy   Without MG With MG P No. of patients 50 13   Age in 2007 or at death 51 (25–83) 60 (46–75) 0.003 No. of male patients 23 (46%) 9 (69%) NS Years of exposure 11 (0–37) 18 (1–44) NS No. of splenectomies 17 (34%) 6 (46%) NS SSI at baseline 7 (3–19) 12 (4–16) NS Chitotriosidase (nmol/ml h) at baseline 16,703 (5,409–132,199) 22,534 (6,417–62,122) NS Data reflect absolute numbers (and percentage) or median (and range). MG NS SSI 4 6 16 19 21 3 Table 3 Studies on the prevalence of monoclonal and polyclonal gammopathies in type I Gaucher disease Reference No. of Gaucher patients Age Polyclonal gammopathies Monoclonal gammopathies 26 63 25–83 26 (41%) 12 (19%) 19 16 9–70 6 (38%) 4 (25%) 21 25 24–78 15 (60%) 2 (8%) 16 23 41.8 ± 18 10 (43%) 8 (35%) 4 22 23–65 14 (64%) 3 (14%) 6 507 16–81 14–25% 5 (1%) Data reflect absolute numbers (and percentage), or, in the study of Marti et al., mean ± standard deviation. 25 29 4 Table 4 Studies on the prevalence and relative risk of multiple myeloma in type I Gaucher disease Reference No. of patients Ethnic background Age Control group No. of patients with MM RR of MM 26 131 Mixed 50 ± 14 Dutch Cancer Registry 2 (1.5%) 51.1 (95% CI: 6.2–184) 25 239 Mixed Not given None 5 (2%) ND 28 48 Jewish 54 ± 20 511 individuals from the same region 2 (4%) ND 29 505 Jewish 38 ± 21 Israeli Cancer Registry 2 (0.4%) ND 27 2,510 Mixed 33 US Cancer Registry 10 (0.4%) 5.9 (95% CI: 2.8–10.8) Data on age reflect mean ± standard deviation; data on number of patients with multiple myeloma reflect absolute numbers (and percentage). MM RR 95% CI ND Immunoglobulin and FLC levels 1 Fig. 1 a b MG  1 1 Cytokines, chemokines, and growth factors 2 P Fig. 2 arrow Dotted lines IL HGF PARC MG  5 32 4 32 30 Table 5 Studies on plasma levels of cytokines, chemokines, and growth factors in Gaucher type I patients Reference No. of GD I patients Age Cytokines Results, no. of patients (%) with elevated levels P 26 22 25–83 IL-6 4/24 (17%) ND IL-10 17/24 (71%) PARC 24/24 (100%) HGF 6/22 (27%) 33 25 NG TNF-α 16/25 (64%) ND 4 22 23–65 IL-1β Not detectable NS TNF-α 4/11 (36%) NS IL-6 19/22 (86%) P IL-10 13/13 (100%) P 32 18 NG IL-1β mRNA 5/19 (26%) P TNF-α mRNA 2/19 (11%) NS IL-6 mRNA 3/19 (16%) NS IL-8 mRNA 3/19 (16%) NS 31 29 16–66 M-CSF 24/28 (86%) P sCD14 25/27 (93%) P IL-8 25/27 (93%) P IL-6 0/27 (0%) NS TNF-α 0/27 (0%) NS 30 21 5–39 IL-1β Mean levels elevated P IL-1RA Mean levels elevated P sIL-2R Mean levels elevated P IL-6 Mean levels elevated P IL-8 Not elevated NS TNF-α 3/21 (14%) NS 35 55 12–67 PARC 55/55 (100%) P 56 12 11–67 TNF-α 1/12 (8%) NS NG ND NS Longitudinal changes 3 Fig. 3 Dotted lines Numbers 1 IL PARC  More specifically, immunoglobulin levels remained stable or decreased in all patients, except for patient #11, who showed an increase in IgM. This patient was different from other MGUS patients because she did not receive therapy. Free light chain levels were more variable, but clearly FLC levels of patients who were to develop or already suffered from MM and/or amyloidosis remained high during ERT (#1–3). Although in most patients no trends could be distinguished, a consistent decrease in free light chains and immunogobulins was seen for example in patient 7, who had an IgAκ M protein. This patient responded very well to ERT, but other patients with excellent clinical responses did not always show a similar decrease in M-protein levels. No relationship was found between clinical response and decrease in either levels of immunoglobulins or FLCs. The course of cytokines did not show a relationship with changes in either FLC or immunoglobulin levels, although in the untreated patient with increasing levels of IgM (#11), also an increase in IL-6 and PARC was noted. On the contrary, a spontaneous decrease in IL-6 was found in patient #2, without therapy for his MM. In patient #1, IL-10 showed a clear decrease after start of ERT but before the diagnosis amyloidosis and MM was made. Discussion 4 6 16 19 21 24 50 24 19 40 41 MGUS patients are at risk for developing MM at a rate of 1% of patients per year. Accordingly, the prevalence of MM in GD I cohorts of 0.4–1.5% clearly exceeds the general prevalence of 0.02% (deduced from The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI)). The assumed diversity in relative risk of developing MM (5.9 and 51.1) can simply be explained by age differences in the cohorts: the highest number of MM patients was clearly established in the highest age groups. 51 4 Fig. 4 Bone marrow aspirate showing plasma cells surrounding a Gaucher cell in a patient with Gaucher disease type I and multiple myeloma  4 4 30 32 4 30 33 52 31 30 35 53 54 55 6 4 35 In summary, there is a high prevalence in GD I of both polyclonal as well as monoclonal gammopathies, including MM. The risk of these diseases increases with age. Mechanisms causing gammopathies remain to be elucidated, but include the disturbance of cytokine levels involved in inflammation and B-cell function. ERT is likely to have a beneficial effect in preventing the occurrence and the progression of gammopathies.