Should your vaccine status be checked and updated before you start treatment?
As part of our programme to derisk disease-modifying therapies (DMTs) for pwMS in our service, we are reviewing our vaccination policy. One issue that has emerged is the possible need to boost immunity to certain types of bacteria that are known to pose a risk in patients on long-term immunosuppression, in particular B cell depleters, such as rituximab, ocrelizumab and ofatumumab. Why?
Chronic B-cell depletion essentially prevents B-cells mounting an adequate antibody response to new antigens. It does this by preventing the formation of so-called germinal centres in the spleen and/or lymph nodes. In other words patients on longterm anti-CD20 therapy behave, from an immunological perspective, if they have had a functional splenectomy. This put patients with longterm B cell depletion at risk of hypogammaglobulinaemia (low immunoglobulin levels) in the future and predisposes them to infections caused by so-called encapsulated bacteria; these include pneumococcus, meningococcus and Haemophilus Influenzae.
When you review the rheumatoid arthritis literature in relation to longterm rituximab (anti-CD20) therapy both these problems have been documented. How do the rheumatologists deal with these problems? They appear to routinely monitor immunoglobulin levels and they proactively vaccinate their patients prior to starting long-term anti-CD20 therapy.
It seems pretty obvious to me, reading the rheumatology literature, that before you start long-term anti-CD20 therapy you should have your vaccination status checked and we should start vaccinating patients against pneumococcus, meningococcus and Haemophilus Influenzae B. In fact, pneumococcal vaccine is already recommended, if possible, for all patients before starting immunosuppressive treatments. It is clear for anti-CD20 therapies that the vaccines will need to be given prior to starting treatment (see Nguyen paper below).
We also recommend doing baseline immunoglobulin levels on all patients before starting treatment as a reference and then to start checking levels from year 3 onwards. I say year 3 because in the ocrelizumab trials we only saw a significant drop in IgM and IgA levels over 2 years and IgG levels were stable. Based on the rituximab data a drop in IgG levels is, therefore, only likely to emerge after 2 years of treatment.
I would be interested to know if any of you had your vaccine status discussed before you started maintenance immunosuppression?
Makatsori et al. Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. QJM. 2014 Oct;107(10):821-8.
BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature.
METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out.
RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia.
CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.
Nguyen et al. Initial Serological Response after Prime-boost Pneumococcal Vaccination in Rheumatoid Arthritis Patients: Results of a Randomized Controlled Trial. J Rheumatol. 2017 Dec;44(12):1794-1803.
OBJECTIVE: To evaluate the initial serological responses to pneumococcal vaccination with the 13-valent protein-conjugated pneumococcal vaccine (PCV13) followed by the 23-valent polysaccharide pneumococcal vaccine (PPV23) among patients with rheumatoid arthritis (RA) treated with biological disease-modifying antirheumatic drugs (bDMARD) according to dosing and intervals between immunizations.
METHODS: Investigator-initiated clinical trial. Patients with RA receiving bDMARD were randomized (1:1:1) to immunization with single dose PCV13 followed by PPV23 after 16 or 24 weeks, or double dose PCV13 followed by PPV23 after 16 weeks. A comparison group of patients with RA treated with conventional synthetic (cs)DMARD received single dose PCV13 followed by PPV23 16 weeks later. Pneumococcal antibodies were collected before and 4 weeks after each vaccination. The primary endpoint was the proportion of participants responding to ≥ 6/12 pneumococcal serotypes 4 weeks after both vaccinations.
RESULTS: Sixty-five participants receiving bDMARD and 35 participants receiving csDMARD were included. After PPV23 vaccination, 87% (95% CI 0.76-0.94) and 94% (95% CI 0.77-0.99), respectively, of participants treated with bDMARD and csDMARD had reached the primary endpoint. There was no significant difference in primary endpoint between the 3 randomization arms. The response for rituximab-treated participants was 25% compared to ≥ 89% in participants treated with bDMARD with other mode of action.
CONCLUSION: The early serological response to prime-boost vaccination with PCV13 followed by PPV23 was very similar among participants receiving bDMARD and csDMARD. However, notable differences in response were observed according to individual bDMARD. It is important to consider the RA treatment when planning pneumococcal vaccination in patients with RA.
Friedman & Winthrop. Vaccinations for rheumatoid arthritis. Curr Opin Rheumatol. 2016 May;28(3):330-6.
PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients experience increased infectious disease-related morbidity and mortality, and vaccinations represent an important element in their care. However, vaccine immunogenicity can be affected by disease-modifying antirheumatic drug (DMARD) therapy, such that vaccine choice and timing can be clinically challenging. We review the indications, safety, and immunogenicity of vaccines in the setting of RA.
RECENT FINDINGS: Recent recommendations highlight the use of influenza, pneumococcal, and shingles vaccines in RA patients. Studies suggest influenza and pneumococcal vaccines are underutilized, but well tolerated in RA patients and generally immunogenic during DMARD use with the exception of rituximab. Though data for other nonlive vaccines are more limited, hepatitis B virus and human papilloma virus vaccines also appear well tolerated and immunogenic in this population. Live vaccines for shingles and yellow fever remain contraindicated in some RA patients; however, limited data suggest they might be well tolerated in certain individuals.
SUMMARY: The review updates rheumatologists on the optimal use and timing of routine vaccinations in the care of RA.