Abstract
Objectives
To evaluate the outcomes of adalimumab (ADA) treatment of patients with non-infectious uveitis and scleritis, focusing on efficacy, retention rate, and safety.
Methods
This retrospective, clinical cohort study included 62 patients (104 eyes) with active ocular inflammation treated with ADA. Primary outcomes were efficacy and cumulative drug retention rate (DRR) of ADA. The secondary outcomes included changes in ocular inflammatory parameters, changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT), corticosteroid-sparing effect, impact of concomitant use of disease-modifying antirheumatic drug (DMARD) and ADA as first or ≥2nd biotherapy line on DRR, and adverse events.
Results
Forty-five patients (72.6%) achieved inactive disease at the end of follow-up. DRR at 6, 12, 24, and 48 months was 96.8%, 89.2%, 63.1%, and 63.1%, respectively. Of the 18 patients whose bi-weekly ADA treatment was escalated to weekly ADA due to primary or secondary inefficacy, 10 patients had inactive disease finally. BCVA improved (p < 0.001) and CMT decreased (p < 0.001) significantly at 6, 12, and 24 months after ADA therapy compared to baseline. Percentage of patients treated with ≥10 mg/day corticosteroid (61.3% vs. 6.4%) and DMARDs combined with ADA (46.8% vs. 37.1%) were lower at 6 months than at baseline. Concomitant DMARDs (p = 0.579) and use of ADA as first or ≥2nd biotherapy line (p = 0.527) had no significant effect on DRR. Most common adverse event was tuberculosis-related infections.
Conclusions
ADA seems to be effective and safe with good DRR to control ocular inflammation. Escalation to weekly ADA treatment may be an effective option in patients with primary or secondary inefficacy.
Subject terms: Uveal diseases, Outcomes research
Introduction
Tumour necrosis factor-alpha (TNF-α) is the main proinflammatory cytokine that activates various immune cells and mediates multiple pathways of inflammation [1]. TNF-α is thought to have a central role in the pathogenesis of many autoimmune diseases such as NIU [2]. TNF-α has been found to be at high levels in the serum and aqueous of patients with uveitis [3] and has therefore become one of the main therapeutic targets. Currently, anti-TNF biologics are considered novel drugs in the management of patients with NIU when corticosteroids and immunosuppressive treatments are not effective or poorly tolerated. Anti-TNF drugs are also shown to be effective in the treatment of ocular inflammatory diseases such as non-infectious scleritis [4, 5].
Large multicentre studies demonstrated ADA was effective in controlling ocular inflammation in patients with NIU and reduced the requirement for steroids [2, 6, 7]. In this manner, ADA has become a second-line therapy over conventional steroid-sparing therapy, especially for the treatment of severe and vision-threatening uveitis [8]. Nevertheless, it is stated that the formation of anti-drug antibodies may affect the efficacy of anti-TNF treatment over time [9].
Drug retention rate (DRR) is considered a measure representing the balance between the efficacy and safety of biological agents and reflects the long-term therapeutic efficacy and probability of treatment persistence [9, 10]. To date, few studies have been published evaluating the retention rate of ADA in patients with ocular inflammatory disease [11–14]. On the other hand, the variations in characteristics of patients included in observational studies and physicians’ preferences for treatment discontinuation may lead to different outcomes.
The aim of this study was to present our experience in the efficacy, retention rate, and safety of ADA treatment in patients with NIU and scleritis at the tertiary referral centre in a real-world setting.
Methods
Patient population and study design
This retrospective, observational, single-centre study included 62 patients (104 eyes) with NIU or scleritis treated with ADA for at least 6 months between 2015 and 2022 at our tertiary referral uveitis center. The study was approved by the local Institution Ethics Committee and conducted in accordance with tenets of the Declaration of Helsinki. All patients received systemic and/or local corticosteroids at the time of diagnosis of uveitis. Before the onset of ADA treatment, patients had uncontrolled ocular inflammation and failed with or without other immunosuppressive drugs such as immunomodulatory therapy, other biologics, or combination therapy (Supplementary Table 1). Patients with follow-up of less than 6 months and lacking data on parameters were excluded from the study. Baseline collected data included the following: age, sex, duration of disease, anatomical classification of uveitis [15], aetiology of uveitis, laterality of involvement, prior and ongoing corticosteroid (local or systemic) and disease-modifying anti-rheumatic drugs (DMARDs). At each visit, all patients underwent a detailed ophthalmologic examination including; assessment of best corrected visual acuity (BCVA), slit-lamp examination, dilated fundus examination, and spectral-domain optical coherence tomography (SD-OCT; Spectralis, Heidelberg Engineering, Heidelberg, Germany). The inflammatory status of each eye and grade of the anterior chamber (AC) or vitritis were evaluated according to the Standardization of Uveitis Nomenclature criteria [15].
Before ADA treatment, patients underwent extensive work-up including complete blood count, complete urine examination, liver and renal function tests, serological tests (for Hepatitis B and C, HIV, Toxoplasma and Syphilis), chest X-ray, tuberculin skin test and Quantiferon test. All patients were consulted to the infectious diseases and internal medicine departments for treatment approval. Isoniazid prophylaxis was started 4 weeks before ADA treatment in patients with suspected latent tuberculosis (TB). Adult patients and children weighing ≥30 kg received a standard 40 mg bi-weekly ADA one week after the loading dose of 80 mg, whereas children weighing <30 kg were treated with 20 mg bi-weekly ADA without a loading dose. As an exception, 40 mg weekly ADA was started after a loading dose (weekly ADA protocol) in adult patients with severe ocular inflammation at baseline. Before the initiation of ADA, the dose of the drugs was adjusted or discontinued in patients receiving corticosteroids or DMARDs. All patients were followed up regularly in our uvea clinic for ophthalmological examination and by rheumatologists for systemic inflammation.
Response to treatment was evaluated in all patients within 3 to 6 months after the initiation of ADA. Inadequate regression of inflammation, unsuccessful tapering of systemic corticosteroid therapy (>10 mg/day), and administration of local corticosteroid injection was accepted as primary inefficacy. Inactive disease was a clinical decision made by uveal disease specialist that was based on no signs of ocular inflammation for 3 months during ADA treatment (with or without concomitant use of DMARDs) and successful tapering of systemic corticosteroid therapy (≤10 mg/day) and no local steroid injections within past 3 months. Relapse was defined as new fluorescein leakage on angiography (e.g., retinal vessels, chorioretinal lesions, optic disc, macula), two-step increase in anterior chamber or vitritis grade, and presence of new scleral inflammation for patients with scleritis. Secondary inefficacy was defined as the occurrence of relapse after inactive disease was achieved. Treatment was considered successful if ocular inflammation was controlled for both eyes. In case of inefficacy, primarily, ADA injection intervals were reduced or DMARD was added depending on the level of ocular inflammation. If ocular inflammation could not be controlled, ADA was switched to other biologics. ADA was discontinued in the event of inadequate efficacy, severe relapse, patient request, or serious adverse events. The reason for discontinuation of treatment and the duration between initiation and discontinuation of ADA were recorded.
Outcomes
The primary outcome of this study was the efficacy of ADA treatment. Efficacy was measured by the number of patients achieving inactive disease and cumulative ADA retention rate. Retention rate was defined as the proportion of patients who were on ADA at the time of assessment and retention time was evaluated as the duration to definitive treatment discontinuation. The cumulative ADA retention rate was calculated at 6th, 12th, 24th, and 48th months of follow-up.
The secondary outcomes included (i) changes in ocular inflammatory parameters (grade of AC and vitritis, and presence of cystoid macular oedema [CMO]), (ii) changes in BCVA and central macular thickness (CMT), and (iii) corticosteroid-sparing effect and changes in concomitant DMARDs. Evaluation time points of these outcome variables were at baseline and 6th, 12th, and 24th months after the initiation of ADA therapy. Other secondary outcomes were (iv) impact of concurrent DMARDs and biologic treatment line (first vs. ≥2nd biotherapy line) on DRR and (v) drug-related adverse events. BCVA was assessed with electronic Snellen chart and converted into a logarithm of the minimal angle of resolution visual acuity values (logMAR) for analysis. CMT was measured automatically by software on SD-OCT. The success of the corticosteroid-sparing effect was defined as a reduction of the corticosteroid dose to ≤10 mg [15].
Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences for Windows version 22.0 (IBM Crop., Armonk, NY, USA). Data were evaluated per patient or per eye at the time points, depending on the relevant outcome. Categorical data were presented as frequency (n) and percentage (%), and numerical variables were presented as the mean and standard deviation (SD) or the median and interquartile range (IQR). Wilcoxon signed-rank test was used to compare the continuous variables. DRR was assessed using Kaplan-Meier survival curves, and the event was determined as definitive discontinuation of ADA. Comparison of survival curves was performed using Log-rank (Mantel-Cox). A p-value of less than 0.05 was considered statistically significant.
Results
Demographic and clinical characteristics
A total of 62 patients (104 eyes) treated with ADA were enrolled in the study, of whom 39 (62.9%) were male and 23 (37.1%) were female. The mean age was 35.81 ± 13.45 (range, 9–66) years, and the median (IQR) duration of disease prior to ADA initiation was 24.00 (53.75) months. The detailed demographics and clinical characteristics of the patients are summarized in Supplementary Table 1.
Primary outcomes
Efficacy: inactive disease and cumulative retention rate
The median (IQR) duration of ADA treatment was 16.00 (12.50) (range, 6–108) months. Forty-seven patients (75.8%) had received ADA for ≥12 months and 20 patients (32.3%) for ≥24 months. The number of patients who had inactive disease under ADA treatment was forty-six (74.2%) at 6 months, 36 (76.6%) at 12 months, and 17 (85.0%) at 24 months (Table 1).
Table 1.
Changes in outcome variables of patients after adalimumab treatment.
| Variables | Baseline | 6 months | 12 months | 24 months |
|---|---|---|---|---|
| Number of patients (eyes) | 62 (104) | 62 (104) | 47 (77) | 20 (32) |
| Inactive ocular inflammation, n (%), patients | 0 (0.0) | 46 (74.2) | 36 (76.6) | 17 (85.0) |
| AC cell grade, n (%), eyes | ||||
| ≤0.5+ | 61 (58.6) | 97 (93.3) | 73 (94.8) | 31 (96.9) |
| >0.5+ | 43 (41.4) | 7 (6.7) | 4 (5.2) | 1 (3.1) |
| Vitreous cell grade, n (%), eyes | ||||
| ≤0.5+ | 68 (66.1) | 97 (93.3) | 70 (90.9) | 30 (93.7) |
| >0.5+ | 36 (33.9) | 7 (6.7) | 7 (9.1) | 2 (6.3) |
| CMO, n (%), eyes | ||||
| Present | 24 (23.1) | 9 (8.7) | 3 (3.9) | 2 (6.3) |
| Absent | 80 (76.9) | 95 (91.3) | 74 (96.1) | 30 (93.7) |
| Systemic corticosteroids, n (%), patients | ||||
| Mean (SD) dose, mg/day | 23.35 (25.35) | 4.25 (13.39) | 0.68 (2.80) | 0 |
| ≥10 mg/day | 38 (61.3) | 4 (6.4) | 1 (1.6) | 0 (0.0) |
| <10 mg/day | 3 (4.8) | 2 (3.2) | 2 (3.2) | 0 (0.0) |
| Concomitant DMARDs use, n (%), patients | ||||
| No | 33 (53.2) | 39 (62.9) | 31 (66.0) | 13 (65.0) |
| Yes | 29 (46.8) | 23 (37.1) | 16 (34.0) | 7 (35.0) |
ADA adalimumab, AC anterior chamber, CMO cystoid macular oedema, SD standard deviation, DMARDs disease-modifying antirheumatic drugs.
Primary inefficacy was observed in 11 patients (19.4%). Of these 11 patients, bi-weekly ADA was escalated to weekly ADA in 9 patients. Azathioprine was added in 1 patient, and treatment was switched from weekly ADA (initial protocol) to infliximab in 1 patient due to primary inefficacy.
One or more relapses occurred in 19 patients (30.6%) during follow-up. The median (IQR) duration between the initiation of ADA and the first relapse was 11.00 (12.00) months. ADA was discontinued in one patient by the rheumatology department due to systemic exacerbation. However, ADA was restarted due to ocular relapse and this patient achieved inactive disease at the last visit. In 18 patients with secondary inefficacy, bi-weekly ADA escalated to weekly ADA (n = 9), or ADA was switched to infliximab (n = 7), or azathioprine was added (n = 2).
In total, bi-weekly ADA was escalated to weekly ADA in 18 patients, and 10 of these patients achieved inactive disease. In 5 of 18 patients, weekly ADA was continued despite not achieving inactive disease, since ocular inflammation significantly regressed after the treatment change. In addition, in 3 patients who initially received weekly ADA treatment, ADA was discontinued due to primary or secondary inefficacy.
During follow-up, 15 patients discontinued ADA permanently and 3 patients temporarily. The cumulative retention rate was 96.8% at 6 months, 89.2% at 12 months, 63.1% at 24 months, and 63.1% at 48 months (Fig. 1). The median duration of ADA treatment in patients who discontinued ADA was 13.67 ± 6.96 months. The most common reason for cessation of ADA was secondary inefficacy (n = 7), followed by adverse events (n = 3), patient’s choice (n = 2), sustained quiescence (n = 1), primary inefficacy (n = 1), and planning for pregnancy (n = 1). Treatment was permanently discontinued in 3 patients due to active TB pneumonia or suspected TB reactivation. In two patients with suspected latent TB reactivation, ADA was restarted six months later after the beginning of TB treatment. ADA treatment of one patient with systemic exacerbation was discontinued at the recommendation of the rheumatology department. However, after the relapse of ocular inflammation, ADA treatment was restarted for this patient.
Fig. 1. Kaplan-Meier analysis of adalimumab retention probability.
This curve shows cumulative adalimumab retention rate up to 48 months. Dotted lines indicate the 95% confidence intervals.
Secondary outcomes
Changes in ocular inflammation parameters
At baseline, approximately 30% of the eyes had AC cell grade and vitritis grade >0.5+, and more than %90 of the eyes achieved AC cell grade and vitritis grade ≤0.5+. CMO completely resolved in 19 of 24 eyes (73.7%) that initially had CMO. Apart from these eyes, CMO developed in 2 eyes during follow-up. Five eyes underwent intravitreal dexamethasone implant for CMO. The therapeutic outcomes of ADA treatment are shown in Table 1.
Changes in best-corrected visual acuity and central macular thickness
The mean logMAR BCVA was 0.51 ± 0.72 (median [IQR]; 0.20 [0.80]) at baseline, 0.29 ± 0.59 (median [IQR]; 0.00 [0.40]) at 6 months, 0.29 ± 0.58 (median [IQR]; 0.05 [0.32]) at 12 months, and 0.23 ± 0.59 (median [IQR]; 0.00 [0.28]) at 24 months. There was a statistically significant difference between each time point after ADA treatment and the baseline (p < 0.001 at each time point, Wilcoxon signed-rank test) (Fig. 2A). While logMAR BCVA was ≤0.1 in 42.3% of eyes at baseline, this rate was 63.4% at 6 months, 66.2% at 12 months, and 65.6% at 24 months. Almost all patients (95.2%) had improvement at least one line or stability in BCVA compared to baseline.
Fig. 2. Changes in the mean best-corrected visual acuity (BCVA) and central macular thickness (CMT) of affected eyes during follow-up period.
The graphs showing the changes in BCVA (A) and CMT (B) from baseline to 24 months of follow-up. The data are presented as the mean and error bars indicate the standard deviation. Statistical significance was determined using Wilcoxon Signed Rank Test.
The mean CMT was 330.32 ± 150.49 µm (median [IQR]; 279.00 [87.00]) at baseline, 278.16 ± 74.83 µm (median [IQR]; 260.50 [68.25]) at 6 months, 265.64 ± 49.47 µm (median [IQR]; 259.00 [65.50]) at 12 months, and 256.25 ± 43.05 µm (median [IQR]; 243.50 [56.00]) at 24 months. The mean CMT at each time point decreased statistically significant compared to baseline (p < 0.001 at each time point, Wilcoxon signed-rank test) (Fig. 2B).
All improvement occurred within 6 months and there was no significant change in BCVA or CMT after 6 months of treatment.
Corticosteroid-sparing effect and changes in concomitant DMARDs use
At the beginning of ADA treatment, 38 patients (61.3%) were receiving ≥10 mg/day oral corticosteroids and 33 patients (53.2%) with topical corticosteroids. However, only 4 patients (6.4%) were still receiving ≥10 mg/day prednisolone at 6 months after ADA therapy and none of the patients received prednisolone at 24 months. In total, oral corticosteroids could be tapered to zero in 58 patients (93.5%) and the mean duration from baseline to the cessation of corticosteroids was 8.94 ± 5.33 (range, 1-24) weeks (Table 1).
At baseline, 29 patients (46.8%) were treated with concomitant DMARDs. The majority of these patients (21 of 29 patients) received azathioprine concurrent with ADA (Supplementary Table 1). Concomitant DMARDs were discontinued in 10 patients during follow-up. However, azathioprine was added to control ocular inflammation in 3 patients and colchicine was added in 1 patient due to systemic inflammatory exacerbation by the rheumatologist. The percentage of patients receiving DMARDs was lower at all evaluation time points compared to baseline (Table 1).
Impact of concomitant DMARDs use and biologic treatment line on drug retention rate
There was no significant difference in the DRR between patients treated in ADA monotherapy compared to those co-administered with DMARDs (p = 0.579, log rank test) (Fig. 3A). Likewise, no significant difference was found between biologic-naive patients and those previously treated with biologic drugs (p = 0.527, log rank test) (Fig. 3B).
Fig. 3. Drug retention rate of adalimumab (ADA).
A ADA in monotherapy vs. combined with disease-modifying antirheumatic drugs (DMARDs) and (B) ADA as first biotherapy line vs. as ≥2nd biotherapy line. Log-rank test was used for statistical analysis.
Adverse events
Nine patients showed some adverse events during follow-up. Adverse events include; elevation of liver function tests (n = 3), suspected latent TB reactivation (n = 3), active TB pneumonia (n = 2), and injection site reaction (n = 1). ADA was definitively discontinued in 2 patients with active TB pneumonia and 1 patient with suspected TB reactivation with the recommendation of the pulmonology department. None of the patients who temporarily or permanently discontinued ADA due to TB-related disease had received isoniazid prophylaxis before treatment and had no history of close contact with anyone receiving treatment for active TB.
Our cohort consisted mainly of male patients with Behçet’s uveitis (BU) (35 patients, 56.5%; male/female: 26/9). The percentage of patients with BU who had inactive disease at 6 months, 12 months, and 24 months was 74.3%, 70.4%, and 81.8%, respectively. The cumulative DRR was 88.2% at 6 months, 84.9% at 12 months, 69.1% at 24 months, and 62.8% at 48 months. Primary inefficacy was observed in 5 patients with BU and relapses occurred in 12 patients with BU. Bi-weekly ADA was escalated to weekly dose in 6 patients and azathioprine was added in 3 patients with BU. ADA was permanently discontinued in 10 patients with BU. At the baseline, 24 patients with BU received systemic corticosteroids. In 21 of these patients, systemic corticosteroids were completely discontinued. In terms of concomitant DMARDs use, a decrease was observed at 6 months (13 patients, 37.1%) compared to the baseline (16 patients, 45.7%). Long-term outcomes of patients with other types of uveitis were similar to those of patients with BU and summarized in Table 2.
Table 2.
Treatment outcomes of patients with non-Behçet uveitis.
| Patient No. | Age | Sex | Diagnosis of uveitis | Duration of ADA treatment (months) | DMARDs at baseline | Systemic corticosteroids at baseline (>10.0 mg/day) | Primer inefficacy | Seconder inefficacy | Concomitant DMARDs at 6 months | Concomitant corticoteroid (>10.0 mg/day) at 6 months | Inflammation at 6 months | Inflammation at 12 months | Inflammation at 24 months | ADA intervals at last visit | Cessation of ADA |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 45 | M | Spondylarthropathy | 108 | No | Yes | Absent | Present | No | No | Inactive | Inactive | Inactive | Weekly | No |
| 2 | 37 | M | Idiopathic uveitis | 14 | Yes | No | Absent | Present | Yes | No | Active | Inactive | - | Weekly | No |
| 3 | 42 | F | Serpiginous choroiditis | 10 | No | No | Absent | Absent | No | No | Inactive | - | - | Bi-weekly | No |
| 4 | 56 | F | Scleritis | 16 | Yes | Yes | Present | Absent | Yes | No | Inactive | Inactive | - | Weekly | No |
| 5 | 30 | F | Vogt-Koyanagi-Harada | 24 | Yes | Yes | Absent | Absent | No | No | Inactive | Inactive | Inactive | - | Yes |
| 6 | 57 | F | Sarcoidosis | 17 | Yes | No | Present | Absent | Yes | No | Active | Inactive | - | Weekly | No |
| 7 | 12 | M | Idiopathic uveitis | 10 | No | No | Absent | Absent | No | No | Inactive | - | - | Bi-weekly | No |
| 8 | 29 | M | Idiopathic uveitis | 12 | Yes | No | Absent | Absent | Yes | No | Inactive | Inactive | - | Bi-weekly | No |
| 9 | 45 | M | Scleritis | 12 | Yes | Yes | Present | Absent | Yes | No | Inactive | Inactive | - | Weekly | No |
| 10 | 49 | M | Serpiginous choroiditis | 14 | No | No | Present | Absent | No | No | Active | Active | - | - | Yes |
| 11 | 14 | M | Pars planitis | 10 | No | No | Present | Absent | No | No | Active | - | - | Weekly | No |
| 12 | 19 | F | Vogt-Koyanagi-Harada | 12 | Yes | Yes | Absent | Absent | Yes | No | Inactive | Inactive | - | Bi-weekly | No |
| 13 | 28 | F | Scleritis | 12 | Yes | Yes | Absent | Absent | Yes | No | Inactive | Inactive | - | - | Yes |
| 14 | 66 | M | Serpiginous choroiditis | 6 | No | No | Absent | Present | No | No | Active | - | - | Weekly | No |
| 15 | 64 | F | Spondylarthropathy | 24 | No | Yes | Absent | Present | No | No | Active | Active | Active | - | Yes |
| 16 | 9 | M | Pars planitis | 6 | Yes | Yes | Absent | Absent | Yes | No | Inactive | - | - | Bi-weekly | No |
| 17 | 61 | F | Spondylarthropathy | 27 | Yes | Yes | Absent | Present | No | No | Inactive | Inactive | Inactive | Bi-weekly | No |
| 18 | 38 | F | Vogt-Koyanagi-Harada | 24 | No | Yes | Absent | Present | Yes | No | Active | Inactive | Inactive | Weekly | No |
| 19 | 15 | M | Idiopathic uveitis | 6 | Yes | No | Absent | Absent | No | No | Inactive | - | - | Bi-weekly | No |
| 20 | 47 | M | Spondylarthropathy | 80 | Yes | Yes | Absent | Absent | No | No | Inactive | Inactive | Inactive | Bi-weekly | No |
| 21 | 45 | F | Scleritis | 14 | No | Yes | Present | Absent | Yes | Yes | Inactive | Inactive | - | Weekly | No |
| 22 | 47 | F | Spondylarthropathy | 80 | No | No | Absent | Absent | No | No | Inactive | Inactive | Inactive | Bi-weekly | No |
| 23 | 19 | F | Pars planitis | 14 | No | No | Present | Present | No | No | Active | Active | - | - | Yes |
| 24 | 9 | F | Pars planitis | 20 | No | No | Absent | Absent | No | No | Inactive | Inactive | - | Bi-weekly | No |
| 25 | 51 | F | Scleritis | 24 | No | Yes | Absent | Absent | No | No | Inactive | Inactive | Inactive | Bi-weekly | No |
| 26 | 33 | M | Serpiginous choroiditis | 24 | No | Yes | Absent | Absent | No | No | Inactive | Inactive | Inactive | Bi-weekly | No |
| 27 | 17 | M | Pars planitis | 10 | Yes | Yes | Absent | Absent | No | No | Inactive | - | - | Bi-weekly | No |
ADA adalimumab, DMARDs disease-modifying antirheumatic drugs.
Discussion
In this retrospective study, we reported the outcomes of ADA treatment regarding efficacy, retention rate, and safety profile in patients with active ocular inflammation. The efficacy and safety of ADA treatment in patients with intermediate, posterior and panuveitis has been demonstrated by recently published, multinational, randomized-controlled VISUAL I and II clinical trials [2, 7]. Thereafter, the VISUAL III clinical trial confirmed the efficacy of ADA treatment in active and inactive NIU patients with ≥78 weeks of follow-up, demonstrating better control of ocular inflammation, improvement in visual acuity, and reduction in systemic corticosteroid use [16]. In a retrospective clinical cohort study of 341 patients, it was reported that 69% of patients treated with ADA achieved inactive disease at the end of follow-up [17]. Similarly to these studies, in the presented study, 74.2% of patients had inactive disease at 6 months and 76.6% of patients at 12 months after initiation of ADA therapy. Nevertheless, our study differed from these studies in several points. First, all patients had active ocular inflammation at baseline in the presented study. Moreover, escalation to weekly ADA was preferred primarily as a treatment change for most patients in the event of inefficacy. Therefore, bi-weekly ADA was escalated to weekly ADA in 18 patients with primary or secondary inefficacy. Intraocular inflammation regressed in more than 80% of patients who were switched to weekly ADA, and 10 of 18 patients achieved inactive disease. Similar to our study, it has been reported that weekly ADA treatment may be an effective option in patients who failed with bi-weekly ADA treatment [18, 19]. These findings may suggest that when bi-weekly ADA is ineffective, intraocular inflammation can be controlled by escalation to weekly ADA treatment.
In this study, DRR was also investigated in order to evaluate the long-term therapeutic effect of ADA. In a study of 392 patients with uveitis treated with ADA, DRR decreased from 92.7% at 6 months to 54.28% at 60 months of follow-up [11]. Bitossi et al. also reported similar results and found that DRR of 64.15% at a median of 36.02 months [13]. Furthermore, in all of these studies mentioned, the most common reason for discontinuation was the lack of efficacy. In contrast to these studies, all of our patients had active ocular inflammation at the initiation of ADA and had various uveitis aetiologies, but the mean duration of ADA treatment was relatively shorter. Nonetheless, our results were compatible with previous studies. Survival analysis showed that there was a significant cumulative ADA retention rate of 96.8% at 6 months, 89.2% at 12 months, 63.1% at 24 months, and 63.1% at 48 months in the presented study and the most common cause of cessation of ADA was secondary inefficacy. In our opinion, higher DRR was obtained in the early period by escalating to weekly ADA rather than cessation of ADA in case of inefficacy. Moreover, as in our study, ADA withdrawal has been reported in a very limited number of patients due to persistent inactivity [11, 13, 17]. Similarly, in a study evaluating the optimization of ADA in Behçet’s patients, 5% of patients had successful withdrawal [20].
Behçet’s disease is more common in regions on the silk road such as our country, and serious ocular inflammations and complications are observed. In the presented study, we revealed that after ADA therapy, 71.4% of patients with BU achieved inactive disease with successful long-term DRR and the most common reason for ADA discontinuation was secondary inefficacy. Similar to the presented study, Fabiani et al. found the ADA retention rate to be 76.9% at the 12 months and 63.5% at the 48 months in their study on patients with Behçet’s disease, and ADA was discontinued most commonly due to secondary inefficacy [12]. Hereby, we may assert that long-term administration of ADA and escalating the weekly dose in case of inefficacy were effective in the management of patients with BU.
Studies are reporting that the formation of anti-drug antibodies during the treatment of rheumatological diseases and uveitis with anti-TNF reduces the effectiveness of treatment [2, 21, 22]. While some studies reported that the use of concomitant immunosuppressives may prevent antibody formation [17, 23, 24], there were also opinions to the contrary [22]. Since our study was retrospective, we could not evaluate the presence of anti-drug antibodies. However, in line with these studies, we investigated the effects of the concomitant use of DMARDs on the retention rate of ADA by comparing survival curves. We found that there was no difference in survival rates between patients receiving ADA as monotherapy and co-administrated with DMARDs. Previous studies have shown that combination of DMARDs with ADA does not provide more benefits than ADA monotherapy corresponding to the presented study [11–13, 25]. The impact of biologic treatment line on efficacy of treatment is also controversial. We found no significant difference in survival rates between biologic naive patients and patients previously treated with other biologic drugs. Several studies have reported that different biological treatment lines have similar effects, in parallel with our results [12, 25]. Contrary to our study and these studies, Llorenç et al. reported that those who received ADA as first biotherapy line had longer drug retention time than those treated with ADA as ≥2nd biotherapy line [11]. Our findings could be explained by the fact that the cohort was small and had limited effect size to identify the influence of DMARDs or prescription of ADA as first or ≥2nd biotherapy line. Nonetheless, our results were in line with most of the studies mentioned above. We believe that this presented study may help future studies with larger patient groups.
Randomized controlled studies have shown that ADA provides control of ocular inflammation by reducing both grade of AC cell and vitritis [26, 27]. A prospective study of 131 patients with refractory uveitis showed that CMO was completely resolved in 70% of patients [27]. Another study reported complete resolution of CMO in 77% of patients [13]. In accordance with the literature, after initiation of ADA therapy, the percentage of eyes with AC cell grade and vitritis grade ≤0.5 was more than 90% at all evaluation time points. In addition, approximately 80% of eyes with CMO showed complete resolution after ADA treatment. Many studies reported that visual acuity remained stable or improved at least one line in approximately 90% of participants [6, 28, 29]. In our study, BCVA remained stable and improved at least one line in 95% of the eyes. Moreover, both mean BCVA and CMT improved statistically significant from baseline at 6 months after the beginning of ADA treatment and remained stable at subsequent time points (p < 0.001). Similar to our study, there are studies that found a decrease in mean CMT in patients receiving ADA treatment [30, 31]. These results highlighted the effect of ADA to regress ocular inflammation. We can also indicate that ADA is beneficial for the improvement and long-term stabilization of BCVA and CMT.
Several studies have demonstrated the success of ADA in patients with ocular inflammation in terms of corticosteroid-sparing effect [2, 7, 28, 29, 32]. In the presented study, 93.5% of patients were able to discontinue corticosteroids. Moreover, at the baseline, 45.2% of patients were treated with at least one concomitant DMARDs, whereas at 12 months after ADA therapy, %34.0 of patients were using concomitant DMARDs. These findings may be considered promising and suggest that ADA therapy may prevent long-term complications of corticosteroids and DMARDs. Albeit the observational nature of this study limited these findings, it may be promoted by long-term prospective studies.
The most commonly reported adverse events of ADA are injection site reactions and allergic reactions [2, 7, 28]. Nevertheless, we found TB-related infections as the most common adverse event in this study. Latent TB screening of these patients with suspected active TB before the beginning of ADA were negative. In support of this, in a study of patients with inflammatory bowel disease receiving anti-TNF drugs, the authors noted that TB reactivation could develop even though latent TB screening was negative [33]. The fact that our country is endemic for TB may have explained this result. Therefore, the development of TB-related diseases should be considered during anti-TNF treatment in TB-endemic countries such as our country. We should also point out that ADA was restarted 6 months after tuberculosis therapy in 2 patients with latent TB reactivation, and no TB reactivation was observed thereafter.
The main limitation of this study was its retrospective design without a control group. The relatively small size and short follow-up time of our cohort with low uveitis heterogeneity also limited this study. We could not assess the anti-drug antibodies in this study. However, we consider that the evaluation of the anti-drug antibodies with prospective studies is necessary to determine the factors on the long-term efficacy of ADA in patients with ocular inflammation.
In conclusion, in this study, we aimed to report our experience in the efficacy, retention rate, and safety of ADA treatment in patients with ocular inflammation. Consistent with the literature, ADA was effective in the control of ocular inflammation and had a good DRR. In addition, in case of inefficacy, shortening ADA intervals may be an effective option rather than switching or adding DMARD, and may increase the long-term retention probability of ADA. Further studies with larger sample sizes and longer follow-up are required to confirm the findings of this study.
Summary
What was known before
Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody directed against TNF-alpha.
Adalimumab was approved by US Food and Drug Administration FDA in 2016 for treatment in patients with non-infectious intermediate, posterior, and panuveitis.
What this study adds
Adalimumab treatment is effective and safe to control ocular inflammation with an excellent retention rate.
Shortening adalimumab injections intervals may be beneficial in case of inefficacy.
Supplementary information
Acknowledgements
We would like to thank Elif Bağatur Vurgun, Department of Ophthalmology, Marmara University School of Medicine, Istanbul, Turkey, for assisting with the data collection.
Author contributions
FÇ: Study supervision. Concept and study design. Data collection, interpretation, analysis, and statistics. Drafting, revision, and final approval of the manuscript. HC: Study supervision. Concept and study design. Data interpretation. Revision and final approval of the manuscript.
Data availability
The data supporting the study findings are available from the corresponding author upon request.
Competing interests
The authors declare no competing interests.
Ethical approval
The study protocol was approved by the Institutional Review Board of Marmara University School of Medicine Hospital.
Informed consent
The study was performed following the Declaration of Helsinki principles, and all patients provided written informed consent about having their medical information used in the study analysis.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41433-023-02800-9.
References
- 1.Moudgil KD, Choubey D. Cytokines in autoimmunity: role in induction, regulation, and treatment. J Interferon Cytokine Res. 2011;31:695–703. doi: 10.1089/jir.2011.0065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Jaffe GJ, Dick AD, Brézin AP, Nguyen QD, Thorne JE, Kestelyn P, et al. Adalimumab in Patients with Active Noninfectious Uveitis. N Engl J Med. 2016;375:932–43. doi: 10.1056/NEJMoa1509852. [DOI] [PubMed] [Google Scholar]
- 3.Santos Lacomba M, Marcos Martín C, Gallardo Galera JM, Gómez Vidal MA, Collantes Estévez E, Ramírez Chamond R, et al. Aqueous humor and serum tumor necrosis factor-alpha in clinical uveitis. Ophthalmic Res. 2001;33:251–5. doi: 10.1159/000055677. [DOI] [PubMed] [Google Scholar]
- 4.Sharma SM, Damato E, Hinchcliffe AE, Andrews CD, Myint K, Lee R, et al. Long-term efficacy and tolerability of TNFα inhibitors in the treatment of non-infectious ocular inflammation: an 8-year prospective surveillance study. Br J Ophthalmol. 2021;105:1256–62. doi: 10.1136/bjophthalmol-2018-312767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Durrani K, Kempen JH, Ying GS, Kacmaz RO, Artornsombudh P, Rosenbaum JT, et al. Adalimumab for Ocular Inflammation. Ocul Immunol Inflamm. 2017;25:405–12. doi: 10.3109/09273948.2015.1134581. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Suhler EB, Lowder CY, Goldstein DA, Giles T, Lauer AK, Kurz PA, et al. Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial. Br J Ophthalmol. 2013;97:481–6. doi: 10.1136/bjophthalmol-2012-302292. [DOI] [PubMed] [Google Scholar]
- 7.Nguyen QD, Merrill PT, Jaffe GJ, Dick AD, Kurup SK, Sheppard J, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388:1183–92. doi: 10.1016/S0140-6736(16)31339-3. [DOI] [PubMed] [Google Scholar]
- 8.Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014;121:785–96.e3. doi: 10.1016/j.ophtha.2013.09.048. [DOI] [PubMed] [Google Scholar]
- 9.Fabbroni M, Cantarini L, Caso F, Costa L, Pagano VA, Frediani B, et al. Drug retention rates and treatment discontinuation among anti-TNF-α agents in psoriatic arthritis and ankylosing spondylitis in clinical practice. Mediators Inflamm. 2014;2014:862969.. doi: 10.1155/2014/862969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Souto A, Maneiro JR, Gómez-Reino JJ. Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases. Rheumatology. 2016;55:523–34. doi: 10.1093/rheumatology/kev374. [DOI] [PubMed] [Google Scholar]
- 11.Llorenç V, Cordero-Coma M, Blanco-Esteban A, Heras-Mulero H, Losada-Castillo MJ, Jovani-Casano V, et al. Drug Retention Rate and Causes of Discontinuation of Adalimumab in Uveitis: Real-World Data from the Biotherapies in Uveitis (BioÚvea) Study Group. Ophthalmology. 2020;127:814–25. doi: 10.1016/j.ophtha.2019.11.024. [DOI] [PubMed] [Google Scholar]
- 12.Fabiani C, Sota J, Vitale A, Rigante D, Emmi G, Vannozzi L, et al. Cumulative retention rate of adalimumab in patients with Behçet’s disease-related uveitis: a four-year follow-up study. Br J Ophthalmol. 2018;102:637–41. doi: 10.1136/bjophthalmol-2017-310733. [DOI] [PubMed] [Google Scholar]
- 13.Bitossi A, Bettiol A, Silvestri E, Di Scala G, Bacherini D, Lopalco G, et al. Adalimumab Accounts for Long-Term Control of Noninfectious Uveitis Also in the Absence of Concomitant DMARD Treatment: A Multicenter Retrospective Study. Mediators Inflamm. 2019;2019:1623847. doi: 10.1155/2019/1623847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Fabiani C, Vitale A, Emmi G, Bitossi A, Lopalco G, Sota J, et al. Long-term retention rates of adalimumab and infliximab in non-infectious intermediate, posterior, and panuveitis. Clin Rheumatol. 2019;38:63–70. doi: 10.1007/s10067-018-4069-3. [DOI] [PubMed] [Google Scholar]
- 15.Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–16. doi: 10.1016/j.ajo.2005.03.057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Suhler EB, Adán A, Brézin AP, Fortin E, Goto H, Jaffe GJ, et al. Safety and Efficacy of Adalimumab in Patients with Noninfectious Uveitis in an Ongoing Open-Label Study: VISUAL III. Ophthalmology. 2018;125:1075–87. doi: 10.1016/j.ophtha.2017.12.039. [DOI] [PubMed] [Google Scholar]
- 17.Eurelings LEM, Missotten TOAR, van Velthoven MEJ, van Daele PLA, van Laar JAM, van Hagen PM, et al. Long-Term Follow-up of Patients With Uveitis Treated With Adalimumab: Response Rates and Reasons for Discontinuation of Therapy. Am J Ophthalmol. 2022;240:194–204. doi: 10.1016/j.ajo.2022.03.017. [DOI] [PubMed] [Google Scholar]
- 18.Liberman P, Berkenstock MK, Burkholder BM, Chaon BC, Thorne JE. Escalation to Weekly Adalimumab for the Treatment of Ocular Inflammation. Ocul Immunol Inflamm. 2021;29:1564–8. doi: 10.1080/09273948.2020.1749857. [DOI] [PubMed] [Google Scholar]
- 19.Lee J, Koreishi AF, Zumpf KB, Minkus CL, Goldstein DA. Success of Weekly Adalimumab in Refractory Ocular Inflammatory Disease. Ophthalmology. 2020;127:1431–3. doi: 10.1016/j.ophtha.2020.04.009. [DOI] [PubMed] [Google Scholar]
- 20.Martín-Varillas JL, Calvo-Río V, Beltrán E, Sánchez-Bursón J, Mesquida M, Adán A, et al. Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet’s Disease. Ophthalmology. 2018;125:1444–51. doi: 10.1016/j.ophtha.2018.02.020. [DOI] [PubMed] [Google Scholar]
- 21.Moots RJ, Xavier RM, Mok CC, Rahman MU, Tsai WC, Al-Maini MH, et al. The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study. PLoS One. 2017;12:e0175207.. doi: 10.1371/journal.pone.0175207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Cordero-Coma M, Calleja-Antolín S, Garzo-García I, Nuñez-Garnés AM, Álvarez-Castro C, Franco-Benito M, et al. Adalimumab for Treatment of Noninfectious Uveitis: Immunogenicity and Clinical Relevance of Measuring Serum Drug Levels and Antidrug Antibodies. Ophthalmology. 2016;123:2618–25. doi: 10.1016/j.ophtha.2016.08.025. [DOI] [PubMed] [Google Scholar]
- 23.Ducourau E, Rispens T, Samain M, Dernis E, Le Guilchard F, Andras L, et al. Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial. RMD Open. 2020;6:e001047.. doi: 10.1136/rmdopen-2019-001047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Leinonen ST, Aalto K, Kotaniemi KM, Kivelä TT. Anti-adalimumab antibodies in juvenile idiopathic arthritis-related uveitis. Clin Exp Rheumatol. 2017;35:1043–6. [PubMed] [Google Scholar]
- 25.Fabiani C, Vitale A, Emmi G, Vannozzi L, Lopalco G, Guerriero S, et al. Efficacy and safety of adalimumab in Behçet’s disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol. 2017;36:183–9. doi: 10.1007/s10067-016-3480-x. [DOI] [PubMed] [Google Scholar]
- 26.Ming S, Xie K, He H, Li Y, Lei B. Efficacy and safety of adalimumab in the treatment of non-infectious uveitis: a meta-analysis and systematic review. Drug Des Devel Ther. 2018;12:2005–16. doi: 10.2147/DDDT.S160431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Li B, Li H, Zhang L, Zheng Y. Efficacy and Safety of Adalimumab in Noninfectious Uveitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Pharmacol. 2021;12:673984. doi: 10.3389/fphar.2021.673984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Díaz-Llopis M, Salom D, Garcia-de-Vicuña C, Cordero-Coma M, Ortega G, Ortego N, et al. Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients. Ophthalmology. 2012;119:1575–81. doi: 10.1016/j.ophtha.2012.02.018. [DOI] [PubMed] [Google Scholar]
- 29.Dobner BC, Max R, Becker MD, Heinz C, Veltrup I, Heiligenhaus A, et al. A three-centre experience with adalimumab for the treatment of non-infectious uveitis. Br J Ophthalmol. 2013;97:134–8. doi: 10.1136/bjophthalmol-2011-301401. [DOI] [PubMed] [Google Scholar]
- 30.Park SE, Jun JW, Lee DH, Lee SC, Kim M. The Effect of Adalimumab in Korean Patients with Refractory Noninfectious Uveitis. Yonsei Med J. 2021;62:177–81. doi: 10.3349/ymj.2021.62.2.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Lejoyeux R, Diwo E, Vallet H, Saadoun D, Tezenas du Montcel S, Bodaghi B, et al. INFLIXIMAB and ADALIMUMAB in Uveitic Macular Edema. Ocul Immunol Inflamm. 2018;26:991–6. doi: 10.1080/09273948.2018.1498110. [DOI] [PubMed] [Google Scholar]
- 32.Tang Lee Say TL, Yang V, Fingret JM, Zagora S, Symes R, Younan C, et al. Adalimumab in patients with vision-threatening uveitis: real-world clinical experience. BMJ Open Ophthalmol. 2021;6:e000819. doi: 10.1136/bmjophth-2021-000819. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Çekiç C, Aslan F, Vatansever S, Topal F, Yüksel ES, Alper E, et al. Latent tuberculosis screening tests and active tuberculosis infection rates in Turkish inflammatory bowel disease patients under anti-tumor necrosis factor therapy. Ann Gastroenterol. 2015;28:241–6. [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data supporting the study findings are available from the corresponding author upon request.