Biologic Treatment for Hidradenitis Suppurativa

Kelsey S. Flood; Martina L. Porter; Alexa B. Kimball

Disclosures

Am J Clin Dermatol. 2019;20(5):625-638. 

In This Article

Biologics Targeting Tumor Necrosis Factor

Most preclinical studies have reported an increase in TNF in HS skin lesions.[3,18] Consistently, Emelianov et al. found TNFα to be elevated in the epidermis and dermis in HS skin compared with control skin with the exception of immunoreactivity of TNFα at the proximal outer root sheath, where it was decreased compared with control skin.[19] Moreover, TNF receptors (TNF-R), TNF-R1 and TNF-R2, are also increased in HS skin.[2] In addition to elevated levels in the skin, HS patients also have higher serum levels of TNFα compared with healthy controls.[20] In contrast to the multiple studies that indicate TNFα is increased in HS, one study found levels of TNF to be decreased in lesional and non-lesional skin compared with control skin.[21] In another study, there was no significant difference in TNFα mRNA expression between lesional and non-lesional HS skin.[22]

Adalimumab

Adalimumab is a fully human IgG1 monoclonal antibody that neutralizes and prevents TNFα from binding to membrane bound and soluble receptors.[23–25] It is currently the only FDA-approved therapy for treatment of moderate-to-severe HS. Adalimumab in HS is dosed at 160 mg subcutaneously at day 0, 80 mg at day 15, and, starting at day 29, it is thereafter dosed at 40 mg weekly. There is no weight adjustment for adalimumab[25] (Table 1).

Less frequent dosing, as used in psoriasis, was previously studied and found not to be efficacious in HS. In a study examining use of adalimumab (160 mg at week 0, 80 mg at week 1, followed by 40 mg every other week [EOW] for 12 weeks), of the ten patients in the study and six who completed the study, no patients achieved the primary endpoint, defined as a 50% decrease in HSSI compared with baseline.[26] Additionally, in a double-blind, randomized clinical trial (RCT) in which 21 patients were randomized to adalimumab (80 mg as an initial dose, followed by 40 mg EOW for 12 weeks) or placebo, reduction seen in the Sartorius score was significant at 6 weeks but not at 12 weeks. Moreover, there was no significant difference in Hurley score, pain VAS, or Dermatology Life Quality Index (DLQI).[27]

Higher dosing of adalimumab was compared with EOW dosing in a phase II study in which 154 patients with moderate-to-severe HS were randomized to adalimumab 40 mg weekly, adalimumab 40 mg EOW, or placebo. After 16 weeks, patients in the weekly dosing cohort demonstrated greater response compared to the EOW dosing cohort. During the open-label component of this study, all patients were transitioned to 40 mg EOW but were later escalated to weekly dosing if their HS PGA was ≥ 3 at follow-up. Of note, 63% of patients had suboptimal response to EOW dosing and were increased to weekly dosing. The results of this study were important as they suggested that weekly dosing, compared with EOW dosing as in psoriasis, is important in the treatment of HS patients.[11] Post-hoc analyses of this study revealed that more patients receiving weekly as compared with EOW dosing and placebo had a positive HiSCR response.[12,25] Moreover, a Cochrane review, which examined the evidence from Kimball et al. and Miller et al., found no statistically significant difference in adalimumab EOW versus placebo in terms of DLQI score, pain, severity score, physician global assessment, or work productivity impairment.[11,27,28] In regards to safety, a study that compared data from studies on adalimumab EOW dosing versus weekly dosing in patients with HS, psoriasis, Crohn's disease, ulcerative colitis, and rheumatoid arthritis (RA) reported that the safety profiles of the two dosing regimens were comparable.[29]

The FDA approved adalimumab based on the results of two phase III, double-blind RCTs, PIONEER I and II, which included 307 and 326 patients, respectively. In PIONEER I, patients were required to stop treatment with oral antibiotics 28 days prior to the baseline visit, whereas in PIONEER II, patients were allowed to continue treatment with oral antibiotics. Patients receiving weekly adalimumab had a greater clinical response, quantified by the HiSCR measure, which was used as the primary endpoint for this study. In PIONEER I, 41.8% of those receiving adalimumab versus 26.0% of subjects receiving placebo and in PIONEER II 58.9% of subjects receiving adalimumab versus 27.6% of those subjects receiving placebo reached the primary end point.[30] In a secondary analysis of PIONEER I and II looking at Patient's Global Assessment of Skin Pain (PGA-SP), treatment with adalimumab also improved skin-related pain.[31]

In regards to efficacy, approximately half of all patients treated with adalimumab can expect to have approximately a 50% reduction in inflammatory abscesses and nodules (HiSCR) as seen in the PIONEER studies.[30] Further, while many patients may experience some symptom improvement after the initial loading dose of adalimumab, the full efficacy of treatment may not be appreciated until after 1 year of treatment. Evidence in regard to long-term efficacy of adalimumab was demonstrated in an open-label extension (OLE) of PIONEER I and PIONEER II in which 151 patients were followed longitudinally for at least 96 weeks. Disease response, measured by HiSCR, was achieved by 52.3% of patients at week 168.[32] It is not well understood why certain patients do not respond to adalimumab but it is likely in part related to the complex pathophysiology of HS.

Infliximab

Infliximab is a chimeric monoclonal antibody directed against TNFα that binds both soluble and transmembrane TNFα[33] (Table 1). Infliximab, unlike adalimumab, allows for weight-based dosing. Commonly used dosing of infliximab in HS patients is 5 mg/kg at weeks 0, 2, and 6,[34,35] although some authors report using a fourth dose at week 10.[36] This is typically followed by maintenance dosing every 8 weeks.[34] Shorter time intervals, such as every 4–6 weeks, and higher doses may be needed in some patients, especially after the loading period. Some authors advocate for treating with methotrexate and infliximab concurrently to prevent adverse events related to immunogenicity.[37,38]

In a double-blind, crossover RCT of 38 patients, those randomized to receive infliximab (5 mg/kg at weeks 0, 2, and 6, followed by a maintenance regimen every 8 weeks through week 22) demonstrated statistically significant improvement in VAS, DLQI, erythrocyte sedimentation rate (ESR), and PGA. More patients treated with infliximab compared with placebo reached the primary end point, defined as ≥ 50% improvement in HSSI from baseline. These results were not statistically significant in the initial analysis (p = 0.092), although they were statistically significant in a post hoc HSSI composite response analysis (p < 0.001).[34]

Studies have demonstrated various results regarding the long-term efficacy of infliximab in HS. In a study of ten patients treated with infliximab, seven patients experienced disease recurrence, in whom the average time to recurrence was 8.5 months.[35] Another study that followed ten patients demonstrated that relapse was common and occurred in half of patients with a median time to relapse of 37 weeks.[37] Other authors have suggested an even shorter duration of response. In a study of seven patients with severe HS, five out seven demonstrated improvement at week 6, but at week 10 only two of five patients receiving treatment demonstrated continued response to infliximab.[36] In a systematic review of 95 patients treated with infliximab, 85.3% demonstrated moderate or marked improvement during treatment. However, of the 48 patients who were followed longitudinally (mean follow-up of 53.8 weeks), only seven were stable after stopping infliximab whereas 15 recurred after stopping infliximab. Of those patients still being treated with infliximab, four were stable and eight demonstrated decreased response on continuous infliximab.[38]

Etanercept

Etanercept, a soluble form of the TNF receptor, prevents the binding of TNF to its native receptor.[39] Some smaller studies have suggested potential efficacy of etanercept in HS, but data obtained from studies of higher quality with larger sample sizes argue against this[40–43] (Table 2). Results from a double-blind study of 20 patients randomized to either etanercept (50 mg twice weekly) or placebo revealed no significant difference in DLQI, patient global assessment, or physician global assessment.[44] Additionally, an open-label prospective clinical trial of 15 HS patients treated with etanercept (50 mg weekly over 12 weeks) did not demonstrate efficacy. PGA scores, lesion counts, and patient pain scores did not significantly improve after treatment. Though DLQI scores improved somewhat (19 vs 15, p = 0.02), the authors reported that this was of minimal clinical significance. Of interest, the patients who did demonstrate a response to etanercept treatment tended to have a lower body mass index (BMI) (27.5) compared to non-responders (36), although this difference was not significant (p = 0.31).[45] As such, underdosing could have been a limitation in these studies.

Studies that did suggest efficacy for etanercept were of smaller sample sizes and less rigorous study design. In an open-label, phase II study of ten patients, etanercept (dosed at 50 mg weekly for 12 weeks) led to a > 50% decrease in disease activity in six and seven subjects at 12 and 24 weeks, respectively.[16] Many of these patients (7 of 10), however, later experienced a recurrence 14–68 weeks after stopping treatment. Those who experienced a recurrence underwent a second course of etanercept; two patients failed the second course of treatment and five had a positive response.[46] Treatment with etanercept for six patients with treatment-resistant HS also suggested some efficacy. After etanercept treatment (25 mg twice weekly), improvement was demonstrated in DLQI scores (mean reduction of 64%) and patient-reported disease activity (mean reduction of 61%) at 24 weeks[47] (Table 2).

Golimumab

Golimumab is an antibody that binds both soluble and transmembrane TNFα.[48] No clinical trials have been performed to assess its efficacy in HS; however, a few case reports have been reported on use of golimumab in HS. A 42-year-old patient with a history of ulcerative colitis developed HS and pyostomatitis vegetans in the absence of any colonic symptoms. Subsequently, a colonoscopy was performed and revealed moderate ulcerative pancolitis. She was therefore initiated on golimumab (dosed at 200 mg subcutaneously initially then 100 mg subcutaneously monthly) and a 2-week course of amoxicillin-clauvanate. This led to resolution of her HS in 2 months, which at time of writing had not recurred on continued golimumab treatment.[49] In a different case report, a patient treated with golimumab 50 mg subcutaneously monthly over 8 months failed to respond to therapy and her HS actually worsened during treatment.[50]

Certolizumab Pegol

Certolizumab is a TNF inhibitor that does not cross the placenta.[51,52] One report describes management of a pregnant patient with HS and psoriasis who had previously been managed with adalimumab. She was switched to certolizumab during the third trimester.[52] Additionally, a retrospective review of off-label TNF inhibitor use for dermatologic indications reported use of certolizumab in two HS patients who did not respond to certolizumab or other TNF inhibitors.[53]

Safety Concerns

A common safety concern in treatment with biologics is increased risk of infections. In psoriasis, the incidence rate of serious infections was higher in patients treated with infliximab (47.8 per 1000 person-years) compared with those patients treated with non-biologic systemic medications (14.2 per 1000 person-years).[54] In data obtained from the Psoriasis Longitudinal Assessment and Registry (PSOLAR), increased risk of serious infections was observed in patients treated with adalimumab and infliximab as compared with non-biologic and non-methotrexate medications.[55] The incidence of cellulitis, a common occurrence in patients with HS, however, was not elevated in the registration studies for adalimumab. Combination therapy, including the use of steroids, appears to increase risk of infection in treated patients. The underlying diagnosis also appears to matter, with lower rates seen, for example, in the psoriasis population than in the rheumatologic populations.[56]

Reactivation of latent tuberculosis is of special concern with use of biologics, especially TNF inhibitors, as TNFα is a key cytokine in the immune response to tuberculosis infection.[57] Among the TNFα inhibitors, risk of active tuberculosis is higher in infliximab and adalimumab compared with etanercept. In a review of phase III clinical trials, post-marketing surveillance, and national registries, ten tuberculosis cases were reported in 4590 patients (0.21%) treated with infliximab, nine cases in 7009 (0.12%) patients treated with adalimumab, and four cases in 7441 patients (0.05%) treated with etanercept.[58] Systemic fungal infections may also be rarely observed with anti-TNF therapy, including histoplasmosis[59] and coccidioidomycosis.[60]

Increased risk of malignancy is another important concern to consider when prescribing biologics. Patients with HS are inherently at an increased risk of non-melanoma skin cancer (NMSC), especially squamous cell carcinoma (SCC). The etiology of this elevated risk is not fully understood but different theories have been proposed. One theory is that longstanding inflammation contributes to this risk.[61,62] For example, diseased skin may facilitate local immune dysregulation in the skin that may promote tumor or infection development; this concept is referred to as the 'immunocompromised cutaneous district'.[63] There is also evidence to suggest that human papilloma virus (HPV) infection may contribute to the development of SCC in HS patients.[62,64] In one study of eight anogenital tumor samples from HS patients, polymerase chain reaction (PCR) revealed the presence of HPV in all samples and, further, HPV-16, a high-risk type, was found in seven of the eight samples.[64] Other evidence suggests that impaired Notch signaling may be involved in both HS and SCC; impaired Notch signaling may explain increased risk of SCC in the HS population.[62] Treatment with anti-TNF therapy appears to additionally impart elevated risk of NMSC. Reports have detailed cases of HS patients treated with adalimumab[65] and infliximab[66] developing metastatic SCC. Therefore, risk stratification for NMSC is important when considering initiating anti-TNF therapy in an HS patient, especially for the HS patient with substantive and long-standing disease burden.

In a meta-analysis of 74 RCTs of TNF inhibitor use in psoriasis, psoriatic arthritis, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, among other diseases (including 23 studies on adalimumab, 28 on etanercept, and 23 on infliximab), the relative risk of NMSC was 2.02 (95% confidence interval [CI] 1.11–3.95) and for other cancers excluding NMSC was 0.99 (95% CI 0.61–1.68).[67] Similarly, in a meta-analysis of rheumatoid arthritis patients receiving treatment with tumor necrosis factor inhibitors, all malignancy risk was not increased (0.95, 95% CI 0.85–1.05) but was increased for NMSC (1.45, 95% CI 1.15–1.76) and melanoma (1.79, 95% CI 0.92–2.67), although the confidence interval for melanoma included the null value.[68] A study by Kamangar et al. also demonstrated increased rates of detection of NMSC among patients treated with biologics.[69]

In contrast to infections and malignancy, more frequently encountered safety concerns include injection site reactions and infusion reactions. In the IBD and rheumatology literature, patients who develop antibodies against a biologic are more likely to develop an infusion reaction.[70,71] Anti-drug antibodies may also limit the efficacy of the biologic. In a meta-analysis of studies assessing use of TNF inhibitors in autoimmune diseases, rates of anti-drug antibodies were highest in infliximab, followed by adalimumab, certolizumab, golimumab, and lastly etanercept.[72] Adalimumab tends to be less immunogenic as it is a human antibody.[25] Certain human leukocyte antigen (HLA) alleles may be protective against formation of anti-drug antibodies whereas others may increase risk of their formation.[23] Concomitant methotrexate treatment with infliximab is suggested to possibly prevent adverse events related to immunogenicity.[37,38] Indeed, it has been reported that infliximab monotherapy, compared with combined infliximab/immunomodulator therapy, primarily being methotrexate, has higher rates of severe adverse events.[38]

Other adverse events, including menstrual disorders, have been reported in association with adalimumab; adverse effects per FDA labeling associated with the discussed TNF-inhibitors can be found in Table 1.[24,73,74]

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