Pemphigus Raises Risk of Developing Rheumatoid Arthritis

Khalaf Kridin, MD, PhD

Patients with pemphigus were found to have more than twice the risk for developing rheumatoid arthritis (RA) as matched controls in a new, large-scale, retrospective cohort study.

Khalaf Kridin, MD, PhD, Lübeck Institute of Experimental Dermatology, University of Lübeck, and colleagues noted that autoimmune diseases are likely to coexist within individuals and their relatives.

"These observations are perceived as part of the concept known as 'autoimmune diathesis,' in which individuals affected by an autoimmune disease are more vulnerable to acquire other autoimmune diseases," Kridin and colleagues indicated.

The investigators found mixed evidence for an association between pemphigus and RA, however, and conducted the study to explore the possible association. “The association between these conditions is inconclusive and yet to be firmly established both epidemiologically and genetically,” Kriden and colleagues wrote.

The investigators identified a total of 1985 patients with pemphigus, diagnosed between 2004-2014, with data from the Clalit Healthcare Services (CHS), the largest health organization in Israel. An age-, sex-, and ethnicity-matched control group of 9875 individuals was constituted from the data source.

Analysis between the groups controlled for healthcare utilization, defined by each individual's total number of visits in the year prior to the diagnosis of pemphigus or date of study enrollment for the controls. Adjustment for comorbid condition was performed with use of the Charlson comorbidity index.

The lifetime prevalence of RA was slightly higher among patients with pemphigus (2.3%; 95% CI, 1.7-3.1) than in the control group (1.8%; 95% CI, 1.5-2.0%), which was not a statistically significant difference. In cases where RA preceded onset of pemphigus, the mean latency from RA to pemphigus was 8.2 years; and when pemphigus preceded, the mean latency to RA was 3.4 years.

During the follow-up period, a total of 15 patients with pemphigus and 25 in the control group developed RA. The incidence of RA was 1.07 (95% CI, 0.62-1.72) and 0.36 (95% CI, 0.24-0.52) per 1000 patient-years among patients with pemphigus and controls, respectively. The total follow-up time was 14,046 person-years for patients with pemphigus, and 70,378.5 person-years for controls.

Kridin and colleagues calculated the crude risk of RA was three-fold higher in patients with pemphigus than in the control group (HR, 3.00; 95% CI 1.58-5.69.After adjustment for several confounding factors, including demographics, healthcare utilization and cormorbidites, pemphigus remained an independent significant risk factor for development of RA (adjusted HR, 2.54; 95% CI, 1.31-4.92).

The investigators consider possible mechanisms for the putative association between pemphigus and RA, including an immunogenetic basis and possible alternative T-Cell regulatory pathways. They also pointed to a possible role of the pro-inflammatory cytokine, interleukin 17 (IL-17).Significantly elevated IL-17 serum levels occur in patients with pemphigus; and excessive IL-17 receptor signaling has been linked to the conversion of acute synovitis into chronically damaging arthritis.

"In pemphigus patients presenting with concerning symptoms of RA, additional investigation may be warranted," Kridin and colleagues advised.

The study, "Patients with pemphigus are at an increased risk of developing rheumatoid arthritis: a large-scale cohort study,” was published online in Immunologic Research.