|CASE BASED REVIEW
|Ahead of print publication
Secukinumab: A safe option to treat psoriasis and psoriatic arthritis in the presence of interstitial lung disease
Padmavathy Rheumatic Care Centre, Vellore, Tamil Nadu, India
13/153, C Sector, VG Rao Nagar, Vellore - 632 007, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Psoriasis is a commonly encountered skin condition with a significant percentage of patients developing arthritis. Psoriasis is associated with multiple comorbid conditions. However, the association of interstitial lung disease (ILD) with psoriasis is rarely reported in the literature. The therapeutic options for psoriasis and psoriatic arthritis are limited in the presence of ILD. We report a 63-year-old female with long-standing psoriasis and psoriatic arthritis with usual interstitial pneumonia pattern ILD. She developed severe arthritis and extensive psoriasis lesions which did not respond to conventional disease-modifying drugs as well as to oral phosphodiesterase inhibitor apremilast. She was planned for biological therapy. Antitumor necrosis factor therapy was not administered in view of coexistent ILD. She was treated with anti-interleukin-17 A monoclonal antibody, secukinumab 150 mg subcutaneous at 0, 1, 2, 3, and 4 weeks, followed by monthly once for 5 months for a total of ten doses. She had a resolution of skin lesions, and her arthritis went into remission. She had no clinical or radiological worsening of ILD. Spirometry showed improvement in forced vital capacity. This case report suggests that secukinumab can be safely used in psoriasis and psoriatic arthritis without worsening of underlying ILD.
Keywords: Interstitial lung disease, psoriasis, psoriatic arthritis, secukinumab
| Introduction|| |
Psoriasis is a chronic autoimmune proliferative skin condition characterized by itchy skin rashes, red scalps with white scales on the skin. The prevalence of psoriasis in India is estimated to be between 0.44% and 2.8%. Among various types of psoriasis, psoriasis vulgaris is the most common subtype. The prevalence of psoriatic arthritis among patients with psoriasis in the Indian population is around 8.7%. Interstitial lung disease (ILD) is documented in patients with psoriasis. The therapeutic options for treating psoriasis and psoriatic arthritis with ILD are limited. The main stay of therapy, methotrexate is not used for fear of worsening ILD. In patients who require biological therapy, anti-tumor necrosis factor (TNF) drugs though not absolutely contraindicated are not used, as they are known to induce an exacerbation of underlying ILD.
| Case Report|| |
A 63-year-old female was diagnosed with psoriasis and psoriatic arthritis 10 years back, for which she took oral methotrexate 10 mg/week for 3 years after which she discontinued treatment. She used to have joints pain on and off with exacerbation of skin lesions during winter months which subsided with over the counter medications.
Two years back, she developed breathlessness on exertion and was diagnosed to have ILD. Computed tomography (CT) chest showed patchy fibrosis in both lower lobes with areas of honeycombing suggestive of usual interstitial pneumonia (UIP) [Figure 1]a. Spirometry showed a restrictive pattern with forced vital capacity (FVC) of 1.6 liters (% predicted FVC-68%). She was treated with azathioprine (started with 50 mg once daily increased to 100 mg once daily) and deflazacort (started with 24 mg/day tapered to 6 mg/day in 3 months) for 2 years.
|Figure 1: (a) Computed tomography (2014) showing honeycombing and early fibrosis in lower lobes suggestive of usual interstitial pneumonia-interstitial lung disease, for which she was treated with azathioprine. (b) Computed tomography (2016) taken after 2 years of treatment with azathioprine shows worsening of interstitial lung disease in the form of increase in honeycombing, fibrosis, and traction bronchiectasis in the lower lobes. (c) Computed tomography (2018) taken after 2 years of treatment with mycophenolate mofetil and completion of ten doses of secukinumab. There is no radiological worsening of computed tomography compared to previous computed tomography 2 years back|
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After 2 years of treatment with azathioprine, she had no improvement and developed increasing breathlessness on exertion Class II Medical Research Council (MRC) and dry cough. She had frequent episodes of pain and swelling of small joints of the hand and feet along with exacerbation of skin lesions. There was no back pain or neck pain suggestive of axial involvement. There was no history suggestive of uveitis or inflammatory bowel disease. She was diagnosed with type 2 diabetes mellitus and hypertension and on regular medications. She attained menopause 9 years back and on regular calcium and Vitamin D supplementations. She is a nonsmoker and has no exposure to environmental toxins.
On examination, she had scalp psoriasis and psoriasis vulgaris over low back and shin of the tibia. There was pitting over the bilateral 3rd, 4th, and 5th fingers (≥20 pits in each nail). She had asymmetric peripheral arthritis involving the right 2nd and 3rd metacarpophalangeal, the left 4th distal interphalangeal, both thumb interphalangeal, and both knee joints. There was dactylitis of the left 4th toe. There were no deformities. There was no enthesitis and spine movements were normal. She had bilateral infrascapular, interscapular, and infraaxillary end-inspiratory crepitations. Cardiovascular, neurologic, and abdomen examinations were normal.
Investigations showed elevated erythrocyte sedimentation rate –86 mm/h and C-reactive protein –26 mg/L. Rest of the investigations (complete blood count, renal function, liver function, uric acid, viral markers, rheumatoid factor, anti-cyclic citrullinated peptide antibody, antinuclear antibody, extractable nuclear antigen by extended line immunoassay comprising 15 antigens, antisynthetase antibody, and antineutrophil cytoplasmic antibodies) were all negative. Echocardiography was normal. Disease Activity Score (DAS) 28 was used to assess the disease activity of psoriatic arthritis, and it showed high disease activity (DAS 28-5.67).
Repeat CT imaging showed an increase in areas of lower lobe fibrosis, honeycombing, and traction bronchiectasis [Figure 1]b compared to CT taken 2 years back [Figure 1]a. Spirometry showed a restrictive pattern with FVC-1.28 L (% predicted FVC-60%) (Drop of 20% in 2 years).
Considering the radiological deterioration and drop in FVC, she was planned for lung biopsy to confirm the diagnosis and further escalation of therapy. She refused treatment and came back after 3 months with increasing breathlessness Class III MRC and dry cough. Spirometry showed further drop in FVC – 1.15 L (% predicted FVC – 53%) (Drop of 10% in 3 months).
In view of worsening ILD and active arthritis, she was started on sulfasalazine 2 g/day and mycophenolate mofetil 2 g/day and was continued on low-dose steroids (prednisolone equivalent 5 mg/day). Pneumococcal and influenza vaccine were administered. With this treatment, there was improvement in breathlessness from Class III MRC to Class II MRC and decrease in cough. Spirometry showed an increase in FVC – 1.21 L (% predicted FVC – 58%).
One year later (while on treatment with sulfasalazine and mycophenolate mofetil), she presented with worsening of psoriasis lesions and peripheral arthritis. She was started on oral phosphodiesterase inhibitor apremilast 30 mg twice daily. However, even after 5 months of taking apremilast, her skin lesions did not subside and there was worsening of peripheral arthritis (DAS 28 – 5.9). Therefore, she was planned for biological therapy. Anti-TNF therapy was not given as it can induce worsening of underlying ILD. Hence, she was treated with anti-interleukin-17 A (IL-17A) monoclonal antibody secukinumab after tuberculosis (TB) screening. (Quantiferon gold TB and Mantoux were negative).
Secukinumab was administered at a dose of 150 mg subcutaneous at weeks 0, 1, 2, 3, and 4 followed by monthly once for 5 months for a total of ten doses. At the completion of ten doses, she had a partial resolution of skin lesions in the form of reduction in scaling, erythema, and induration [Figure 2] and her arthritis was in remission (DAS 28-1.6).
|Figure 2: Psoriasis vulgaris over the leg (a) and reduction in scaling, erythema, and induration after secukinumab (b)|
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Her cough subsided and she remained in Class II MRC. Repeat CT imaging after completing ten doses of secukinumab showed no radiological worsening [Figure 1]c compared to previous CT [Figure 1]b. Spirometry showed improvement in FVC – 1.36 L (% predicted FVC – 65%) (FVC – 1.24 L before starting secukinumab).
The initial deterioration of FVC and subsequent improvement is shown in [Figure 3].
|Figure 3: Trend in forced vital capacity. There is decline in % predicted forced vital capacity after initial treatment with azathioprine. There is improvement in % predicted forced vital capacity after treatment with mycophenolate mofetil, and this improvement in forced vital capacity persists after completion of ten doses of secukinumab|
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| Discussion|| |
In this case report, we have documented ILD (UIP pattern) in a 63-year-old female with psoriasis vulgaris of 10-year duration. There are isolated case reports of ILD in psoriasis. In one of the case reports, a 56-year-old male with long-standing psoriasis developed cough and was diagnosed with UIP.
In another retrospective study, clinical and radiological characteristics of patients with concomitant psoriasis and ILD were documented. In this study, out of 939 ILD patients, 21 patients had concomitant or prior psoriasis. UIP was the predominant radiologic pattern (9), followed by nonspecific interstitial pneumonia (7), organizing pneumonia (3), and chronic hypersensitivity pneumonitis (2). Nearly 62% of patients with psoriasis and ILD were drug naive and 38% had previous exposure to immunosuppressive drugs. The authors concluded that patients with psoriasis are at increased risk of developing ILD irrespective of previous or concomitant exposure to immunosuppressive drugs. Idiopathic pulmonary fibrosis (IPF) was the most common clinical manifestation, whereas UIP pattern was the most common radiologic feature.
In another retrospective study, interstitial pneumonia was detected in 2% of patients with psoriasis who need biological therapy. Patients with psoriasis and ILD were older compared to psoriasis without ILD. Generalized pustular psoriasis was more common in psoriasis with ILD. Ground-glass and/or irregular linear reticular opacity in the bilateral lower lobes was the most common radiologic finding. Most of the patients were asymptomatic or had only mild respiratory symptoms. Only half of the patients with interstitial pneumonia were detected by chest radiograph.
IL-17 A is a key cytokine in pathogenesis of lung fibrosis. In a mouse model, IL-17 A + granulocyte macrophage-colony stimulating factor (IL-17 A + GM-CSF+) expressing neutrophils represented the major inflammatory cells in the fibrotic lungs of mice. The levels of serum cytokines IL-17 A and GM-CSF were elevated in mice with fibrotic lungs. In another mouse model with bleomycin-induced lung fibrosis, higher levels of serum, skin, and lung IL-17 A levels were documented. IL-17 A enhanced pulmonary fibroblast proliferation and type 1 collagen expression which were attenuated by treatment with anti-IL-17A.
IL-17 A plays an important role in connective tissue-related ILD. In a single-center study, lung biopsies of patients with rheumatoid arthritis (RA)-related ILD were compared with lung biopsies of IPF and normal lung tissue. It was shown that lung biopsies of RA-ILD showed significantly higher expression of IL-17A receptor in areas of fibroblast accumulation and fibrosis when compared with either IPF or normal lung tissue.
In patients with scleroderma, the levels of serum IL-17A were increased compared to healthy controls. IL-17 is overproduced by T-cells in scleroderma patients, and they induce the proliferation of fibroblast and the production of IL-17.
In patients with scleroderma, serum IL-17A level was positively correlating with high-resolution CT radiological scores on the lung imaging.
IL-17 in lungs has got a physiological role in defense against pathogens as well as in maintaining epithelial cell homeostasis. IL-17 has a pathogenetic role in lung inflammation, cystic fibrosis, hypersensitivity pneumonitis, asthma, lung fibrosis, and obstructive airway disease.
The potential mechanisms of IL 17-induced lung fibrosis include transforming growth factor-beta-dependent and beta -independent pathways. IL-17 increases synthesis and secretion of collagen from epithelial cells and also promote epithelial–mesenchymal transformation in alveolar epithelial cells. IL-17 stimulation of fibroblasts results in nuclear factor kappa-beta (NF-κβ) activation and profibrotic effects of IL-17 could be limited by inhibitor of NF-κβ activator 1.
Autophagy regulates lung fibrosis and IL-17 promotes lung fibrosis by suppressing autophagy. IL-17 neutralization was associated with increased autophagy facilitating collagen degradation in lung animal models.
Upstream regulators that increase IL-17 are increased in the lung during fibrogenesis. B-cell -activating factor (BAFF) is elevated in patients with IPF. BAFF is required for CD3+ T-cells to produce IL-17. Osteopontin and extracellular adenosine also increase IL-17 levels during lung fibrosis.
Our patient had UIP pattern ILD. IL-17 pathway could be a potential explanation for concomitant psoriasis and ILD in our patient. Previous methotrexate usage could be another potential explanation for ILD in our patient. However, in our patient, methotrexate was used 10 years back. Furthermore, a recent meta-analysis of randomized controlled trials showed that methotrexate use is not associated with increased risk of adverse infectious and noninfectious respiratory events in psoriasis, psoriatic arthritis, and inflammatory bowel disease.
Our patient had improvement in ILD with mycophenolate mofetil. However, she had worsening of psoriasis skin lesions and significant peripheral arthritis which did not respond to sulfasalazine and apremilast; hence, she was considered for biological therapy. Anti-TNF therapy increases the risk of incident ILD as well as exacerbation of preexisting ILD in RA. In a systematic review of literature, 31 cases of anti-TNF-induced ILD was reported. 26 out of 31 patients developed ILD within 20 weeks of initiation of treatment with a mortality rate of 35.5%. However, there are also reports of improvement of ILD in RA with anti-TNF treatment., Anti-TNF therapy though not absolutely contraindicated was not given to our patient. Anti-IL-17 monoclonal antibody secukinumab was used considering the fact that blocking IL-17 could promote resolution of skin lesions, arthritis, and ILD. Preclinical data have shown that anti-IL-17 therapy may be effective in lung fibrosis. In a mouse model study, blocking IL-17 A promotes the resolution of pulmonary inflammation and fibrosis through transforming growth factor-beta-dependent and beta-independent pathways.
Secukinumab is a recombinant fully human monoclonal antibody against IL-17 A. Secukinumab was approved by the Food and Drug Administration (FDA) in January 2015 to treat adults with moderate-to-severe plaque psoriasis. In January 2016, FDA approved it to treat adults with ankylosing spondylitis and psoriatic arthritis.
The clinical experience of secukinumab in ILD is limited and has been inconclusive. There are case reports showing improvement of ILD with secukinumab. In one of the case report, an elderly Japanese woman with long-standing psoriasis was documented to have early stages of ILD on CT imaging. Administration of secukinumab resulted in resolution of ILD. In another patient, psoriasis and ILD were initially treated with ustekinumab with which there was a good response. Later, while on ustekinumab therapy, ILD worsened which was successfully treated with secukinumab.
There are also case reports of secukinumab-induced worsening of ILD. In one of the reports, secukinumab induced ILD after 18 weeks of therapy in a patient with long-standing history of psoriasis. There was complete resolution of ILD 5 weeks after stopping secukinumab. In another case report, there was paradoxical exacerbation of latent interstitial pneumonia after administration of secukinumab in a patient with psoriasis vulgaris. The case reports showing clinical experience of secukinumab in ILD are summarized in [Table 1].
|Table 1: Case reports showing clinical experience of secukinumab in interstitial lung disease|
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Our patient had improvement in ILD (decrease in cough and breathlessness and improvement in FVC with no radiological deterioration) at the end of ten doses of secukinumab. This could be attributable to continuous background usage of mycophenolate mofetil. However, it is important to note that secukinumab did not result in worsening of ILD in our patient. This case suggests that secukinumab could be a safe therapeutic option in psoriasis and psoriatic arthritis with ILD.
There is also a chance that in our patient psoriasis and ILD is unrelated. However, she has no evidence of other connective tissue diseases. In our patient, IPF is a possibility but clinical course of events are not suggestive of IPF. Even if ILD is unrelated to psoriasis, it is still reassuring that secukinumab can be safely used without worsening of ILD. There are limitations to our case report. This is only a single case report; we need more evidence to recommend secukinumab in ILD. Furthermore, this patient needs to be followed up for longer periods of time for any late-onset worsening of ILD considering the fact that there are case reports of worsening of ILD with secukinumab.
| Conclusion|| |
Secukinumab does not seem to worsen preexisting ILD and may be a safe therapeutic option in patients with psoriasis and psoriatic arthritis who have concomitant ILD.
Declaration of patient consent
The author certifies that he has obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]