How do we use biologics in rheumatoid arthritis patients with a history of malignancy? An assessment of treatment patterns using Scandinavian registers.

Immune competence is of importance for the occurrence and outcome of malignancies, as exemplified by the effects of immune checkpoint inhibitors in the treatment of malignancies.[1] An increased risk for malignancies has been one of the main concerns since the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) for the treatment of chronic inflammatory arthritis. Most treatment guidelines have therefore issued caution against using bDMARDs (tumour necrosis factor inhibitors (TNFi) in particular) in patients with a history of cancer within 5–10 years. So far, most (though not all) studies of cancer incidence following treatment with TNFi and other bDMARDs, and of recurrence of pre-treatment cancers following treatment with TNFi, have been reassuring.[2-9] The 2015 ACR recommendations for treatment of rheumatoid arthritis (RA) recommend that patients with a history of previous solid organ malignancy should be treated as patients without this condition,[10] though acknowledging the low level of evidence, whereas previous recommendations suggested rituximab.[11] Similarly, there is no consensus regarding the time period from cancer diagnosis until the safe initiation of a bDMARD. Thus, scientific evidence supporting clinical decision-making in this context is scarce.

The aim of the present study was to assess the relative use of different bDMARDs in patients with RA and history of cancer. We used real-life data from the DANBIO (Denmark), ROB-FIN (Finland), NOR-DMARD (Norway) and ARTIS (Sweden) bDMARD registers. We identified patients with RA who initiated any bDMARD between year 2010–2017, regardless of type or number of prior bDMARDs. We identified patients with a clinical rheumatologist-assigned diagnosis of RA regardless of fulfilment of exact classification criteria. We identified the subgroup of patients with prior malignancy 10-year prior to starting the bDMARD in question through linkage to national cancer registers. Any malignancy (invasive or in situ) apart from benign tumours was defined as malignancy. Patients could contribute more than one treatment course. Both non-melanoma and melanoma skin cancer were included. The frequency of RA patients with a history of malignancy (according to the definition above) in each bDMARD group, as well as basic demographic and disease characteristics (age, gender, number of prior bDMARDs, years from cancer diagnosis until start of the bDMARD) was assessed across the different bDMARD groups. Switches from bio-original to biosimilar were regarded as one treatment.

A total of 42 638 RA patients initiating a bDMARD treatment were included (table 1). Initiators of non-TNFi biologics were generally older than TNFi-initiators, with the highest age at start for rituximab, especially in Sweden and Finland (table 1). Overall, among the bDMARD initiators in Denmark, Finland, Norway and Sweden, 344/11 230=3%, 288/4766=6%, 56/1876=3% and 1703/24 766=6.9%, respectively, had prior cancer. Whereas there was little variation across individual TNFi inhibitors ranging from 1% to 6%, the proportion of patients with a history of cancer at treatment start was higher among patients on non-anti-TNF bDMARDs, especially for rituximab (8–17%). The median time (years) since the cancer diagnosis ranged from 2 to 7 years, with a tendency towards a shorter time for rituximab (table 1).

Table 1

Number and characteristics of patients with RA starting a bDMARD, a TNF inhibitor or a non-TNF inhibitor, during 2010–2017, as well as number of those patients with a previous history of cancer 10-year prior to starting the bDMARD in question, distinguishing invasive and in situ cancer, across different bDMARDs. Data from four large Scandinavian biologics registers. Information when the number of patient was less than 5 is not presented

	TNF inhibitors					Non-TNF inhibitors
Patients (n)	Adalimumab	Certolizumab pegol	Etanercept	Golimumab	Infliximab	Abatacept	Rituximab	Tocilizumab
Denmark	1212	1444	2816	434	1528	1109	984	1703
Finland	666	428	1018	517	241	544	910	442
Norway	102	460	468	150	208	92	223	173
Sweden	2984	2012	6529	1861	2714	2701	3488	2477
TOTAL	4964	4344	10 831	2962	4691	4446	5605	4795
Any history of cancer	Adalimumab	Certolizumab pegol	Etanercept	Golimumab	Infliximab	Abatacept	Rituximab	Tocilizumab
Denmark N (%) patients with history of cancerN patients with in situ/invasive cancer	12 (1%)5/7	26 (1.8%)17/9	53 (1.9%)22/31	5 (1.2%)<5/<5	27 (1.8%)11/16	16 (1.4%)6/10	169 (17.2%)17/152	36 (2.1%)18/18
Finland N (%) of patients with any history of cancerN. patients with in situ/invasive cancer	16 (2.4%)1/15	16 (3.7%)2/14	35 (3.4%)2/33	20 (3.8%)2/18	8 (3.3%)3/5	44 (8%)5/39	118 (13%)3/115	31 (7%)2/28
Norway N (%) of patients with any history of cancerN. patients with in situ/invasive cancer	2 (2.0%)N/A	7 (1.5%)N/A	6 (1.3%)N/A	3 (2.0%)N/A	5 (2.4%)N/A	1 (1.0%)N/A	26 (11.7%)N/A	6 (3.5%)N/A
Sweden N (%) patients with any history of cancerN. patients with in situ/invasive cancer	152 (5.1%)61/91	108 (5.3%)31/77	397 (6.1%)142/255	83 (4.5%)38/45	139 (5.1%)59/80	186 (6.9%)63/123	493 (14%)98/395	145 (5.9%)45/100
ALL N (%) patients with any history of cancer	182 (3.7%)	157 (3.6%)	491 (4.5%)	111 (3.7%)	179 (3.8%)	247 (5.6%)	806 (14.4%)	218 (4.5%)
Time (years) since cancer*, median (IQR)	Adalimumab	Certolizumab pegol	Etanercept	Golimumab	Infliximab	Abatacept	Rituximab	Tocilizumab
Denmark	4 (2–5)	7 (2–7)	3 (2–6)	4 (4–7)	5 (2–7)	4 (2–7)	3 (1–6)	6 (3–8)
Finland	5 (4–6)	4 (2–5)	4 (2–6)	3 (1–6)	3 (2–6)	3 (4–6)	3 (2–6)	3 (1–5)
Norway	<5 patients	7 (5–8)	6 (3–9)	<5 patients	5 (2–9)	<5 patients	2 (2–5)	6 (2–8)
Sweden	4 (2–6)	4 (2–7)	4 (2–7)	4 (2–7)	4 (2–7)	4 (2–6)	3 (1–6)	4 (2–7)
Median (IQR) age at bDMARD start, years	Adalimumab	Certolizumab pegol	Etanercept	Golimumab	Infliximab	Abatacept	Rituximab	Tocilizumab
Denmark All History of cancer	56 (46–65)63 (55–70)	57 (48–66)52 (41–67)	59 (50–68)60 (47–73)	56 (45–66)60 (60–70)	60 (49–69)60 (47–73)	59 (50–68)63 (47–71)	61 (52–70)66 (58–73)	59 (50–69)61 (43–71)
Finland All History of cancer	51 (43–61)62 (56–70)	53 (44–62)63 (55–69)	52 (41–63)66 (59–70)	52 (43–62)67 (60–69)	48 (37–59)59 (54–62)	56 (48–65)65 (61–72)	63 (56–71)68 (61–75)	54 (51–61)66 (57–72)
Norway All History of cancer	52 (50–54)<5 patients	54 (53–55)64 (60–75)	53 (52–53)63 (57–75)	52 (50–53)<5 patients	55 (53–56)<5 patients	54 (53–56)<5 patients	58 (56–59)63 (58–69)	54 (53–55)67 (52–68)
Sweden All History of cancer	58 (46–67)67 (57–72)	58 (47–67)67 (52–74)	58 (46–67)67 (56–73)	58 (46–66)65 (50–71)	59 (48–67)65 (55–73)	61 (51–69)69 (61–75)	64 (54–72)68 (61–74)	59 (48–67)65 (58–73)
Female, %	Adalimumab	Certolizumab pegol	Etanercept	Golimumab	Infliximab	Abatacept	Rituximab	Tocilizumab
Denmark All History of cancer	78%83%	75%85%	77%85%	74%<5 patients	75%74%	79%75%	78%77%	77%78%
Finland All History of cancer	73%69%	75%88%	78%86%	76%80%	70%100%	84%91%	74%76%	78%71%
Norway All History of cancer	85%<5 patients	75%71%	76%100%	77%<5 patients	73%<5 patients	84%<5 patients	77%64%	84%71%
Sweden All History of cancer	76%79%	76%77%	77%78%	78%78%	74%72%	81%82%	76%71%	80%77%
Prior bDMARDs (n; median, IQR)	Adalimumab	Certolizumab pegol	Etanercept	Golimumab	Infliximab	Abatacept	Rituximab	Tocilizumab
Denmark All History of cancer	1 (0–2)0 (0–0)	1 (0–2)0 (0–0)	1 (0–2)0 (0–0)	1 (0–2)0 (0–1)	1 (0–2)0 (0–1)	1 (0–2)0 (0–0)	0 (0–2)0 (0–0)	1 (0–2)0 (0–0)
Finland All History of cancer	0 (0–1)0 (0–1)	1 (0–2)2 (1–4)	0 (0–1)0 (0–1)	0 (0–2)1 (0–3)	0 (0–1)0 (0–2)	1 (0–2)1 (0–2)	0 (0–2)0 (0–1)	2 (1–3)1 (0–3)
Norway All History of cancer	1 (0–1)<5 patients	0 (0–1)0 (0–0)	0 (0–1)1 (0–2)	1 (0–2)<5 patients	0 (0–1)<5 patients	3 (2–4)<5 patients	2 (1–2)0 (0–1)	2 (1–3)3 (1–3)
Sweden All History of cancer	1 (0–1)1 (0–2)	0 (0–2)0 (0–2)	0 (0–1)0 (0–1)	1 (0–1)1 (0–2)	0 (0–1)0 (0–1)	2 (1–3)1 (1–3)	1 (0–2)1 (0–2)	2 (1–3)2 (1–3)

*Time from cancer diagnosis was defined as the time from first diagnosis of cancer until the start of the bDMARD.

TNF, tumor necrosis factor; IQR, interquartile range; bDMARD, biologic disease-modifying anti-rheumatic drug; N/A, non-available.

As expected, we noted that the proportion of patients starting a bDMARD during the period 2010–2017 with a prior malignancy was low. Among these initiators, however, there was a clear preference for non-TNFi, in particular rituximab. The latter could in part be explained by differences in age at treatment start, as patients on rituximab tend to be older compared with patients on other bDMARDs. However, the small differences in median age among patients with history of cancer across the bDMARD groups under study supports the hypothesis that there is a preference for rituximab by clinicians for treatment of patients with history of cancer. Rituximab is being used for several haematological malignancies, which might at least partly explain the preference, although the underlying evidence for this preference in other types of cancers remains incomplete. Another interesting observation was that the proportion of female patients with a history of cancer was somewhat higher compared with patients with no history of cancer in the TNFi groups, but not in the non-TNFi group. A possible explanation for this could be the different choice of bDMARD in different types of cancer. Finally, there is heterogeneity not only in treatment channelling, but also due to different prescription patterns across countries.

Our results underscore both the reluctance to use bDMARDs and especially TNFi in RA patients with a history of malignancy, which implies a risk for undertreatment of some patients, and the need for more data on the benefit–risk ratio in this treatment context.

According to RA treatment recommendations, patients with a history of previous solid organ malignancy should be treated as patients without this condition, although the level of evidence is low.

This large multinational register-based study quantified the proportion of RA patients starting a bDMARD who had a prior malignancy (1–6%). This proportion was significantly higher for rituximab (8–17%), demonstrating a preference for rituximab in this patient population.

There is a reluctancy to use bDMARDs and especially TNF inhibitors in RA patients with a history of malignancy, which might imply a risk for undertreatment of some patients. This underscores the need for more data.