Occurrence of adverse events associated with the initiation of methotrexate and biologics for the treatment of psoriasis in routine clinical practice

Figures & data

Table 1. Baseline characteristics of PsO/PsA patients initiating biologics or methotrexate treatment.

	Biologics N = 909	Methotrexate N = 5385
Age in years; mean [SD]	46 [14]	51 [15]
Sex (Women), n (%)	405 (45%)	2550 (47%)
Psoriasis Type, n (%)
PsO	476 (52%)	3726 (69%)
PsO with PsA	433 (48%)	1659 (31%)
Pharmacological agent, n (%)
Adalimumab	417 (46%)	–
Etanercept	284 (31%)	–
Secukinumab	88 (10%)	–
Ustekinumab	61 (7%)	–
Infliximab	31 (3%)
Other biologics	28 (3%)	–
Methotrexate	–	5385 (100%)
Route of administration
Oral (tablet)	–	5008 (93%)
subcutaneous	–	377 (7%)
eGFR ml/min/1.73m2; mean [SD]	96 [19]	93 [18]
eGFR categories, n (%)
> =60 ml/min/1.73m^2	727 (80%)	4683 (87%)
30-59 ml/min/1.73m^2	13 (1.4%)	199 (3.7%)
<30 ml/min/1.73m^2	7 (0.8%)	14 (0.3%)
missing	162 (18%)	489 (9%)
Comorbid conditions, n (%)
Hypertension	199 (22%)	1327 (25%)
Diabetes Mellitus	90 (10%)	448 (8%)
Myocardial infarction	17 (2%)	118 (2%)
Peripheral arterial disease	9 (1%)	95 (2%)
Cerebrovascular disease	15 (2%)	131 (2%)
Heat Failure	17 (2%)	111 (2%)
Atrial fibrillation	20 (2%)	148 (3%)
Acute kidney injury (past 6 months)	0 (0%)	7 (0.1%)
Chronic kidney disease diagnosis	17 (2%)	50 (1%)
Cancers (past 2 years)	8 (0.9%)	117 (2.2%)
Liver disease	27 (3 %)	45 (1%)
Fatty liver disease	4 (0.4%)	13 (0.2%)
Subacute liver failure	0 (0%)	1 (<0.1%)
Other unspecified liver diseases	23 (2%)	31 (0.6%)
Mild infections (past 6 months)	47 (5%)	288 (5%)
Severe infections (past 6 months)	18 (2%)	69 (1%)
Other treatments for psoriasis in past 6 months,n (%)
Topical corticosteroids	475 (52%)	3363 (62%)
Topical calcineurin inhibitors	38 (4%)	237 (4%)
Other systemic agents	180 (20%)	907 (17%)
Sulfasalazine	46 (5%)	148 (2%)
Alitretinoin	37 (4%)	224 (4%)
Leflunomide	3 (0.3%)	3 (<0.1%)
Apremilast	58 (6%)	44 (01%)
Dimethyl fumarate	1 (0.1%)	3 (<0.1%)
Ciclosporin	7 (0.8%)	16 (0.3%)
Other ongoing medications, n (%)
RASi	158 (17%)	982 (18%)
Diuretic	48 (5%)	349 (6%)
Beta-blocker	88 (10%)	586 (11%)
Lipid-lowering	74 (8%)	597 (11%)
Anti-diabetics	66 (7%)	341 (6%)
Systemic glucocorticoids	127 (14%)	658 (12%)
Antimicrobials	188 (21%)	1234 (23%)
NSAIDs	355 (39%)	1738 (32%)
C-reactive protein (mg/dL) categories, n (%)
<1 mg/dL	116 (13%)	555 (10%)
≥1-<3 mg/dL	234 (26%)	952 (18%)
≥3-<10 mg/dL	146 (16%)	997 (19%)
≥10 mg/dL	69 (8%)	532 (10%)
Missing	344 (38%)	2349 (44%)
Hemoglobin g/dL, n (%)
<10 g/dL	7 (0.8%)	30 (0.6%)
> =10 g/dL	727 (80%)	4693 (87%)
Missing	175 (19%)	662 (12%)
AST (IU/L), n (%)
Normal (<100 IU/L)	479 (53%)	3671 (68%)
Mild elevation (100–249 IU/L)	9 (1.0%)	24 (0.4%)
Moderate elevation (250–2000 IU/L)	2 (0.2%)	5 (<0.1%)
Large elevation (>2000 IU/L)	0 (0%)	2 (<0.1%)
Missing	419 (46%)	1683 (31%)
ALT (IU/L), n (%)
Normal level (<100 IU/L)	736 (81%)	4835 (90%)
Mild elevation (100–249 IU/L)	13 (1.4%)	94 (1.7%)
Moderate elevation (250–2000 IU/L)	5 (0.6%)	6 (0.1%)
Large elevation (>2000 IU/L)	0 (0%)	2 (<0.1%)
Missing	155 (17%)	448 (8.3%)

Abbreviations: eGFR: estimated glomerular filtration rate; PsO: psoriasis; PsA: psoriatic arthritis; RASi: Renin-angiotensin system inhibitors; NSAIDs: non-steroidal anti-inflammatory drugs; AST: aspartate aminotransferase; ALT: alanine aminotransferase.

Table 2. Follow-up time, number of events, incidence rates and relative risk for the association between biologics vs. methotrexate and study outcomes.

Composite adverse event safety outcome	Biologics			Methotrexate			^bIPTW HR (95% CI); Methotrexate vs. Biologics
	Follow-up time year, mean (SD)	No. events / No. persons	^aIR × 1000 PY (95% CI)	Follow-up time year, mean (SD)	No. events / No. persons	^aIR × 1000 PY (95% CI)
Renal
Acute kidney injury	2.0 (2.2)	3/909	1.6 (0.3–4.7)	1.7 (1.9)	16/5385	1.8 (1.0–2.9)	0.53 (0.1–2.88)
^cLaboratory-based CKD progression	3.7 (3.2)	11/909	3.2 (1.6–5.7)	5.5 (3.9)	139/5385	4.7 (3.9–5.5)	1.03 (0.48–2.22)
^cClaims-based CKD	3.6 (3.2)	13/909	3.8 (2.0–6.5)	5.5 (3.9)	154/5385	5.2 (4.4–6.1)	1.06 (0.53–2.14)
Hematological
Any anemia	1.7 (2.1)	206/909	60.3 (52.3–69.1)	1.1 (1.6)	1759/5385	59.1 (56.3–61.9)	1.79 (1.48–2.16)
Mild-moderate anemia	1.9 (2.1)	96/909	57.1 (46.3–69.8)	1.3 (1.7)	897/5385	124.3 (116.3–132.7)	1.93 (1.49–2.5)
Severe anemia	2.0 (2.2)	30/909	16.2 (10.9–23.2)	1.6 (1.9)	100/5385	11.4 (9.3–13.9)	0.67 (0.45–1.01)
Aplastic anemia	1.6 (2.2)	3/909	0.9 (0.2–2.6)	1.6 (2.0)	7/5385	0.2 (0.1–0.5)	0.39 (0.12–1.34)
Serious infections	2.0 (2.2)	10/909	5.3 (2.6–9.8)	1.6 (1.9)	46/5385	5.2 (3.8–7.0)	0.89 (0.39–2.01)
Hepatic
Mild	1.9 (2.1)	71/909	38.0 (29.6–47.9)	1.5 (1.8)	550/5385	62.6 (57.5–68.1)	1.46 (1.03–2.06)
Moderate-severe	2.0 (2.2)	17/909	9.1 (5.3–14.6)	1.6 (2.0)	102/5385	11.6 (9.5–14.1)	2.22 (1.19–4.15)
Major GI AEs	2.0 (2.2)	8/909	4.3 (1.9–8.4)	1.6 (1.9)	32/5385	3.6 (2.5–5.1)	0.62 (0.25–1.59)
Severe Allergic hypersensitivity reactions	2.0 (2.2)	0/909	0.0 (0.0–0.0)	1.6 (2)	2/5385	0.2 (0.0–0.8)	^cNA

^aNumber of events, person-years, and incidence rates were calculated in the original unweighted population.

^bAnalyses were adjusted for the following variables: age, sex, eGFR, psoriasis type, hypertension, diabetes, myocardial infarction, heart failure, atrial fibrillation, liver disease, mild infections (6 months prior), moderate-severe infections (6 months prior), history of cancer, CKD diagnosis, AKI (6 months prior), topical treatment (corticosteroids, topical calcineurin inhibitors), other systemic Pso/PsA treatment (sulfasalazine, acitretin, leflunomide, apremilast, dimethyl fumarate, cyclosporine), other medications (ACEi/ARB, beta-blocker, Lipid-lowering, anti-diabetics, systemic glucocorticoids, antimicrobials, NSAID), hs-CRP, Hb, AST, ALT and year of treatment initiation.

^cFor outcome CKD, individuals were analyzed according to their initially assigned treatment group irrespective of discontinuation, treatment switch, or enrichment (intention-to-treat approach).

^dHR cannot be calculated due to zero event in a reference group.

Abbreviations: CKD: chronic kidney disease, GI: gastrointestinal, AEs: adverse events.

Figure 1. Absolute Risk, absolute risk difference (ARD), and estimated number needed to harm (NNH) for each composite adverse event safety outcome in PsO/PsA patient initiating methotrexate and biologics at 1, 3, and 5 years of therapy. The Nelson- Aalen estimator derived absolute risk estimates from cumulative incidence curves. Risk differences are shown per 1000 persons and rounded to the nearest integer.

^aNNH can be interpreted as the number of subjects that would be required to start methotrexate (and not biologics) to observe 1 excess adverse event.

Abbreviations: CKD: chronic kidney disease; ARD: absolute risk difference; NNH: number needed to harm; b) Indicates that a negative number is needed to harm, arising when methotrexate has lower adverse event risks than biologics.

Analyses were adjusted for: age, sex, eGFR, psoriasis type, hypertension, diabetes, myocardial infarction, heart failure, atrial fibrillation, liver disease, mild infections (6 months prior), moderate-severe infections (6 months prior), history of cancer, CKD diagnosis, AKI (6 months prior), topical treatment (corticosteroids, topical calcineurin inhibitors), other systemic Pso/PsA treatment (sulfasalazine, acitretin, leflunomide, apremilast, dimethyl fumarate, cyclosporine), other medications (ACEi/ARB, beta-blocker, Lipid-lowering, anti-diabetics, systemic glucocorticoids, antimicrobials, NSAID), hs-CRP, Hb, AST, ALT and year of treatment initiation.

Figure 2. Weighted cumulative incidence plots for the selected adverse event occurring during the use of biologics or methotrexate in routinely cared patients with PsO/PsA. Shaded areas represent 95% confidence intervals.

Data availability statement

The SCREAM project contains sensitive personal data that as per GDPR regulations cannot be publicly shared. We however welcome collaborative project proposals that abide to GDPR, national and institutional regulations for data sharing and data access. For enquiries, please contact [email protected].