Dear Editor
Psoriasis, particularly when moderate to severe, is associated with an increased risk of incident chronic kidney disease (CKD)1, although specific renal diseases observed in psoriasis patients remain poorly defined. Of special interest is IgA nephropathy (IgAN), which presents with episodic macroscopic hematuria and can lead to CKD and end-stage kidney disease. Several case reports link psoriasis to IgAN as well as elevated serum levels of IgA-containing immune complexes2–4, however, no large-scale epidemiological studies have evaluated this association. Other forms of glomerular disease (GD) in psoriasis have also been reported, with cross-sectional studies yielding mixed findings3,5,6 and one population-based cohort study finding psoriasis to be associated with an increased risk for glomerulonephritis without elucidating specific renal etiologies of glomerular damage7. Further understanding of the relationship between psoriasis and glomerular disease is thus warranted.
We conducted a population-based cohort study investigating incident IgAN and GD in psoriasis patients using data from The Health Improvement Network (THIN) from 1994–2014. THIN is a broadly representative electronic medical records database in the United Kingdom that has been previously validated for studying psoriasis8. Diagnostic codes were used to identify psoriasis patients (exposed) and the primary outcomes of IgAN and GD. Prescription codes for phototherapy or systemic medications identified patients with moderate-to-severe psoriasis. Algorithms to match psoriasis patients to patients without psoriasis (unexposed), define psoriasis severity, and identify start and end of follow-up time have previously been described1. Subjects with IgAN or GD prior to start of follow-up were excluded.
Risk factors for IgAN and GD were assessed as potential confounders in initial multivariable models for both outcomes. Covariates were measured on or before start date and included age, sex, body mass index, smoking and drinking habits, socioeconomic status (Townsend score), NSAID use, hypertension, diabetes, hyperlipidemia, cardiovascular disease, arthritis, and CKD.
Statistical analyses were performed using STATA 13.0 (StataCorp, College Station, TX, USA). Patient characteristics were summarized and compared using the Chi-square test and two-sided t-test for categorical and continuous variables, respectively. We obtained hazard ratios (HR) for the outcomes in exposed vs. unexposed patients using Cox proportional hazards regression. Initial multivariable models included covariates thought a priori to be confounders and those significant in univariable analyses (p ≤0.05). Starting with the highest p value >0.05, covariates were sequentially removed and eliminated if the exposure HR did not change ≤10%. Log-log survival plots verified that the proportional hazard assumption was met. Two-sided p values <0.05 determined statistical significance.
This study was consistent with the STROBE guidelines, Declaration of Helsinki, and approved by the IRB at University of Pennsylvania.
We identified 205,815 psoriasis patients (mild: 193,013; moderate-to-severe: 12,806) and 1,019,140 patients without psoriasis. Table 1 summarizes baseline cohort characteristics. The most common therapies for moderate-to-severe psoriasis were oral systemics (78.60%), specifically methotrexate (69.13%).
Table 1.
Baseline characteristics and incidence rates of outcomes in patients with and without psoriasis
| BASELINE CHARACTERISTICS | |||||||
| Any Psoriasis | Mild Psoriasis | Moderate-to-severe Psoriasis | |||||
| Unexposed | Overall PsO | Unexposed | Mild PsO | Unexposed | Moderate-to-severe PsO | ||
| N | 1,019,140 | 205,815 | 955,721 | 193,013 | 63,415 | 12,806 | |
| Age, mean (SD) | 50.66 (17.82) | 47.17 (17.55) | 50.62 (17.83) | 47.00 (17.67) | 51.36 (17.68) | 49.83 (15.30) | |
| Female sex, N (%) | 570,359 (55.96) | 106,569 (51.78) | 534,679 (55.94) | 99,975 (51.80) | 35,676 (56.26) | 6,598 (51.52) | |
| BMI, mean (SD)1 | 26.39 (5.47) | 26.76 (5.64) | 26.40 (5.47) | 26.66 (5.59) | 26.37 (5.38) | 28.11 (6.11) | |
| Drinking history, N (%)2 | |||||||
| None | 115,738 (11.36) | 21,634 (10.51) | 108,415 (11.34) | 20,221 (10.48) | 7,321 (11.54) | 1,415 (11.05) | |
| Current | 651,393 (63.92) | 133,805 (65.01) | 611,581 (63.99) | 125,285 (64.91) | 39,811 (62.78) | 8,521 (66.54) | |
| Past | 43,615 (4.28) | 8,257 (4.01) | 41,052 (4.30) | 7,398 (3.83) | 2,562 (4.04) | 860 (6.72) | |
| Smoking history, N (%)3 | |||||||
| None | 488,477 (47.93) | 80,067 (38.90) | 458,226 (47.95) | 75,124 (38.92) | 30,249 (47.70) | 4,945 (38.61) | |
| Current | 219,759 (21.56) | 58,963 (28.65) | 206,406 (21.60) | 55,579 (28.80) | 13,351 (21.05) | 3,386 (26.44) | |
| Past | 209, 354 (20.54) | 45,790 (22.25) | 196,829 (20.59) | 42,073 (21.80) | 12,525 (19.75) | 3,717 (29.03) | |
| Townsend4, median quintile (IQR) | 3 (1,4) | 3 (2,4) | 3 (1,4) | 3 (2,4) | 3 (1,4) | 3 (1,4) | |
| Hypertension | 210,359 (20.64) | 35,801 (17.39) | 196,995 (20.61) | 32,939 (17.07) | 13,362 (21.07) | 2,864 (22.36) | |
| Diabetes | 67,635 (6.64) | 12,558 (6.10) | 63,499 (6.64) | 11,349 (5.88) | 4,136 (6.52) | 1,209 (9.44) | |
| Hyperlipidemia | 95,117 (9.33) | 16,734 (8.13) | 89,114 (9.32) | 15,346 (7.95) | 6,003 (9.47) | 1,388 (10.84) | |
| Cardiovascular disease (CVD)5 | 90,411 (8.87) | 15,530 (7.55) | 84,404 (8.83) | 14.459 (7.49) | 14,459 (7.49) | 6,007 (9.47) | |
| Psoriatic arthritis | Not applicable | 10,308 (5.01) | Not applicable | 5,504 (2.85) | Not applicable | 4,804 (37.51) | |
| NSAID use | 537,227 (52.71) | 93,476 (45.42) | 504,529 (52.79) | 84,373 (43.71) | 32,698 (51.56) | 9,106 (71.11) | |
| INCIDENCE RATES OF IgA NEPHROPATHY AND GLOMERULAR DISEASE IN PATIENTS WITH AND WITHOUT PSORIASIS | |||||||
| Any Psoriasis | Mild Psoriasis | Moderate-to-severe Psoriasis | |||||
| Unexposed | Overall PsO | Unexposed | Mild PsO | Unexposed | Moderate-to-severe PsO | ||
| IgAN | |||||||
| Median (IQR) duration of follow- up years |
5.57 (2.37,9.92) | 5.19 (2.15,9.60) | 5.53 (2.35,9.87) | 5.26 (2.17,9.71) | 6.30 (2.89,10.75) | 4.39 (1.92,7.85) | |
| Number (%) of new IgAN cases | 113 (0.01) | 29 (0.01) | 100 (0.01) | 24 (0.01) | 13 (0.02) | 5 (0.04) | |
| Incidence of IgAN per 100,000 person years (95% CI) |
1.71 (1.42–2.06) | 2.28 (1.58–3.28) | 1.63 (1.34–1.98) | 1.99 (1.34–2.97) | 2.92 (1.70–5.03) | 7.33(3.05–17.62) | |
| Glomerular disease | |||||||
| Median (IQR) duration of follow- up, years |
5.57 (2.37,9.92) | 5.19 (2.15,9.60) | 5.52 (2.35,9.86) | 5.26 (2.17,9.71) | 6.29 (2.89,10.75) | 4.39 (1.93,7.85) | |
| Number (%) of new glomerular disease cases |
467 (0.05) | 93 (0.05) | 427 (0.04) | 83 (0.04) | 40 (0.06) | 10 (0.08) | |
| Incidence of glomerular disease per 100,000 person years (95% CI) |
7.08 (6.47–7.75) |
7.31 (5.96–8.95) |
6.94 (6.31–7.63) | 6.89 (5.56–8.54) | 8.98 (6.59–12.25) | 14.67 (7.89–27.26) | |
p<0.001 for all
19.78% and 20.37% of BMI data were missing in patients without and with psoriasis, respectively
20.45% and 20.46% of drinking data were missing in patients without and with psoriasis, respectively
9.96% and 10.20% of data on smoking habits were missing in patients without and with psoriasis, respectively
Townsend score is a proxy of socioeconomic status based on employment status, car/home ownership, and household overcrowding. A higher Townsend index score correlates with greater socioeconomic deprivation (lower socioeconomic status). 4.12% and 4.87% of data on Townsend score were missing in patient without and with psoriasis, respectively.
Congestive heart failure, coronary artery disease, myocardial infarction, or peripheral artery disease
Patients with moderate-to-severe psoriasis had higher incidence rates of IgAN and GD (Table 1). In fully adjusted models (Table 2), both mild and moderate-to-severe psoriasis groups were more likely to develop IgAN; however, this risk was only statistically significant for moderate-to-severe psoriasis (HR 4.75, 95% CI 1.92–11.76). In fully adjusted analyses, only patients with moderate-to-severe psoriasis were at a statistically significantly increased risk for developing GD (HR 2.05, 95% CI 1.10–3.84). The excess risk of IgAN and GD attributable to moderate-to-severe psoriasis was 1 in 8,888 and 1 in 10,562 patients, respectively.
Table 2.
Hazard Ratios for IgAN and glomerular disease in unadjusted models, adjusted models, and various sensitivity analyses
| N | Any psoriasis HR (95% CI) |
Mild psoriasis HR (95% CI) |
Moderate to severe psoriasis HR (95% CI) |
|||
|---|---|---|---|---|---|---|
| Unexposed | Psoriasis | |||||
| Primary unadjusted models | ||||||
| IgAN | 1,019,140 | 205,815 | 1.33 (0.88–2.00) | 1.16 (0.75–1.80) | 4.24 (1.73–10.38) | |
| Glomerular disease | 1.03 (0.83–1.29) | 0.97 (0.77–1.23) | 2.08 (1.11–3.88) | |||
| Primary fully adjusted models | ||||||
| IgAN1 | 1,019,140 | 205,815 | 1.37 (0.87–2.18) | 1.16 (0.70–1.92) | 4.75 (1.92–11.76) | |
| Glomerular disease2 | 1.04 (0.83–1.30) | 0.98 (0.78–1.24) | 2.05 (1.10–3.84) | |||
| Excluding patients with PsA | ||||||
| IgAN | 1,019,140 | 195,507 | 1.34 (0.83–2.15) | 1.20 (0.73–1.99) | 4.81 (1.52–15.26) | |
| Glomerular disease | 1.06 (0.84–1.33) | 0.99 (0.79–1.26) | 2.69 (1.33–5.40) | |||
| Restricting to patients with at least annual GP visits | ||||||
| IgAN | 970,990 | 192,912 | 1.38 (0.87–2.17) | 1.16 (0.70–1.92) | 4.59 (1.86–11.36) | |
| Glomerular disease | 1.03 (0.83–1.29) | 0.98 (0.77–1.23) | 1.97 (1.06–3.70) | |||
| Redefining outcome to also require a code for renal biopsy | ||||||
| IgAN | 1,019,140 | 205,815 | 2.00 (0.69–5.79) | 1.29 (0.36–4.63) | 11.84 (2.61–53.81) | |
| Glomerular disease | 0.87 (0.46–1.65) | 0.67 (0.32–1.39) | 4.34 (1.36–13.83) | |||
| Excluding patients with history of methotrexate use | ||||||
| IgAN | 1,018,292 | 197,182 | 1.32 (0.82–2.12) | 1.17 (0.71–1.92) | 7.92 (2.49–25.15) | |
| Glomerular disease | 1.04 (0.83–1.30) | 0.99 (0.78–1.25) | 3.68 (1.64–8.24) | |||
| Excluding patients with history of cyclosporine use | ||||||
| IgAN | 1,018,510 | 204,803 | 1.33 (0.83–2.12) | 1.10 (0.66–1.84) | 5.16 (2.09–12.78) | |
| Glomerular disease | 1.01 (0.81–1.27) | 0.99 (0.78–1.24) | 1.56 (0.74–3.28) | |||
| Excluding patients with a history of CKD | ||||||
| IgAN | 993,669 | 201,957 | 1.61 (1.00–2.59) | 1.34 (0.79–2.25) | 5.97 (2.40–14.85) | |
| Glomerular disease | 1.03 (0.82–1.30) | 0.96 (0.76–1.23) | 2.22 (1.18–4.15) | |||
Our age/sex/BMI adjusted model was the fully adjusted model. Initial multivariable models included other demographic variables (smoking/drinking habits and Townsend score) as well as risk factors for glomerular disease including hypertension, diabetes, hyperlipidemia, cardiovascular disease, arthritis, and NSAID use. None of these potential confounders altered point estimates significantly (a minimum of 10%), reducing our model back to the age/sex/BMI adjusted model.
Our age/sex adjusted model was the fully adjusted model. Initial multivariable models included demographic variables (BMI, smoking/drinking habits, and Townsend score) as well as risk factors for glomerular disease including hypertension, diabetes, hyperlipidemia, cardiovascular disease, arthritis, and NSAID use. None of these potential confounders altered point estimates significantly (a minimum of 10%), reducing our model back to the age/sex adjusted model.
Our results were robust to multiple sensitivity analyses (Table 2), suggesting that surveillance bias, outcome misclassification, and confounding from medications are unlikely to explain our findings. Unknown, unmeasured confounders are possible, although known risk factors for renal disease did not explain the association. The primary limitation was that IgAN and GD are statistically rare, thus our estimates have wide confidence intervals.
This work advances the literature by illustrating that the association between moderate-to-severe psoriasis and IgAN and glomerular disease is unlikely to be due to chance alone or to common confounders measured in routine clinical practice. Defects in host response to mucosal infections may predispose patients to both diseases, as streptococcal infections trigger and flare guttate psoriasis and may also incite or exacerbate pre-existing IgAN9,10. In contrast to the findings of Chiu et al., mild psoriasis was not associated with an increased risk for GD possibly due to inherent differences in study populations or varying outcome definitions.
In conclusion, patients with moderate-to-severe psoriasis have an increased risk of glomerular disease, particularly IgAN. Clinicians should maintain a high index of suspicion when patients present with renal dysfunction.
Acknowledgments
Statement of funding sources that supported work
This study was supported in part by the National Institutes of Health through K24AR064310 (JMG) and T32AR007465-32 (SKG and JW), K23AR068433 (JT), K23DK093556 (MRD) as well as an unrestricted grant from Pfizer to the trustees of the University of Pennsylvania (JMG).
Conflict of interest, disclosures
M.R. Denburg has received research funding from Genentech and Mallinckrodt (unrelated to this study) and has a consultancy agreement with Infiniti Medical
J. Takeshita has received a research grant from Pfizer (unrelated to this study) and payment for continuing medical education work related to psoriasis.
J.M. Gelfand: In the previous 12 months, Dr. Gelfand served as a consultant for Abbvie, Astrazeneca, Celgene Corp, Coherus, Eli Lilly, Janssen Biologics (formerly Centocor), Sanofi, Merck, Novartis Corp, Endo, and Pfizer Inc., receiving honoraria; and receives research grants (to the Trustees of the University of Pennsylvania) from Abbvie, Amgen, Eli Lilly, Janssen, Novartis Corp, Regeneron, and Pfizer Inc.; and received payment for continuing medical education work related to psoriasis. Dr. Gelfand is a co-patent holder of resiquimod for treatment of cutaneous T cell lymphoma
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