Relapsing polychondritis associated with pustular psoriasis successfully treated with secukinumab: a case-based review

Rationale Relapsing polychondritis (RP) is an immune-mediated systemic inflammatory disease involving cartilage and proteoglycan-rich tissues. Pustular psoriasis (PP) is a psoriasis subtype characterized by skin erythema and sterile pustules. In previous studies, there were few reports on patients with RP combined with psoriasis, and treatment strategies are not standardized. Patient concerns An 80-year-old Chinese woman with a 7-year history of atrial fibrillation, a 1-year history of coronary atherosclerotic heart disease, and no familial history, had a 2-month history of skin rash, erythema, swelling and pain in both hands, swollen bilateral auricles, and fingertip gangrene. Diagnosis Based on the diagnostic criteria for generalized pustular psoriasis proposed by Fujita et al. in 2018 and RP proposed by McAdam et al. in 1975, we diagnosed RP with PP as the predominant manifestation. Interventions We started therapy with subcutaneous secukinumab 150 mg weekly for the first month, then 150 mg monthly thereafter. Outcomes After 2 weeks of secukinumab administration, the patient showed significant remission of pustular skin lesions, with almost no joint pain, swollen bilateral auricles, and no adverse reaction. Conclusions Pustular lesions secondary to RP-associated gangrene and swollen auricles were observed, demonstrating a potential immune correlation between RP and psoriasis in some patients. Although data related to the use of secukinumab for RP and PP is very limited due to the rarity of the two conditions presented together, secukinumab provides a novel therapeutic option. Further prospective studies are needed to support our findings.


Introduction
Relapsing polychondritis (RP) is an immune-mediated systemic inflammatory disease involving cartilage and proteoglycan-rich tissues, such as ears, nose, laryngo-tracheo-bronchial tree, joints, skin, and blood vessels [1].The clinical manifestations vary depending on the affected areas, including distal necrosis, sterile pustules, erythema elevatum diutinum, and Raynaud's phenomenon [2,3].The etiology and pathophysiology of RP remains uncertain.However, RP probably results from a combination of genetic susceptibility, triggering factors, and a subsequent abnormal autoimmune reaction [4][5][6].A prior study demonstrated that one-third of the patients with RP may display associated autoimmune diseases, such as antineutrophil cytoplasmic antibody-associated vasculitides, and hematological disorders [7].Similarly, patients with psoriasis have been shown to develop autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome [8].The association between RP and psoriasis has only been reported in a few cases over many decades of study.Here, we report a case of RP with pustular psoriasis (PP) who experienced significant improvement in joint and skin symptoms after receiving two doses of secukinumab.The reporting of this study conforms to CARE guidelines [9].

Patient information and clinical findings
An 80-year-old Chinese female presented at our hospital with a 2-month history of skin rash, erythema, swelling, and pain in both hands and fingertip gangrene.Two months prior, the patient developed the scattered appearance of a bright red, spot-like rash and erythema with skin desquamation and itching over the entire body without any obvious cause.Subsequently, some of the rash subsided, ulcerated, and scabbed, while other ulcer surfaces and the surrounding scabs developed secondary pustules.Simultaneously, the patient's left fourth fingertip turned dark and gradually became necrotic.Subsequently, a 10-mm black dry gangrenous lesion appeared that was accompanied by pain.The edge of the lesion ruptured, showing secondary pustules and a bright red wound.The patient's bilateral auricles were swollen with no involvement of the earlobe.The right ear had secondary ruptured pustules.She had paroxysmal hoarseness without any other accompanying symptoms.The patient was diagnosed with psoriasis 20 years prior and had been taking prednisone and methotrexate regularly for about 1 year.After the psoriatic lesions resolved, she discontinued the medication without relapse.Additionally, she had a history of atrial fibrillation lasting more than 7 years and regularly takes rivaroxaban (15 mg qd po).The patient has a history of coronary atherosclerotic heart disease and regularly takes aspirin (100 mg qd po) and atorvastatin (20 mg qn po).However, the patient has no history of food and drug allergies, and other thrombotic diseases.At the time of admission, the physical examination results of the patient were as follows: temperature, 36.2 °C; pulse rate, 79 beats/min; respiratory rate, 18 breaths/min; blood pressure, 122/83 mmHg; and weight, 46 kg.Raynaud's phenomenon was observed in both hands, and a black carbonized area of gangrene approximately 10 mm in length was visible at the tip of the left fourth finger.Pustules, ulceration, and yellowish exudate were observed on the edge of the gangrenous area.Multiple distal nail detachments, subungual hyperkeratosis, and nail wrinkles were observed on both hands.The auricles of both ears were red and swollen with pustules and ulcerations.Erythema covered by white scales at the edge, thickened skin, rash, and pustules were distributed over the entire body.Bilateral interphalangeal joints and wrist joints were tender (Figs. 1, 2, and 3).Relevant laboratory examinations are shown in Table 1.Histopathology of the gangrene margin at the digital end showed Kogoj spongiform pustules and acanthosis elongation of the stratum spinosum (Fig. 4).Cardiac ultrasound indicated right atrial enlargement and mild tricuspid valve regurgitation.Chest CT showed thickening of the tracheal wall.Finally, wrist radiography revealed a small amount of effusion in wrist joints, with no significant bone destruction (Fig. 5).Based on the diagnostic criteria proposed by Fujita et al. in 2018 (extensive flush accompanied by multiple sterile pustules and Kogoj's spongiform pustules) [10] and RP proposed by McAdam et al. in 1975 (bilateral ear chondritis, respiratory tract chondritis, and non-erosive seronegative polyarthritis) [11], we diagnosed RP with PP as the predominant manifestation.

Timeline
The patient was admitted on December 27, 2023.Her symptoms were rated using a series of scales: severity criteria for generalized pustular psoriasis [10], a score of 5; and RPDAI [12], a score of 27.We started therapy with subcutaneous secukinumab 150 mg weekly for the first month and monthly thereafter.Two weeks later, symptoms such as skin pustules, erythema, ulcers, erythema and swelling of auricles, and joint pain improved compared to that experienced prior to treatment (Severity criteria for GPP, 2; RPDAI, 14) (Figs. 2 and 3).Subsequently, the patient's necrotic fingertips were continuously treated with debridement and dressing changes, with no recurrence during the follow-up period (Table 2).

Discussion
This represents the first case report of RP associated with PP that was successfully treated with secukinumab.The presence of Raynaud's phenomenon is not uncommon in some patients with RP.A clinical study of 66 patients with RP showed that 17% of patients had Raynaud's.phenomenon, and there was a numerically higher proportion of patients carrying Discoidin, CUB, and LCCL Domain Containing 2 (DCBLD2) ultra-Lrare damaging qualifying variants with cardiovascular manifestations, including venous thromboembolism, Raynaud's phenomenon, and aortitis [3].Unlike patients with primary Raynaud's phenomenon, persistent digital ischemia, ulceration and gangrene can occur in patients with secondary Raynaud's phenomenon [13].Immune-associated endothelial dysfunction and overproduction of vasoconstrictors have been suggested to be important in the pathogenesis of connective tissue disease-associated RP [14].Based on the patient's diagnosis, the formation of gangrene may involve multiple factors: (1) a large number of vasoactive molecules associated with psoriasis are upregulated, including vascular endothelial growth factor which enhances vascular permeability and intercellular/ vascular cell adhesion molecules involved in trafficking of lymphocytes to inflammatory lesions, and modification of the cutaneous microvasculature maintains the clinical lesional state and promotes inflammatory cell migration [15].These factors trigger immune-associated endothelial dysfunction.(2) RP causes vasculitis (including leucocytoclastic vasculitis and lymphocytic vasculitis) and thrombosis [6,14].(3) Age-related thickening, hardening, and loss of elasticity of arteries.A systematic search of articles published in PubMed/ MEDLINE, Web of Science, ChinaInfo System, LILACS, and SciELO, registered from 1960 to February 2024 was performed.In addition to our case report, five studies consisting of eight patients with RP and psoriasis were retrieved.Table 1 summarizes this report and all cases of RP associated with psoriasis published in the literature [16][17][18][19][20][21].Sex predilection (5 females, and 4 males) was not observed, and age varied from 15 to 80 years.Psoriasis preceded the onset of RP in all cases by 1-20 years.Among the patients with concurrent RP, four patients had psoriasis vulgaris (PsV), two had PsV complicated by psoriatic arthritis (PsA), one had generalized pustular psoriasis (GPP) complicated by PsA, and one had GPP complicated by ankylosing spondylitis.The treatment regimen comprised glucocorticoids, non-steroidal anti-inflammatory and analgesic agents, and biologics (adalimumab, etanercept, and secukinumab).Except for two cases without documented outcomes, the remaining patients all exhibited a favorable prognosis.The skin lesions were predominantly characterized by erythema and pustules.The incidence of RP-related damage (77.78% in ears, 44.44% in the nose) was similar to the probabilities reported in the literature (85% in ears, 54% in the nose) [6].No significant tendency towards the development of erosive or non-erosive arthritis was observed.
Interestingly, the clinical course and severity of psoriasis did not correlate with the occurrence or clinical course of RP in these previous cases.However, we observed the occurrence of psoriatic pustules at the skin lesion margin of RP (digital gangrene and auricular swelling) in our case, and the nature of the skin lesions was confirmed by pathology.In genetically susceptible individuals with RP, molecular mimicry may occur between cartilage micro-injuries, infections, or stimuli and cartilage structure, which may trigger a series of inflammatory responses similar to other autoimmune diseases [22].
Relapsing polychondritis usually exhibits immunological abnormalities.A large infiltration of CD4 + T lymphocytes, B cells, or plasma cells occurs in the lesion [23].After stimulation with mitogens and collagen antigens, increased levels of various cytokines, including TNF-α, IL-1, IL-6, and IL-17, as well as autologous chondroitin sulfate proteoglycans are expressed by T cells.These cytokines can lead to the degradation of chondroitin sulfate proteoglycans or direct inhibition of the synthesis of glucosaminoglycans by chondrocytes [1].Additionally, inflammation increases protease activity and causes cartilage degradation [7].Psoriasis is considered a disease primarily mediated by T helper cell subsets and the cytokines that they secrete.The cells infiltrating the dermis are a mixture of CD4 + and CD8 + T cells, which are predominantly memory T cells expressing cutaneous homing receptors, namely, cutaneous leucocyte-associated antigen (CLA) receptor and chemokine receptor 4 (CCR4).These cells migrate into the epidermis by binding to basement membrane type IV collagen through the expression of α1β1 integrin and participate in the formation of psoriatic lesions [24].Innate immune cytokines such as IL-1, IL-6, IL-17, and TNF-α are upregulated in psoriatic lesions [24].The shared pathogenic mechanisms may ultimately lead to secondary PP in our patient due to RP-related skin lesions.Therefore, we acknowledge the persistent systemic inflammation and immune damage caused by RP, which expose the skin lesions to immune attacks and make them susceptible to immune aggression.
In psoriasis, expression of IL-17 mRNA is higher in skin with lesions than in skin without lesions [25].Additionally, IL-17A levels are significantly correlated to disease severity [26,27].The current paradigm for RP pathogenesis involves cytokine-mediated immunologic activity via IL-17A and TNF-α, leading to the expression   Secukinumab is a recombinant human IgG1 kappa monoclonal antibody that selectively targets IL-17A and blocks its interaction with the IL-17 receptor.Inhibition of the downstream effects of this proinflammatory cytokine thereby interferes with key psoriatic disease pathways while promoting normalization of immune function and skin histology [29].
In prior research, secukinumab has been successfully employed in the therapeutic management of psoriasis (a dose of 300 mg or 150 mg), exhibiting a commendable efficacy and safety profile [30,31].Based on the body mass (46 kg) of the patient, a weekly dosage of 150 mg was recommended.Ultimately, the patient exhibited a favorable response to treatment, with amelioration of symptoms and a reduction in inflammatory indices (CRP decreased from 8.92 mg/L to 3.22 mg/L, ESR from 64 mm/h to 19 mm/h).However, due to the very limited data related to the use of secukinumab for RP and PP, whether low-dose secukinumab is applicable in a broader spectrum of patients with RP complicated by psoriasis and has the potential to reduce the risk of relapse requires further investigation.

Conclusions
This is the first case report of RP associated with PP that was successfully treated with secukinumab, adding to new evidence emphasizing a potential immune correlation between RP and psoriasis in some patients.The clinical course of psoriasis correlates with the clinical course of RP in our case, and partially shared pathogenic mechanisms may ultimately lead to secondary PP in our patient due to RP-related skin lesions.

Fig. 1 a
Fig. 1 a Scattered appearance of a bright-red spot-like rash, erythema with skin desquamation, and necrotic left fourth fingertip.b The edge of the gangrenous area is ruptured, showing secondary pustules, nail wrinkles, distal nail detachment, and subungual hyperkeratosis.c The edge of the gangrenous area is ruptured, showing secondary pustules and a bright red wound

Fig. 2 aFig. 3 a
Fig. 2 a, b The patient's auricles are red and swollen, with no involvement of the earlobe.The right ear shows ruptured pustules.c The auricles are normal after treatment

Fig. 4
Fig. 4 Histopathology of the gangrene margin at the digital end.The pathological results of the skin tissue at the edge of gangrene and the other skin lesions show hyperkeratosis and parakeratosis of the epidermis and subcutaneous tissue, formation of local ulcers, Kogoj spongiform pustules, acanthosis elongation of the stratum spinosum, severe acute and chronic inflammation of the dermis and subcutaneous tissue, formation of multiple abscesses, and fibrogranular tissue hyperplasia

Fig. 5 a
Fig. 5 a Degenerative changes in the left hand, slightly narrowed joint space in the fourth distal interphalangeal joint, and no significant abnormalities in the remaining joints.b, c Thickening of the wall of the main bronchial tube

Table 1
Changes in patient-related laboratory examination indicators