Combination of secukinumab and acitretin for generalized pustular psoriasis: A case report and review of literature

Abstract

Generalized pustular psoriasis (GPP) is characterized by painful and occasionally disfiguring cutaneous manifestations with sepsis-like systemic symptoms, and is a rare severe variant of psoriasis. Currently, there is no standard treatment for GPP. Here, we report a case of a female patient with ankylosing spondylitis (AS) and mild scalp psoriasis, who developed GPP and alopecia following three courses of adalimumab therapy. The patient’s condition gradually improved following cessation of adalimumab and treatment with secukinumab and acitretin. After eight weeks of treatment, the patient achieved almost complete clearance of her psoriasis, her alopecia improved, and her AS was relieved. Therefore, we believe that a combination of secukinumab with acitretin may be a rational approach for the treatment of severe GPP.

Introduction

Generalized pustular psoriasis (GPP) is a severe multisystem disease, which features the sudden and widespread eruption of superficial sterile pustules. ¹ Among patients diagnosed with GPP, up to 65% have concurrent psoriasis vulgaris. ² Although the pathogenesis of GPP is unclear, studies have suggested the involvement of an interleukin (IL)-1 subfamily of cytokines, based on an imbalance of the IL-36 axis favouring of pro-inflammatory activity. ³ Factors that may trigger, or exacerbate GPP, include drugs, infections, pregnancy, and stress. ²

Tumour necrosis factor-α (TNF-α) inhibitors, such as infliximab, adalimumab, golimumab, and certolizumab, have been used in the treatment of ankylosing spondylitis (AS), rheumatoid arthritis, inflammatory bowel disease and psoriasis. ⁴ With the increasing use of these drugs, GPP induced by TNF-α inhibitors has received attention.^5–8 For example, it has been estimated that approximately 0.6%–5.3% of patients administered TNF-α antagonists develop a paradoxical psoriasis, with infliximab being the most common cause. ⁹ Compared with classical psoriasis, TNF-α related psoriasis occurs most often on the palms, soles, and scalp. ⁹ Some manifestations are presented with palmoplantar pustulosis and GPP.^9,10

Currently, there is no standard treatment for GPP. Therefore, first-line treatment for the condition consists of established therapies, such as acitretin, cyclosporine, methotrexate and infliximab. ¹¹ Recently, several treatments targeting IL-17, IL-23 or IL-36R (e.g., ixekizumab, secukinumab, brodalumab, guselkumab, ustekinumab and spesolimab) have been shown to have some efficacy.^2,11,12 We describe here, a case of a female patient with AS and scalp psoriasis, who developed GPP after her third course adalimumab therapy. Her GPP was successfully treated with secukinumab and acitretin, and her AS was controlled.

Case report

A 49-year-old woman of Han Chinese origin presented with a 10-day history of GPP. She had a five-year history of mild scalp psoriasis and had been suffering from AS for more than 2 years. She had received leflunomide for her AS but stopped treatment after a month because of abnormal liver function test results. Her father had a history of psoriasis vulgaris.

Prior to this pustular eruption, the patient had received 40 mg adalimumab administered subcutaneously every other week on three occasions for her gradual worsening of AS and pain in both knees. Following her third course of adalimumab treatment, her back pain and stiffness had improved. However, she had developed a pustular rash on her palms, soles and scalp. The lesions were surrounded by a red halo and studded with a tense vesicle that contained clear fluid which later developed into a pustule. After the pustules had dried up, the lesions became scaly and erythematous and varied in size. Her rash gradually spread to her face, limbs, and tips of her fingers and toes.

Dermatological examination showed pustular papules and plaques and confluent erythema involving the trunk and limbs. Infiltrative erythema was distributed symmetrically on both her hands and feet, together with light yellow pustules. Dried-up pustules were present with brown-yellow crusts on their surface. Some of the lesions were fused. Purulent lakes were also noted as a result of fusion of the pustules and alopecia was visible on her scalp (Figure 1a–d). She also had a fissured tongue (Figure 1e). Her Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score was 27 (range 0–72) and her dermatology life quality index (DLQI) was 20 (i.e., very large effect on patient's life). ¹³

Figure 1.

(a–d) Cutaneous manifestations prior to therapy with secukinumab. (e) The patient also had a fissured tongue. (f–i) At the seven-month follow-up, the patient had achieved almost complete clearance of her psoriasis following treatment with a combination of secukinumab and acitretin and (j) however, she continued to have fissured tongue.

Despite discontinuation of the adalimumab treatment 15 days previously, the lesions kept exacerbating with new lesions appearing on her face, ears, neck, trunk, and bilateral upper and lower extremities. The patient developed extensive painful abscesses on her palms and soles which made walking impossible. Plaque with silver scales developed on the top area of her scalp, with alopecia (positive for the pull test). Her blood was positive for human leukocyte antigen B27 (HLB27) but negative for antinuclear antibodies, hepatitis B, tuberculosis and syphilis. Blood test result showed no obvious abnormalities (i.e., white blood cells [WBC] count, 5.01 × 10⁹/l; neutrophils 67%; monocytes, 1.02 × 10⁹/l). However, some of her inflammatory biomarkers were elevated (i.e., C-reactive protein [CRP], 2.2 mg/dl; erythrocyte sedimentation rate, 92 mm/h). Bacteriological and mycological swab cultures were negative, her liver and kidney function were within the normal range and chest computed tomography (CT) scans showed no obvious abnormalities. Skin biopsy of the pustular area showed psoriasiform epidermal hyperplasia accompanied by neutrophil aggregation within the superficial epidermis (Figure 2).

Figure 2.

(a, b) Skin biopsy of the pustular area showed psoriasiform epidermal hyperplasia accompanied by neutrophil aggregation within the superficial epidermis, which caused pustule formation. (a. haematoxylin and eosin [H&E] staining; magnification ×5; b. H&E staining; magnification ×10).

Due to her flared psoriatic lesions and generalized pustulosis following adalimumab therapy, without any evidence of infection and typical pathological findings, a diagnosis of GPP was made, which may have been triggered by the TNF-α inhibitor. A decision was made to administer the IL-17 inhibitor, secukinumab 300 mg subcutaneously at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance dosing starting at week 8, with the aim of simultaneously treating both her GPP and AS.

Initially, there was no improvement in her GPP and her rash continued to worsen. Indeed, following the first secukinumab administration, the erythema became hypertrophied, confluent, and dark grey-red and was accompanied by a fever (38.0°C). Subsequently, oral acitretin (30 mg/d) was added to her treatment after one week of treatment with secukinumab. At eight weeks, the combination of acitretin with secukinumab had resulted in a 75% reduction in her GPPASI score (i.e., 7) (Figure 3). Except for a few patches on her lower extremities, the colour, thickness, and scales of her lesions improved greatly. In addition, the psoriatic plaques on her scalp improved, and regrowth of her hair was noted. Her back pain and stiffness related to AS were also relieved. Laboratory studies showed increased total cholesterol (6.43 mmol/l) and triglycerides (5.6 mmol/l); hyperlipidaemia is a recognised side effect of acitretin therapy. The drug was not withdrawn at this stage because the patient’s GPP continued to improve but the dosage was reduced by 10 mg per month until it was discontinued.

Figure 3.

The patient’s Generalized Pustular Psoriasis Area and Severity Index (GPPASI) scores over seven months of treatment with secukinumab and acitretin.

At the seven-month follow-up, the patient had achieved almost complete clearance of her psoriasis but she continued to have fissured tongue (Figure 1f–j). To further improve her AS, the dose interval of secukinumab was reduced to 150 mg per month without any additional medications. Her total cholesterol and triglyceride levels returned to normal. The patient has not had any adverse effects from the combination treatment of secukinumab with acitretin.

The reporting of this study conforms to CARE guidelines. ¹⁴ The patient provided consent for publication of her anonymised data. Ethical committee approval was not required for this case report.

Discussion

A rare, severe variant of psoriasis, GPP presents as a widespread formation of sterile pustules on the trunk and limbs with associated erythema. It is generally thought that GPP results from innate immune system overload and unrestrained IL-36 cytokine activity. ¹² Researches have reported that GPP can be triggered by either overexpression of IL-36 agonist or dysfunction of IL-36R antagonist (IL-36RA), caused by mutations in the IL-36RN gene. ¹⁵ These genetic abnormalities lead to an uncontrolled stimulus feedback loop and excessive production of proinflammatory cytokines. ¹⁵ Subsequently, this induces chemokines to attract a large number of neutrophils into the epidermis, that results in pustules, which are a characteristic feature of GPP. ¹⁶

Flare-ups of GPP can be triggered by several factors. ² In addition, several reports suggest that GPP may be induced by some TNF-α inhibitors.^5–9 Currently, the aetiology of paradoxical psoriasis is unknown. However, based on published data, we suggest that there may be three explanations for the mechanism of TNF-α inhibitor related psoriasis. Firstly, genetic variations susceptible to psoriasis may play a role in the occurrence of psoriasiform skin disease following anti–TNF-α treatment. Secondly, unopposed activation of the interferon (IFN)-α pathway following neutralization of TNF-α may explain the skin lesions. One study showed that TNF-α regulates human plasmacytoid dendritic cells by suppressing IFN-α production and enhancing T cell activation. ¹⁷ Finally, in addition to TNF-α and IFN-α, multiple key cytokines may also participate in the reactions of psoriatic skin in the IL-23/IL-17 axis. In our case, the patient’s blood was positive for HLA-B27. In previous studies, a relatively high prevalence of HLA-B27 was been reported in patients with GPP, acrodermatitis continua, palmoplantar pustulosis psoriatic arthritis, and SAPHO syndrome.^18–20 While the relationship between HLA-B27 and pathogenesis of GPP is unclear, it has been shown that patients with pustular psoriasis have an increased frequency of the HLA-B27 allele compared with the general population. ²¹

Due to its serious and potentially life-threatening consequences, GPP must be diagnosed accurately and treated quickly. ²² However, there are no standardized treatment guidelines for GPP. In our case, the patient, who had mild scalp psoriasis and AS, developed GPP after a third course of adalimumab therapy. We stopped adalimumab treatment and switched to another biological agent, secukinumab. Secukinumab is a monoclonal human IL-17A antagonist, and has been shown to be effective in the treatment of GPP. ²³ In addition, the drug has been shown to be effective and generally well tolerated in the treatment of adults with active AS. ²⁴ However, after one week’s treatment with secukinumab, the patient’s rash and pustules continued to worsen and she developed a fever. We decided to combine the biologic with a conventional systemic agent as an alternative therapeutic approach. We added acitretin to the patient’s therapy which resulted in a significant clinical improvement within four weeks. The patient’s GPPASI score decreased 25% at four weeks and by 75% at eight weeks. In addition, at eight weeks, her back pain, and stiffness related to AS had abated.

Acitretin, an oral retinoid and metabolite of etretinate, has shown good efficacy in the treatment of GPP. ²³ Similar to other retinoids, acitretin is thought to work via stimulation of retinoic acid receptors causing inhibition of keratinocyte hyperproliferation and also by inhibiting the activation of Th17 cells. ²⁵ Interestingly, while acitretin is thought to be a medication with a slow onset of action in treating psoriasis vulgaris and takes more than 12 weeks to reach peak effect, it works much faster in pustular psoriasis and achieves a good effect within two weeks. ¹¹ In our case, the combination of acitretin and secukinumab achieved good control of the GPP within two weeks. Compared with biologics alone, or other conventional treatment options, the combination of secukinumab and acitretin in our patient not only resulted in fast improvement in symptoms, but also was without significant adverse effects. Side effects of acitretin are common and include chapped lips, dryness of the nose and eyes, and hyperlipidaemia; these were noted in our patient. However, these side effects resolve quickly after drug withdrawal. It is important to note that premature epiphyseal closure triggered by acitretin is a particular concern when prescribing retinoids to children. Nevertheless, some researches have suggested that the risk can be minimized by using only low doses of the drug (i.e., 0.25 to <1 mg/kg/day, for no more than 12 to 18 months). ²⁶

To our knowledge, only a few cases of combination therapy of secukinumab with acitretin for the treatment of severe psoriasis have been previously reported (Table 1).^27–30 Importantly, the efficacy of the combination therapy was not limited to adults. One study reported the success of secukinumab and acitretin in a case series involving four paediatric patients. ²⁸ The combination therapy demonstrated good efficacy in GPP, annular pustular psoriasis, plaque and erythrodermic psoriasis. Our experience suggests that secukinumab and acitretin combination therapy may be an effective and rapid treatment option for severe GPP induced by adalimumab. Furthermore, it had a good effect on GPP and AS and no severe adverse reactions were observed during follow-up. Therefore, we believe that the combination of secukinumab and acitretin is a rational approach for the treatment of severe GPP.

Table 1.

Case reports using acitretin in combination with secukinumab for severe psoriasis

Reference	No. patients	Disease	Age, y	Sex	History of disease	Almost/Complete skin clearance
Herrero Moyano M et al. 27	1	Annular pustular psoriasis	29	F	22 years	3 months
Albela H et al. 28	1	GPP	4	M	4 years	1 week
	2	GPP	11	M	2 weeks	1 month
	3	GPP	8	F	4 years	1 month
	4	GPP	10	F	4 years	1 month
Polat Ekinci A et al. 29	1	PsO, PsA	64	F	13 years	4 weeks
	2	PsO & erythrodermic	37	M	20 years	6 weeks
	3	PsO & intermittent pustular	76	M	10 years	24 weeks
Paolo G et al. 30	1	GPP	41	F	6 years	2 months
Our case	1	GPP	49	F	10 days	8 weeks

F, female; M, male; GPP, generalized pustular psoriasis; PsO, chronic psoriasis; PsA, peripheral psoriatic arthritis.

In summary, we presented a case of GPP in a patient with AS that was successfully treated with secukinumab and acitretin. After eight weeks, the patient achieved almost complete clearance of her psoriasis, her alopecia improved, and her AS was relieved. Therefore, combining secukinumab with acitretin may be a rational approach for the treatment of severe GPP. However, randomised, controlled studies, involving large number of patients with GPP, are required to confirm the efficacy and safety of this treatment regimen.