Relevance of laboratory investigations in monitoring patients with psoriasis on etanercept or adalimumab

Authors


  • Funding sources
    This was an investigator-initiated study. The Radboud University Nijmegen Medical Centre was supported in part by UMC St Radboud Foundation, who received funding from Wyeth Pharmaceuticals for the project. Wyeth Pharmaceuticals played no role in the design and conduct of the study, data collection, data management, data analysis, interpretation of the data, manuscript preparation, manuscript review or manuscript approval.

  • Conflicts of interest
    These are listed in Appendix 1.

Paula van Lümig.
E-mail: P.vanLumig@derma.umcn.nl

Summary

Background  Guidelines concerning biological treatment of patients with psoriasis recommend different pretreatment and monitoring laboratory panels in variable frequencies to monitor treatment.

Objectives  To investigate the relevance of laboratory investigations in monitoring patients with psoriasis on etanercept or adalimumab.

Methods  A prospective cohort study over 5 years was conducted in all consecutive patients with psoriasis on etanercept or adalimumab. All laboratory investigations performed for monitoring treatment were analysed. Laboratory abnormalities were graded according to the Common Terminology Criteria for Adverse Events v4.03. The primary endpoint was the percentage of patients with a grade 3 or grade 4 laboratory abnormality. The secondary endpoints were defined as: (i) significant changes in laboratory parameters during etanercept or adalimumab treatment and (ii) the percentage of patients having a laboratory abnormality requiring discontinuation of etanercept or adalimumab treatment.

Results  Laboratory parameters were available for 162 patients treated with etanercept and/or adalimumab. The number of treatment episodes was 155 for etanercept and 58 for adalimumab. Follow-up was 316 patient-years for etanercept and 54 patient-years for adalimumab. Thirty-eight of 146 patients treated with etanercept (26%) had one or more grade 3 and/or grade 4 laboratory abnormalities. For adalimumab, this was eight of 58 (14%). These were predominantly considered unrelated to biologic therapy. For both biologics, significant changes were observed in mean laboratory parameters during treatment compared with pretreatment as well as significant trends. However, mean values during treatment remained within normal ranges. Laboratory abnormalities did not lead to permanent discontinuation of biologic treatment in any patient.

Conclusions  In this cohort, the incidence of biologic therapy-related serious laboratory abnormalities was low. Our findings do not support a need for routine laboratory testing in patients with psoriasis on etanercept or adalimumab beyond the laboratory testing required for concomitant therapies or comorbidities.

Patients with psoriasis treated with biologics are monitored routinely with laboratory investigations according to existing guidelines.1–8 Several laboratory investigations including analysis of clinical chemistry (liver and kidney function tests) and haematology (full blood cell counts), urinalysis, hepatitis B/C and human immunodeficiency virus (HIV) serology, analysis of autoantibodies and a pregnancy test are recommended before the initiation of treatment. During biologic treatment, laboratory investigations are repeated periodically with variable panels and frequencies.1–8 Most guidelines advise laboratory investigations at pretreatment, after the start of therapy at 4–12 weeks and at 3–6-monthly intervals thereafter.7,8

However, the clinical relevance of these laboratory investigations remains to be determined. Moreover, a venipuncture is an invasive procedure for the patient and this procedure and the laboratory investigations involve healthcare costs. Therefore, the objectives of this study were to investigate (i) how frequently serious abnormal laboratory parameters were observed during etanercept or adalimumab treatment, (ii) significant changes in laboratory parameters during etanercept or adalimumab treatment and (iii) the percentage of patients having a laboratory abnormality requiring discontinuation of etanercept or adalimumab treatment. In addition, we investigated the relationship between serious abnormal laboratory parameters and the use of etanercept or adalimumab.

To meet the objectives, all laboratory investigations of a prospective cohort consisting of all consecutive patients with psoriasis treated with etanercept and/or adalimumab between February 2005 and April 2010 were analysed.

Patients and methods

Patients

All consecutive patients starting biological treatment for psoriasis in the Dermatology outpatient clinic of the Radboud University Nijmegen Medical Centre are enrolled in a prospective patient registry in which daily practice efficacy and pharmacovigilance data, including laboratory investigations, are collected. In the Netherlands, biological treatment was approved for the treatment of patients with psoriasis who had not responded to phototherapy, methotrexate and ciclosporin, or who had contraindications to or did not tolerate these therapies. Furthermore, a Psoriasis Area and Severity Index (PASI) of at least 10 was required.9

Laboratory investigations

At pretreatment, laboratory investigations included routine clinical chemistry and haematology analyses, determination of antinuclear antibodies (ANA), hepatitis B and C serology, a serum pregnancy test if applicable and a urinanalysis. General laboratory investigations were repeated at weeks 6 and 12, every 12 weeks afterwards and at other occasions when indicated (Table 1). Additional laboratory analyses were performed according to clinical signs and concomitant medication. All laboratory investigations were performed at the department of Laboratory Medicine or Medical Microbiology of the Radboud University Nijmegen Medical Centre.

Table 1.   Pretreatment and monitoring laboratory investigations
ChemistryHaematologyAdditional
  1. aThese laboratory tests were only performed at pretreatment. The other tests were performed at pretreatment, weeks 6 and 12 and every 12 weeks afterwards.

CreatinineHaemoglobinAntinuclear antibodiesa
C-reactive proteinHaematocritHepatitis B/C serologya
Direct bilirubinWhite blood cell count 
Total bilirubinWhite blood cell differentiationSerum pregnancy testa
Alkaline phosphatasePlatelet count 
Alanine aminotransferase  
γ-Glutamyl transferase  
Cholesterola  
Triglyceridesa  
Urinalysisa  

Methods

Treatments were analysed as separate treatment episodes. A treatment episode was defined as a new course of biological treatment or a restart after an interruption of at least 6 months.

In patients who were treated with both etanercept and adalimumab, laboratory investigations were analysed separately. In cases where patients had more than one treatment episode with the same biologic, laboratory investigations were analysed per treatment episode of that biologic.

For categorizing laboratory abnormalities, the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) of the National Cancer Institute of the U.S.A. were used (Table 2).10 Where the CTCAE criteria did not provide a classification, a grading scale was designed at our own discretion, as described in Table 2.

Table 2.   Grading scale for abnormal laboratory parameters
Laboratory parameterGrade
1a2b3c4d
  1. aGrade 1, mild adverse event (AE). bGrade 2, moderate AE. cGrade 3, severe AE. dGrade 4, life-threatening or disabling AE. eCommon Terminology Criteria for Adverse Events v4.03 grading scale. fGrading scale designed at our own discretion.

Creatinine (μmol L−1) increasede♂ > 110–165♂ > 165–330♂ > 330–660♂ > 660
♀ > 90–135♀ > 135–270♀ > 270–540♀ > 540
C-reactive protein (CRP) (mg L−1) increasedf≥ 10–29≥ 30–49≥ 50–99≥ 100
Direct bilirubin (μmol L−1) increasede> 5–7·5> 7·5–15> 15–50> 50
Total bilirubin (μmol L−1) increasede≥ 17–25≥ 26–50≥ 51–169≥ 170
Alkaline phosphatase (ALP) (U L−1) increasede> 120–300> 300–600> 600–2400> 2400
Alanine aminotransferase (ALT) (U L−1) increasede≥ 45–112≥ 113–224≥ 225–899≥ 900
γ-Glutamyl transferase (GGT) (U L−1) increasede♂ ≥ 50–124♂ ≥ 125–249♂ ≥ 250–999♂ ≥ 1000
♀ ≥ 35–87♀ ≥ 88–174♀ ≥ 175–699♀ ≥ 700
Haemoglobin (mmol L−1) decreasede♂ < 8·1–6·2♂ < 6·2–4·9♂ < 4·9–4·0♂ < 4·0
♀ < 7·3–6·2♀ < 6·2–4·9♀ < 4·9–4·0♀ < 4·0
White blood cell count (× 109 L−1) increased> 11·0–14·0f> 14·0–17·0f> 17·0–20·0f> 20·0f
White blood cell count (× 109 L−1) decreased< 3·5–3·0e< 3·0–2·0e< 2·0–1·0e< 1·0e
Neutrophils (%) increasedf> 70–75> 75–80> 80–85> 85
Neutrophils (%) decreasedf< 40–35< 35–30< 30–25< 25
Lymphocytes (%) increasedf> 40–45> 45–50> 50–55> 55
Lymphocytes (%) decreasedf< 20–15< 15–10< 10–5< 5
Monocytes (%) increasedf> 13–15> 15–17> 17–19> 19
Monocytes (%) decreasedf< 4–3< 3–2< 2–1< 1
Eosinophils (%) increasedf> 6–8> 8–10> 10–12> 12
Basophils (%) increasedf> 2–4> 4–6> 6–8> 8
Platelet count (× 109 L−1) increased> 350·0–400·0f> 400·0–450·0f> 450·0–500·0f> 500·0f
Platelet count (× 109 L−1) decreased< 120·0–75·0e< 75–50·0e< 50·0–25·0e< 25·0e

The primary endpoint was the percentage of patients having a grade 3 or grade 4 laboratory abnormality. The secondary endpoints were defined as (i) significant changes in laboratory parameters during etanercept or adalimumab treatment and (ii) the percentage of patients having a laboratory abnormality requiring discontinuation of etanercept or adalimumab treatment.

Laboratory parameters were analysed and represented separately for men and women when the grading scale differed for the two genders. The white blood cell differentiation into neutrophils, lymphocytes, monocytes, eosinophils and basophils was reported as percentages, as the percentage distribution of the different types of leucocytes should stay constant, irrespective of the absolute leucocyte count. Because of increased coefficients of analytical variation below the lower detection limits, C-reactive protein (CRP) results below 5 mg L−1, direct bilirubin results below 5 μmol L−1 and total bilirubin results below 10 μmol L−1 were not specified and were imputed as being 5, 5 and 10, respectively.

Alanine aminotransferase (ALT) results were analysed for all patients, and separately for the group of patients who were not on concomitant methotrexate or acitretin. In addition, CRP results were analysed for all patients and for the group of patients with and without concomitant psoriatic arthritis. Serum cholesterol and triglycerides were measured under nonfasting conditions and were used as indicators for further investigation.

Differences in mean laboratory parameters before the start of biologic treatment and during biologic treatment were analysed in all patients who were not on biologic treatment at the time they were screened for etanercept or adalimumab. In addition, trends in the course of the laboratory parameters were analysed using linear regression.

Statistics

Paired t-tests were performed for comparison of mean pretreatment laboratory results and mean results during treatment. < 0·05 was considered to be statistically significant. Linear regression was used to calculate regression coefficients with 95% confidence intervals (CI).

Results

Patient characteristics and treatment

Laboratory results were available for 162 patients with psoriasis who were treated with etanercept and/or adalimumab and were collected by 2077 different venipunctures. One hundred and three patients (64%) were male (Table 3). The mean age (± SD) was 50·9 (± 12·1) years and the mean duration of psoriasis (± SD) was 26·4 (± 12·9) years. Forty-six patients (28%) had psoriatic arthritis.

Table 3.   Patient characteristics
Patient characteristics= 162
Male gender, n (%)103 (64)
Age (years), mean ± SD50·9 (12·1)
Duration of psoriasis (years), mean ± SD26·4 (12·9)
Psoriatic arthritis, n (%)46 (28)

One hundred and forty-six patients were treated with etanercept and 58 patients with adalimumab (Table 4). Forty-two patients had been treated with both etanercept and adalimumab. Five patients were treated with etanercept during two separate treatment episodes and two patients had three etanercept treatment episodes. The total number of treatment episodes was 155 for etanercept and 58 for adalimumab. The mean treatment episode duration (± SD) was 2·0 (± 1·5) years for etanercept and 0·9 (± 0·5) years for adalimumab; the number of patient-years of follow-up was 316 for etanercept and 54 for adalimumab. The mean weekly dose was 60·0 mg for etanercept and 25·2 mg for adalimumab.

Table 4.   Treatment characteristics
 EtanerceptAdalimumab
Patients (n)14658
Treatment episodes (n)15558
Treatment episode durations (years)
 Mean ± SD2·0 (1·5)0·9 (0·5)
 Median (range)1·8 (0·07–5·2)0·9 (0·02–1·9)
Patient-years316·654·1
Mean weekly dose (mg)60·025·2

From 155 etanercept treatment episodes, 118 consisted of etanercept monotherapy, 26 consisted of etanercept combined with methotrexate (24 patients) and 11 consisted of etanercept combined with acitretin (11 patients). From 58 adalimumab treatment episodes, 43 consisted of adalimumab monotherapy, 13 consisted of adalimumab combined with methotrexate (13 patients) and two consisted of adalimumab with acitretin (two patients).

Patients used concomitant methotrexate or acitretin as bridge therapy when transitioning from the classic systemic treatment to biologic treatment, or as add-on therapy during the course of biologic treatment because of unsatisfactory efficacy. Methotrexate and acitretin as bridge therapies were applied for variable lengths of time, varying from 2 weeks to continuously throughout the course of biologic treatment.

Severe laboratory abnormalities during biologic treatment

All laboratory investigations categorized as grade 3 or 4 adverse events observed during etanercept or adalimumab treatment are represented in Table 5. Thirty-eight patients of 146 etanercept-treated patients (26%) had one or more grade 3 and/or grade 4 laboratory abnormalities. For adalimumab, this number was eight of 58 (14%).

Table 5.   Number of patients with grade 3 and grade 4 abnormal laboratory parameters during etanercept or adalimumab treatment
 Etanercept (= 146)Adalimumab (= 58)
Grade 3Grade 4Grade 3Grade 4
  1. aOne patient had an exacerbation of psoriasis, recent erysipelas, urinary tract infection and arthritis. The second patient had a nonspecified infection. bGrades 3 and 4 increased CRP were found in the same patients. One of these patients had an active arthritis and psoriasis. In the other patient, the increased CRP was assessed as possibly related to active psoriasis at one occasion and at the other occasion the patient had gastro enteritis. cIn all three patients the increased total bilirubin levels were pre-existing and transient. dPatient 1: pre-existent abnormal ALT activity, history of nonalcoholic fatty liver disease and alcohol use, partially transient. Patient 2: probably related to concomitant methotrexate use, partially transient after discontinuation of methotrexate. eProbably related to concomitant methotrexate use, partially transient after lowering the dose of methotrexate. fPatient 1: possibly related to alcohol use, partially transient. Patient 2: certainly related to alcohol abuse. gPatient 1: transient and probably related to alcohol use. Patient 2: pre-existing, partially transient and possibly related to fatty liver disease and diabetes mellitus. hTransient and probably related to alcohol use. iGrades 3 and 4 abnormal GGT activities were found in the same patient, certainly related to alcohol abuse. jPre-existing, partially transient, medical history of liver fibrosis. kIn patient with Felty syndrome. CRP, C-reactive protein; ALT, alanine aminotransferase; GGT, γ-glutamyltransferase.

CRP increased2a02b2b
Total bilirubin increased3c000
ALT increased2d01e0
GGT increased
 ♂2f01i1i
 ♀2g1h1j0
Leucocytosis3001
Leucopenia1k000
Neutrophilia8011
Neutropenia0100
Lymphocytosis13520
Lymphopenia1010
Monocytosis1k100
Monocytopenia1001
Eosinophilia0310
Thrombocytosis3311
Thrombocytopenia1k000

In all patients with grade 3 or grade 4 laboratory abnormalities of CRP, total bilirubin, ALT and GGT, the abnormal results were pre-existent, (largely) transient or considered more likely related to comorbidity or the concomitant use of methotrexate.

In 13 etanercept-treated patients (9%), severe haematological laboratory abnormalities were considered possibly or probably interrelated [grade 3 and/or 4 lymphocytosis (= 10), grade 3 lymphocytosis (= 1), grade 4 thrombocytosis (= 1), grade 3 leucopenia and grade 3 thrombocytopenia (= 1)]. In two patients on adalimumab (3%) the grade 3 lymphocytosis that developed during treatment was considered possibly related. Clinical consequences of these laboratory abnormalities are described in the section entitled ‘Laboratory abnormalities with clinical consequences’.

Laboratory parameters during etanercept treatment

Mean CRP, alkaline phosphatase (ALP), platelet counts and neutrophil percentages were significantly lower during etanercept treatment than at pretreatment (Table 6). ALP and neutrophil percentages also showed a significant declining trend.

Table 6.   The effect of etanercept on laboratory parameters
Laboratory parameterEtanercept
No. of treatment episodesaPretreatmentbDuring treatmentcP-valuedNo. of treatment episodeseRegression coefficient (95% CI)f
  1. aNumber of treatment episodes available for comparison of mean pretreatment laboratory results and mean results during treatment. bValues are mean pretreatment values ± SEM. cValues are mean values during treatment ± SEM. dP-value for difference between pretreatment value and value during treatment. eNumber of treatment episodes available for linear regression. fLinear regression coefficients with 95% confidence intervals (CI).

Creatinine (μmol L−1)12579 (1)79 (1)0·7801520·05 (−0·04 to 0·13)
C-reactive protein (mg L−1)1239·0 (0·8)6·4 (0·3)<0·001152−0·03 (−0·06 to 0·0008)
Direct bilirubin (μmol L−1)965·0 (0·02)5·0 (0·003)0·276150−0·0002 (−0·0006 to 0·0001)
Total bilirubin (μmol L−1)12412·1 (0·5)12·1 (0·4)0·9601520·007 (−0·01 to 0·02)
Alkaline phosphatase (U L−1)7186 (3)76 (2)<0·001135−0·26 (−0·45 to −0·07)
Alanine aminotransferase (U L−1)12435 (2)40 (2)<0·0011520·08 (0·007 to 0·16)
γ-Glutamyl transferase (U L−1)9240 (4)38 (3)0·306146−0·19 (−0·40 to 0·01)
Haemoglobin (mmol L−1)1258·9 (0·1)9·0 (0·1)<0·001152−0·001 (−0·008 to 0·006)
White blood cell count (× 109 L−1)1257·9 (0·2)7·6 (0·2)0·0731520·006 (−0·005 to 0·02)
Neutrophils (%)12465 (1)58 (1)<0·001152−0·12 (−0·20 to −0·04)
Lymphocytes (%)12425 (1)32 (1)<0·0011520·12 (0·03 to 0·21)
Monocytes (%)1246·2 (0·2)6·3 (0·1)0·597152−0·01 (−0·03 to 0·005)
Eosinophils (%)1242·6 (0·2)2·6 (0·1)0·9751520·002 (−0·005 to 0·009)
Basophils (%)1240·5 (0·04)0·7 (0·03)0·0021520·001 (−0·002 to 0·004)
Platelet count (× 109 L−1)125265 (7)244 (6)<0·001152−0·08 (−0·51 to 0·35)

Mean ALT, haemoglobin, lymphocyte and basophil percentages were significantly higher during etanercept treatment compared with pretreatment. For ALT activities and lymphocyte percentages, a significant increasing trend was also detected.

During etanercept therapy, all mean levels of laboratory parameters that were significantly different compared with pretreatment remained within normal reference ranges (Table 6).

In the group of patients who were not on concomitant methotrexate or acitretin treatment, mean (± SEM) ALT values also increased from 35 (± 2) U L−1 at pretreatment to 41 (± 2) U L−1 during etanercept therapy and linear regression also showed a significant incline [regression coefficient 0·11 (95% CI 0·03–0·19)].

Laboratory parameters during adalimumab treatment

Mean ALP and neutrophil percentages were significantly lower during adalimumab treatment than at pretreatment. Mean haemoglobin and lymphocyte percentages were significantly higher during adalimumab treatment than at pretreatment. No significant trends were observed (Table 7). During adalimumab therapy, all mean levels of laboratory parameters with a significant difference in pretreatment and treatment values remained within normal reference ranges.

Table 7.   The effect of adalimumab on laboratory parameters
Laboratory parameterAdalimumab
No. of treatment episodesaPretreatmentbDuring treatmentcP-valuedNo. of treatment episodeseRegression coefficient (95% CI)f
  1. aNumber of treatment episodes available for comparison of mean pretreatment laboratory results and mean results during treatment. bValues are mean pretreatment values ± SEM. cValues are mean values during treatment ± SEM. dP-value for difference between pretreatment value and value during treatment. eNumber of treatment episodes available for linear regression. fLinear regression coefficients with 95% confidence intervals (CI).

Creatinine (μmol L−1)1775 (4)72 (3)0·226540·001 (−0·1 to 0·1)
C-reactive protein (mg L−1)177·6 (1·1)6·0 (0·4)0·095540·008 (−0·07 to 0·09)
Direct bilirubin (μmol L−1)165·1 (0·1)5·1 (0)0·164530·001 (−0·004 to 0·006)
Total bilirubin (μmol L−1)1711·5 (1·1)10·4 (0·7)0·12954−0·04 (−0·1 to 0·02)
Alkaline phosphatase (U L−1)1773 (2)68 (2)0·02254−0·02 (−0·2 to 0·2)
Alanine aminotransferase (U L−1)1838 (4)36 (5)0·45154−0·1 (−0·4 to 0·08)
γ-Glutamyl transferase (U L−1)1735 (6)34 (7)0·81654−0·5 (−1·3 to 0·3)
Haemoglobin (mmol L−1)178·6 (0·2)8·8 (0·2)0·025540·03 (−0·004 to 0·06)
White blood cell count (× 109 L−1)178·3 (0·6)7·9 (0·5)0·296540·009 (−0·04 to 0·05)
Neutrophils (%)1665 (2)58 (2)0·00354−0·1 (−0·3 to 0·1)
Lymphocytes (%)1626 (2)34 (2)<0·001540·1 (−0·07 to 0·3)
Monocytes (%)165·8 (0·6)5·2 (0·4)0·35754−0·02 (−0·06 to 0·02)
Eosinophils (%)162·1 (0·3)1·9 (0·4)0·58754−0·006 (−0·03 to 0·02)
Basophils (%)160·5 (0·1)0·5 (0·1)0·872540·009 (−0·009 to 0·03)
Platelet count (× 109 L−1)17258 (18)247 (13)0·165540·1 (−0·5 to 0·7)

Laboratory abnormalities with clinical consequences

Laboratory abnormalities did not lead to permanent discontinuation of biologic treatment in any patient. Biologic treatment was temporarily interrupted in patients presenting with an infection clinically with or without elevated infection parameters. Elevated infection parameters during biologic treatment without clinical signs of infection occasionally led to temporary discontinuation.

Two patients (1%) required a temporary interruption of biologic treatment due to severe haematological laboratory abnormalities. One patient had a leucopenia (grade 1), neutropenia (grade 2) and lymphocytosis (grade 3) 4 months after the start of adalimumab treatment per label. Consequently, adalimumab was temporarily discontinued for 4 weeks, during which time the laboratory abnormalities returned to normal. The laboratory abnormalities did not recur during the subsequent year of adalimumab treatment.

Etanercept was interrupted temporarily in a patient with Felty syndrome due to a grade 3 leucopenia and a grade 3 thrombocytopenia 5 months after the start of etanercept at a dosage of 25 mg twice a week, which were considered possibly related. The laboratory abnormalities were partially transient.

C-reactive protein

Mean CRP was significantly lower during biologic treatment than at pretreatment, both in the group of patients with psoriatic arthritis and the group of patients without psoriatic arthritis. In the group of patients with psoriatic arthritis mean (± SEM) CRP decreased from 9·5 (± 1·2) mg L−1 at pretreatment to 6·4 (± 0·7) mg L−1 during biologic treatment (< 0·05). In the group of patients without psoriatic arthritis, mean (± SEM) CRP decreased from 8·5 (± 0·9) mg L−1 at pretreatment to 6·4 (± 0·3) mg L−1 during treatment (< 0·01).

Antinuclear antibodies

Etanercept

Seroconversion occurred in four patients during etanercept treatment, from negative to weakly positive in two patients, from negative to cytoplasmic dot pattern in one patient and from negative to 3+ in the fourth patient. None of these patients showed clinical signs of lupus erythematosus or other connective tissue diseases.

In two patients on etanercept, ANA was weakly positive at the time of screening for etanercept, but became 1+ positive (nucleoli and dot, respectively) during etanercept treatment. These patients did not have any signs or symptoms of autoimmune disease either.

In a third patient, autoimmune antibody patterns changed from positive anti-SS-A at screening to positive anti-SS-A and anti-SS-B during etanercept treatment. This patient turned out to have Sjögren disease in combination with psoriasis. The relation between this seroconversion and etanercept therapy was uncertain, and etanercept was continued. No other autoimmune antibodies or symptoms developed afterwards.

Adalimumab

Seroconversion occurred in two patients during adalimumab treatment from negative to weakly positive and from negative to 1+, respectively, without signs of autoimmune disease.

Discussion

Recommendations about laboratory testing in patients with psoriasis treated with biologics should be based on a consideration of the potential risks and benefits. To justify the patient burden of repeated venipunctures, possible further investigations and the use of healthcare resources, abnormal laboratory parameters should have clinical consequences and early detection and adjustment of treatment should result in a better outcome.6

In the present cohort, 38 patients treated with etanercept (26%) and eight patients treated with adalimumab (14%) had one or more grade 3 and/or grade 4 laboratory abnormalities. Severe laboratory abnormalities were mainly considered unrelated to the biologic therapy and changes in mean values remained within normal reference ranges.

Two patients (1%) required a temporary interruption of biologic treatment due to severe haematological laboratory abnormalities. Laboratory abnormalities did not lead to complete discontinuation of treatment, whereas a patient’s clinical signs and symptoms of, for example, infection without laboratory testing did lead to interruption or discontinuation of biologic treatment.

Confounders in this study were comorbidity and comedication, which were taken into account when assessing the relation between serious laboratory abnormalities and the biologic therapy. Severe laboratory abnormalities were mainly considered unrelated to the biologic, although a causal relation could not be excluded with certainty.

Laboratory panels for monitoring biologic therapy vary between guidelines, between guidelines and daily practice and between physicians. In addition, the frequency of testing differs considerably.1–8 In a literature review (using the Cochrane databases and MEDLINE) evaluating the evidence for screening and monitoring tests in patients with psoriasis on biologic therapy, the authors were unable to make definitive recommendations either in favour or against them based on the available literature.2 Current recommendations for laboratory screening and monitoring are mainly based on short-term clinical trials and literature reviews, rather than cohort studies examining the relevance of different laboratory screening and monitoring strategies.2

This study was based on prospectively collected laboratory data from a cohort of patients with psoriasis treated with biologics in daily practice for 5 years. As most patient-years of follow-up were available for etanercept and adalimumab, these therapies were evaluated.

A distinct finding in this study was a significant reduction in neutrophil counts for etanercept as well as adalimumab. This has been described previously in patients with inflammatory arthritides with a few patients developing a serious infection. In our cohort, no serious infections associated with neutropenia were seen.11

In the literature, elevated liver enzymes have been reported for anti-tumour necrosis factor (TNF) treatments.12–14 In the present cohort, a significant increase of mean ALT during etanercept treatment was found as well, but mean ALT activities did not exceed normal reference ranges. In the investigator judgement, severely elevated ALT activities in our cohort were more likely due to concomitant therapy or comorbid disorders than to the biologic treatment.

Renal impairment has commonly been reported during adalimumab treatment in clinical trials,13 but was not found in our cohort.

CRP decreased during biologic treatment in patients with and without psoriatic arthritis. This has been reported in several studies in the literature.15,16 Also, a correlation with the PASI score has been reported. With the CRP assay used (Architect; Abbott, Abbott Park, IL, U.S.A.), levels below 5 mg L−1 were not specified and were imputed as 5. Still, a significant decrease was measured during biologic treatment. The relevance of low levels of CRP could be discussed, although Ridker et al.17 showed that achieving CRP levels of < 2 mg L−1 is associated with a significant improvement in event-free survival in patients with acute coronary syndrome in their history, regardless of their levels of low-density lipoprotein cholesterol.

The purpose of laboratory investigations before starting treatment with biologics is to detect pre-existent abnormalities which form contraindications or risk factors for starting biologic therapy and to provide a baseline value. Baseline laboratory parameters are important for interpreting abnormal laboratory test results which evolve during biologic treatment in terms of clinical significance and causality. We therefore propose that the pretreatment laboratory panel should at least encompass the laboratory parameters assessed during treatment.

During treatment, the monitoring of ALT, GGT and CRP can be considered. ALT testing seems useful, as a small but statistically significant increase in ALT was detected during etanercept treatment. ALT and GGT testing is also important because of common comorbidities in patients with psoriasis affecting liver function tests, such as nonalcoholic fatty liver disease, diabetes and alcohol use. CRP testing can be considered to detect infections, although most patients have infections in the interval between hospital visits.

Monitoring of the full blood cell count and white blood cell differentiation can also be considered, as some severe haematological abnormalities and statistically significant declining trends were observed in our cohort. Previously these adverse effects have also been described in the literature and in the Summary of Product Characteristics of etanercept and adalimumab.12,13

In the present study no (biologic therapy-related) severe laboratory abnormalities or clinically significant changes of creatinine, direct and total bilirubin and ALP were found during treatment. Hence, routine laboratory monitoring of these parameters does not seem useful.

A positive ANA is nonspecific and does not preclude a patient from starting biologic therapy. However, in our opinion, it is important to have a baseline test result, as seroconversion of ANA during TNF-α blocking therapy is a known phenomenon and rarely patients with a lupus-like syndrome have been reported in the literature.18 ANA can then be reassessed in case of signs or symptoms of lupus erythematosus.

A pregnancy test performed at pretreatment is recommended, as data on the use of biologic therapies during pregnancy are still sparse, together with data associating TNF antagonists with VACTERL.8

HIV testing is recommended to be performed at screening only in patients at risk and hepatitis B and C testing is recommended to be performed in all patients at screening, although there is insufficient evidence to support this.1,2,4,5,7,8

The literature review of Huang et al.2 recommended against a standard urinalysis. Although not analysed in this study, we would suggest evaluating urine by strip analysis before starting treatment to have a baseline value and to repeat urinalysis only when there is clinical suspicion and symptoms of a urinary tract infection.

This study does not support routine laboratory testing in patients with psoriasis treated with biologics beyond the laboratory testing required for concomitant antipsoriatic systemic medication or comorbidities. Routine testing every 3 months may not be necessary either. However, this has not been investigated in other prospective studies. Additional evidence in a larger group of patients with a longer follow-up and future implementation studies could provide more evidence as to which laboratory panels and intervals are appropriate.

At least as important as laboratory testing is obtaining an appropriate history and physical examination to estimate potential risks for the individual patient when deciding on treatment and monitoring strategies.

What’s already known about this topic?

  •  There are no evidence-based studies examining strategies for laboratory monitoring in patients with psoriasis on biologics. Current recommendations for pretreatment and monitoring laboratory testing are mainly based on short-term clinical trials and literature reviews.

What does this study add?

  •  This study was based on prospectively collected laboratory data from a cohort of patients with psoriasis treated with biologics in daily practice for 5 years.

Appendix

Appendix 1

P.P.M. van Lümig carries out clinical trials for Abbott and Janssen-Cilag, has received speaking and consulting fees from Wyeth and Schering-Plough and has received reimbursement for attending a symposium from Schering-Plough and Pfizer.

R.J.B. Driessen has received funding from Merck Serono and carried out clinical trials for Wyeth, Schering-Plough, Centocor, Abbott, Merck Serono and Barrier Therapeutics, has received speaking and consulting fees from Wyeth and Schering-Plough and has received reimbursement for attending a symposium from Merck Serono, Wyeth and Janssen-Cilag.

M.A.M.A. Roelofs-Thijssen has no conflicts to declare.

J.B.M. Boezeman has no conflicts to declare.

P.C.M. van de Kerkhof serves as a consultant for Schering-Plough, Celgene, Centocor, Allmirall, UCB, Wyeth, Pfizer, Sofinnova, Abbott, Actelion, Galderma, Novartis, Janssen-Cilag and LEO Pharma and receives research grants from Centocor, Wyeth, Schering-Plough, Merck Serono, Abbott and Philips Lighting.

E.M.G.J. de Jong served as a consultant for Biogen, Merck Serono, Wyeth and Abbott and has received research grants from or was involved in clinical trials from Schering-Plough, Abbott, Merck Serono, Wyeth, Centocor and Janssen-Cilag.

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