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Untangling the neurologic comorbidities of bullous pemphigoid

DII small banner By Warren R. Heymann, MD
June 6, 2017

Bullous pemphigoid
Response of a patient with bullous pemphigoid (BP) after 6 omalizumab injections as monotherapy. A, Involvement of the back of a steroid-refractory patient with BP before omalizumab treatment. B, Four months after beginning omalizumab as monotherapy, the inflammatory plaques have largely resolved, leaving postinflammatory hyperpigmentation and a small number of erosions and mild, transient erythema. The patient cleared completely after a second cycle of omalizumab treatment.
Credit: JAAD

Comorbidities are the darlings of the dermatologic literature in the 21st century, based on an epidemiologic ability to sort through vast databases, finding associations and correlations that may or may not have direct clinical relevance.

Bullous pemphigoid (BP) has been the focus of such attention, leading to the concept of mutimorbidity. In a study of 105 cases of BP compared to 315 control patients, Sim et al, found that 88 cases of BP (84%) were multimorbid with at least 2 chronic diseases. The mean number of comorbid conditions was 3.2 +/- 1.6 in patients with BP compared to 2.4 +/- 1.6 in control patients (p < 0.001); 43% of cases had ≥ 4 comorbidities compared to 27% in controls (p = 0.003). The most common comorbities of BP in this study were hypertension (73%), neuropsychiatric disorders (71%) and diabetes (40%). The odds ratio (OR) of developing neurological disease was 10.93 compared an OR of 2.38 for associated hypertension. The 1-year mortality of cases and controls were 21.0% and 17.8% respectively. The authors concluded that a significant proportion of patients with BP are multimorbid, having a higher number of comorbidities compared to matched controls. This disease burden likely impacts the prognosis of patients with BP. (1)

The 75-year-old man I evaluated today with BP (see image) was typical, having associated diabetes and hypertension. My goal is to either get rituximab approved, or use mycophenolate mofetil, but for now, it’s prednisone with all its attendant issues regarding his comorbidities.

Awareness of the spectrum of comorbid diseases is essential for optimal patient care. A thorough review of systems, while being attuned to pertinent symptoms, may reveal a previously undiagnosed disorder. Of course comorbities have practical management implications, often necessitating a “yin and yang” balancing act of therapeutic pros and cons.

One of the areas of greatest interest of BP comorbities is the realm of associated neurologic diseases, including cerebrovascular disease, dementia, multiple sclerosis (MS), seizures, Parkinson disease, and amyotrophic lateral sclerosis. (2)
Lai et al performed a meta-analysis of 14 studies, with 23,369 BP cases and 128,697 controls. Patients with BP were significantly more likely to have stroke (RR 2.68), Parkinson’s disease (RR 3.42), dementia (RR 4.46), epilepsy (RR 2.98), and multiple sclerosis (RR 12.40) compared to controls. (3) The relative risk of multiple sclerosis in patients with BP is striking.

The significant association MS and BP was confirmed in a register-based matched cohort study on all Danish patients with a hospital-based diagnosis of BP (n=3281), with an OR of 9.7. Additionally, there was an estimated prospective risk of developing MS, if diagnosed with BP, with a hazard ratio of 9.4. (4). As Patsatsi and Murrell acknowledge in the editorial accompanying this study, the pathogenesis of BP and MS is strongly intertwined, based on the fact of an increased prevalence of MS at baseline, but also a high prospective risk of developing MS during follow-up in patients with BP. (5)
According to Lai et al, the mechanism underlying this association remains obscure. It has been postulated that degenerative neurological diseases expose BPAG1, triggering an immune response against both epithelial and neuronal isoforms of BPAG1. Recent findings from experimental models indicated that BPAG1-specific autoimmunity alone may not fully explain the disease process. Expression of BPAG2 has also been demonstrated in the human brain. It has been demonstrated that sera from BP patients with neurological diseases can recognize both BPAG1 and BPAG2 in the human epidermal and brain extracts. This suggests that both BP antigens 1 and 2 may play a role in the pathogenesis of neurologic disease. More experimental research is needed to elucidate the relationship between BP antigen-specific antibodies and the development of neurological disorders. (3) Hopefully that knowledge will enable clinicians to obviate BP and any associated neurologic complications. Until such time, it is essential that dermatologists keep comorbidities, especially neurologic disorders, in mind when managing patients with BP.

1. Sim B, et al. Multimorbidity in bullous pemphigoid: A case-control analysis of BP patients with age and gender matched controls. J Eur Acad Dermatol Venereol 2017; May 9 [Epub ahead of print]
2. Heymann WR. The association of bullous pemphigoid and neurologic disorders: A real braintease. Skinmed 2015; 13: 386-7.
3. Lai YC, et al. Bullous pemphigoid and its association with neurological diseases: A systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2016; 30: 2007-15.
4. Kibsgaard L, et al. Increased frequency of multiple sclerosis among patients with bullous pemphigoid: A population-based cohort study on comorbidities anchored around the diagnosis of bullous pemphigoid. Br J Dermatol 2017; 176: 1486-91.
5. Patsatsi A, Murrell DF. Multiple sclerosis is the neurological disorder most highly associated with bullous pemphigoid. Br J Dermatol 2017; 176: 1428-9.

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