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Complex immunologic disease requires intense collaboration across subspecialties for optimal care. For that reason, Cleveland Clinic’s Department of Rheumatic and Immunologic Diseases recently developed the nation’s first combined fellowship in rheumatology and infectious disease (ID), designed to train physicians to practice in both of those specialties.
These dual-trained specialists will be well suited to engage in clinical care and research in a multitude of areas, including:
Rheum-ID hybrids also will be well poised to sort out the complexities of the growing list of rheumatic complications of infections, such as spirochetes; blood-borne viral illnesses like HCV, HBV and HIV; and the emerging field of arboviruses, associated with rheumatic complications.
Here we share two situations at the intersection of rheumatology/immunology and infectious disease:
An 18-year-old female presented for evaluation of possible immunodeficiency. She was in her usual state of health until two years prior, when she was admitted for meningococcal meningitis. She was treated and recovered. One year later, she presented with flu-like symptoms and was diagnosed again with meningitis secondary to Neisseria meningitidis. Her history is also notable for frequent upper respiratory tract infections.
The patient’s laboratory evaluation revealed a complement deficiency assay (CH50) of 0, C7 deficiency (<5 U/mL) and absent AH50 without evidence of humoral immune deficiency. She was diagnosed with primary C7 deficiency.
Complement plays a key role in protection against a variety of infections. Activation of terminal complement components (or membrane attack complex: C5-C9) is crucial for controlling infections with encapsulated organisms, such as Neisseria spp. Patients with genetic deficiencies of terminal complement, such as the patient presented here, have a significantly increased risk of recurrent invasive meningococcal infection.
The patient was educated on methods to reduce her infection risk, including revaccination against all five available meningococcal serotypes every three to five years. She has done well since.
Eculizumab is a monoclonal anti-complement C5 antibody that is FDA-approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (both diseases that involve uncontrolled activation of the complement system). Not surprisingly, eculizumab is associated with a significantly increased risk of meningococcal disease — 1,000 to 2,000 times greater than that of a healthy person.
The rheumatology community will be increasingly exposed to eculizumab, as it also is used to treat refractory lupus nephritis. Therefore, it is crucial that rheumatologists become aware of the drug’s unique risk, as well as the current recommendations to offset it.
A black box warning was added to the eculizumab package insert after two of 196 PNH patients developed meningococcal infections while using the drug during clinical trials.1 The insert recommends meningococcal vaccines for recipients of eculizumab, although recent data show some patients developed meningococcal disease even after receiving vaccinations.
Currently available are vaccines for the most common serotypes, the meningococcal conjugate vaccine (MenACWY) and a serogroup B meningococcal vaccine (MenB). While most eculizumab-associated meningococcal infections have been non-groupable Neisseria meningitides, both meningococcal vaccines should be given at least two weeks before the first dose of eculizumab, if possible.
Interestingly, breakthrough infection has been reported, so antibiotic prophylaxis is also required.
Both the case study and the use of eculizumab involve a significantly increased risk of systemic neisserial infection and are perfect examples of the opportunity for collaboration between rheumatology, immunology and infectious disease.
Rheumatology offers many more opportunities, as the specialty encompasses every organ system and diseases with protean manifestations. Patients with primary immunodeficiencies may also present with autoimmune conditions, such as connective tissue diseases, inviting even more interdisciplinary collaboration.
Dr. Calabrese is staff in the Department of Rheumatic and Immunologic Diseases. In 2018, she was the first graduate of Cleveland Clinic’s combined fellowship in rheumatology and infectious disease.
Dr. Fernandez is staff in the Department of Allergy and Clinical Immunology.