30 - An overview of other diseases with monoclonal or increased polyclonal immunoglobulins

Chapter 30

30.1. Introduction

This chapter provides an overview of other diseases with monoclonal or increased polyclonal immunoglobulins. It covers the use of free light chain (FLC) and immunoglobulin heavy/light chain (Hevylite®, HLC) measurements in lymphoid malignancies, plus autoimmune and infectious diseases. The role of serum FLCs (sFLCs) as a marker of mortality is also discussed.

30.2. sFLCs in lymphoid malignancies

Although monoclonal proteins are a feature of plasma cell dyscrasias, they can also be detected in other B-cell malignancies such as chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) [656][657]. Consistent with this, many studies have demonstrated that inclusion of sFLC analysis in a screening panel alongside serum protein electrophoresis (SPE) identifies additional patients with CLL or lymphoma (Chapter 23).

The incidence of sFLC abnormalities varies widely according to the lymphoid subtype (Table 30.1). For example, an abnormal κ/λ sFLC ratio is found in approximately 5% of patients with Hodgkin lymphoma (HL; Section 31.2) but around 50% of patients with mantle cell lymphoma (MCL; Section 31.4). sFLCs may be produced directly by the tumour (e.g. diffuse large B-cell lymphoma [DLBCL]; Section 31.3) or by B-cells in the surrounding microenvironment (e.g. HL; Section 31.2).

There is a growing body of literature on the use of sFLCs as a prognostic marker in lymphoid malignancies (Table 30.1). For example, in DLBCL the absolute κ and λ sFLC levels were more predictive of outcome than the sFLC ratio (Section 31.3.2), whereas in MCL the sFLC κ/λ ratio but not absolute levels were associated with overall survival (Section 31.4). In CLL, both a monoclonal and a polyclonal sFLC elevation are associated with inferior outcome (Section 33.3). It should be noted that polyclonal FLC elevation may be due to renal impairment or polyclonal stimulation (Chapter 7).

Disease Incidence of sFLC abnormalities Prognosis Monitoring
Abnormal κ/λ
sFLC ratio
Abnormal κ/λ
sFLC ratio
HL[658][659][660][661]5 - 7% ~30%
(κ and/or λ)
NHLDLBCL [662][663][664]9 - 14% 19 - 32%
(κ and/or λ)
FL[657]4 - 8% unknown unknown unknown unknown
MZL: MALT[657]16% unknown unknown unknown unknown
MCL[657][665][666][667]36 - 77% 40%
(κ and/or λ)
BL[657]12% unknown unknown unknown unknown
WM [668][669][670]77% 83%
CLL [671][672][673][675][676][678]30 - 40% 32%
(κ and/or λ)

Table 30.1. Summary of the incidence of FLC abnormalities, and the role of sFLC measurements in HL, NHL and CLL. ✓: parameter shown to be of value; ✗: parameter shown not to be of value; iFLC: involved FLC; HL: Hodgkin lymphoma; NHL: non-Hodgkin lymphoma; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; MZL: marginal zone lymphoma; MALT: lymphoma of mucosa-associated lymphoid tissue; MCL: mantle cell lymphoma; BL: Burkitt lymphoma; WM: Waldenström’s macroglobulinaemia; CLL: chronic lymphocytic leukaemia.

sFLCs may be a useful marker for monitoring lymphoma. Their short serum half-life and the large clinical range provide a sensitive marker for assessment of response to treatment. The sFLC component indicating response may vary between the different lymphoma subtypes. For example, in Waldenström’s macroglobulinaemia (WM), the involved FLC (iFLC) concentration was found to be a useful marker to monitor disease and may show response to treatment and progression earlier than IgM measurements (Section 32.3.2). In MCL, both the κ/λ sFLC ratio and summated κ + λ FLC concentrations (ΣFLC) may be informative for monitoring (Section 31.4). In cryoglobulinaemia, sFLCs could possibly serve as a useful tool for monitoring response, since direct measurement of cryoglobulins is technically difficult (Section 34.2).

sFLC concentrations may also have prognostic value in predicting the risk of developing NHL in immunosuppressive states (e.g. HIV infection or recipients of solid organ transplants) and in conditions associated with chronic B-cell activation (e.g. primary Sjögren’s syndrome and hepatits C virus infection). These are discussed in Chapter 35.

30.3. Hevylite in lymphoid malignancies

Preliminary findings suggest that abnormal HLC ratios are found in a significant percentage of lymphoma patients, particularly those with indolent types (follicular lymphoma [FL], marginal zone lymphoma [MZL] and WM). In a study of 145 patients with indolent and aggressive lymphomas, 64/145 (44%) had an abnormal HLC ratio (Table 30.2 and Figure 30.1) [679] . By comparison, a monoclonal protein was detected in the serum of 38/145 (26%) patients by SPE and 45/145 (31%) patients by immunofixation electrophoresis (IFE) [679]. This suggests that HLC assays provide a more sensitive means of detecting monoclonal protein production in lymphoproliferative malignancies than conventional electrophoretic techniques. HLC analysis may also be useful in situations where the monoclonal protein concentration is low and accurate quantitation by SPE is difficult (Section 32.4.1). In addition, evidence suggests that HLC analysis is useful for monitoring WM (Section 32.4.2).

In lymphoma patients, the most frequent HLC ratio abnormality was IgM, detected in approximately two-thirds of cases [679]. Approximately one quarter of patients had abnormal HLC ratios for more than one immunoglobulin class.

Disease HLC at diagnosis Prognosis Monitoring
HLC ratio
IFE positive
HLunknown unknown unknown unknown
NHLDLBCL [657][663][679]24 - 44% 0 - 24% IgMκ/IgMλ HLC ratio
predicts PFS
FL[657][679]17% 8 - 24% unknown unknown
MZL[657][679]44% 36 - 37% unknown unknown
MCL [657][679]11% 20 - 22% unknown unknown
BL[657]unknown 12% unknown unknown
WM[679][680][681]97 - 100% 100% Initial data
supports use
Initial data
supports use
CLL [673]unknown 17% unknown unknown

Table 30.2. Summary of the incidence of HLC and IFE abnormalities, and the role of HLC measurements in HL, NHL and CLL. PFS: progression-free survival; other abbreviations defined in Table 30.1.

To date, only one study has investigated the prognostic value of HLC measurements in lymphoma. In a preliminary investigation following patients with DLBCL, multivariate analysis indicated that the IgMκ/IgMλ HLC ratio was predictive of progression free survival (Section 31.3.2) [663].

The concentration of the uninvolved HLC-pair (e.g. IgGλ in a patient with monoclonal IgGκ) provides information on polyclonal immunosuppression. This is prognostic in a number of plasma cell disorders, including monoclonal gammopathy of undetermined significance (MGUS; Chapter 13) and multiple myeloma (Chapter 20). Emerging evidence suggests that HLC-pair suppression may be present in a significant number of lymphoma patients. For example in WM, HLC-pair suppression was present in a quarter of individuals (Section 32.4.3). Further studies on the prognostic utility of HLC-pair suppression in lymphoproliferative disorders are warranted.

Heavy chain disease (HCD) is characterised by the production of a monoclonal immunoglobulin heavy chain with no associated light chains (Section 34.3). As HLC assays do not recognise the monoclonal heavy chain protein, they allow quantitation of the intact immunoglobulins and provide an indirect estimate of the heavy chain production (by subtraction of summated HLC values from total immunoglobulin measurements). In a study of 15 γ-HCD patients, Kaleta et al. [682] found that 20% of patients also had monoclonal sFLC production.

30.4. sFLCs as a biomarker of immune stimulation and inflammation

Measurement of polyclonal sFLCs provides an indication of total immunoglobulin synthesis that may serve as a biomarker of immune stimulation and inflammation (Chapter 35) [683].

In a number of autoimmune diseases, the concentrations of polyclonal sFLCs correlate with disease activity. These include systemic lupus erythematosus (SLE; Section 35.4.1), Sjögren’s syndrome (Section 35.4.2), and rheumatoid arthritis (RA; Section 35.4.3). Patients at risk of disease flare could be monitored with sFLCs, to allow early intervention and possibly reduce end-organ damage and mortality. Increased concentrations of polyclonal sFLCs have also been described in a number of inflammatory diseases. These include pneumonitis (Section 35.8.1), rhinosinusitis (Section 35.7), IgG4-related disease (Section 35.8.5), viral infections e.g. hepatitis C virus (Section 35.8.2), and HIV (Section 35.6).

Hutchison and Landgren [683] speculated that sFLC measurement might complement the use of C-reactive protein (CRP) assays as a biomarker of inflammation. First, however, they suggested that a better understanding of the intra-patient variation in FLC measurements is required (Section 7.2.6), alongside knowledge of whether it is advantageous to correct sFLC measurements for renal clearance or use unmodified measurements (Section 6.3).

30.5. Cerebrospinal fluid FLCs and multiple sclerosis

The development of Freelite® assays that are validated for use in cerebrospinal fluid (CSF) provides an important tool to aid in the diagnosis of multiple sclerosis (MS). In this condition, κ FLC CSF concentrations are typically high, whilst λ FLC concentrations are only moderately elevated (Chapter 36). An elevated κ FLC index supports a diagnosis of MS, with similar diagnostic accuracy to oligoclonal band detection (Section 36.2).

30.6. sFLCs as a marker of mortality

General population studies have revealed an association between elevated polyclonal sFLCs and reduced survival, leading to the speculation that sFLC measurements could form a useful early investigation in a general health assessment. This is discussed further in Section 35.10.