Practical management of high and low immunoglobulins

The practical management of high and low immunoglobulins in the rheumatology clinic was the topic of a dedicated session during the 2024 Irish Society for Rheumatology Autumn Meeting.

The presentation on high immunoglobulins by Prof John Quinn, Consultant Haematologist, Beaumont Hospital, Dublin, focused on clinical aspects of monoclonal proteins.

Prof Quinn specifically spoke about the presentation and the management of myeloma, a haematological malignancy, and how red flags for the disease can emerge  during testing in rheumatology clinics.

He noted that myeloma has had the greatest improvement in five-year survival rates in the last 20 years in any cancer, and there are approximately 350 new cases diagnosed annually in Ireland.

Multiple myeloma (MM) is caused by malignant plasma cells that secrete monoclonal paraprotein.

Subtypes of disease can be dictated by the predominant immunoglobulin (Ig; IgG is the most common) and light chain (kappa or lambda).

Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma and MM are determined by the percentage of plasma cells in the bone marrow; presence of end-organ disease; paraprotein levels (greater or less than 30g/L); kappa/lambda light chain ratio (>100); bone marrow plasma cell percentage; and urinary M-protein levels (>500mg/24 hours).

A very high light chain ratio is thus a significant risk factor for MM, Prof Quinn noted.

“If you find a light chain ratio of over 100, that is now regarded as being diagnostic of myeloma…. If you see a high light chain ratio, it is something to act on quickly.”

On the other hand: “If the light chain ratio is normal and the M protein is small, you can reassure the patient they almost certainly have nothing to worry about, though they still have to be referred to us and monitored [if they have MGUS].”

The risk of MGUS, which is always a precursor for MM, increases with age, especially over 70 years, and it is very common in presenting patients, Prof Quinn said.

“For every case of myeloma, you find a hundred cases of MGUS… it is present in about 10 per cent of patients attending a geriatrician. It is mostly IgG, and is not usually related to the presenting complaint, but does have to be differentiated from myeloma.”

In relation to triage and monitoring, he pointed to the 2023 British Society for Haematology guidelines on MGUS investigation and management.

“Refer all newly detected M-Proteins to the haematology clinic – but not those with polyclonal/oligoclonal patterns.”

Prof Quinn reiterated that the higher the light chain ratio, the higher the risk of disease progression.

He also cautioned clinicians to “keep an eye out for light chain amyloidosis”, of which there are about 30-40 cases diagnosed annually in Ireland. “It can be really sneaky and patients can have really vague symptoms such as borderline albumin, a subtle change in the light chain ratio…. If you suspect someone has amyloidosis and if they’ve had any type of biopsy in the last 18 months, I write to the pathologist and ask them to do a Congo red stain [which detects amyloid].”

The second speaker of this session, Dr Khairin Khalib, Consultant Immunologist, Beaumont Hospital, gave a practical presentation on managing low immunoglobulin in rheumatology. She noted that autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies (PID). Dr Khalib referenced a study of 2,183 PID patients, where 26 per cent had autoimmunity/inflammation, and 13 per cent had autoimmune rheumatological conditions.

Determining if PID is primary or secondary is key, as it impacts patient management, Dr Khalib said.

Primary antibody deficiencies (PADs) are the most common PID, and the most prevalent symptomatic form of PAD is common variable immunodeficiency, which is defined by profoundly low IgG and IgA and/or IgM, as well as failure to mount antibodies against vaccination.

In relation to secondary antibody deficiency (SAD), key diagnostic criteria include severe or recurrent bacterial infections, reduced IgG <4g/L (excluding paraprotein), and failure of adequate response to unconjugated polysaccharide vaccine. Risk factors for SAD include family history of PID, chronic sinusitis, bronchiectasis, early-onset autoimmune disease, multiple autoimmune disorders, especially cytopaenias, and recurrent infections that respond poorly to antibiotics, Dr Khalib told the meeting.

Moving on to management, she said, aside from antibiotic prophylaxis (doxycycline, azithromycin, and septrin), the main treatment for significant antibody deficiency is immunoglobulin replacement therapy (IgRT). The primary goal of immunoglobulin replacement is the prevention of sepsis, pneumonia, and other serious acute bacterial infections, as well as reducing recurrent sinopulmonary infections and improving quality-of-life. Reversible causes for SAD are treated pre IgRT. Once initiated on treatment, “assess the adequacy of IgRT with trough IgG and infection frequency and monitor for signs of recovery, ie, normalising of IgA and a jump in IgG,” Dr Khalib said, adding that serum electrophoresis is a key test.

In terms of guidelines, Dr Khalib cited the British Society for Immunology and United Kingdom Primary Immunodeficiency Network consensus guideline for the management of immunoglobulin replacement therapy (2022). This can be accessed at https://academic.oup.com/cei/article/210/1/1/6655640 and includes 22 statements for initiation, 22 statements for monitoring, 11 statements for home therapy, and 19 statements for discontinuation of IgRT. She also cited the American Academy of Allergy, Asthma and Immunology’s ‘Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees’, which can be accessed at www.jacionline.org/article/S0091-6749(22)00152-X/fulltext.

Careful consultation with patients on treatment administration – whether intravenously in hospital/local units, or subcutaneously at home – is also important to optimise results and to take into account their preferences/needs, she told the meeting.

Dr Khalib summarised her presentation with these key points: Confirm SAD diagnosis, as PID – though rare – can present with non-infectious symptoms and increase autoimmune risk. Monitoring at-risk patients is crucial for early diagnosis and treatment. Consider both numerical and clinically relevant hypogammaglobulinaemia, focusing on infection burden, organ damage, and the need for ongoing suppression. In patients with high infection burden, ensure prompt infection treatment, antibiotic prophylaxis, and consider IgRT. She also cautioned about interpreting serology results in hypogammaglobulinaemia (false negatives) and in patients on IgRT (external source).