A Patient with Pustulotic Arthro-osteitis with Isolated Spinal Lesions Successfully Treated with Risankizumab

Abstract

Pustulotic arthro-osteitis (PAO) is a rare chronic inflammatory arthropathy associated with palmoplantar pustulosis (PPP). PAO involves various extra-palmoplantar sites, including spinal lesions. Systemic treatment, including biologics, is required for refractory cases of PAO. We herein report a man diagnosed with PAO who predominantly manifested spinal symptoms. Initial treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and bisphosphonates achieved a minimal response. Risankizumab, an anti-interleukin-23 p19 antibody, was subsequently administered, which resulted in significant improvement after the fourth dose, resolving both spinal and cutaneous manifestations. This case report highlights risankizumab as a potential therapeutic option for refractory PAO with spinal involvement.

Introduction

Palmoplantar pustulosis (PPP) is a chronic recurrent dermatological disorder characterized by sterile pustules on the palms and soles (1). Its osteoarticular manifestation, pustulotic arthroosteitis (PAO), includes inflammatory synovitis, osteitis, and spondylitis, which can lead to functional impairment (2). Smoking and tonsillar or dental infections are presumed to be important triggering factors exacerbating PPP (3). As another triggering factor, dental metal allergies may induce or exacerbate PPP (4). Treatment of PPP is challenging and usually requires prolonged management (5). Therapeutic standards and published guidelines for PAO treatment have not been completely defined. Anti-interleukin (IL)-23 p19 agents have been approved for refractory PPP under the Japanese health insurance system (6), and the clinical benefits of these biologics against PAO have been suggested.

Previous therapeutic attempts with anti-tumor necrosis factor (TNF) inhibitors (infliximab, adalimumab, etanercept) have shown limited efficacy for PAO (7), while IL-17 and IL-23 inhibitors have shown beneficial effects in patients with PPP (8). More recently, IL-23-inhibitors, guselkumab, and risankizumab have been shown to be effective for PPP, and both agents have been approved for the treatment of PPP in Japan (9,10). Nevertheless, real-world evidence regarding its efficacy in PAO remains scarce.

We herein report a refractory PAO patient treated effectively with risankizumab who achieved dermatological and rheumatologic improvement.

Case Reort

A 63-year-old man presented with a 3-month history of persistent thoracic pain. Three months prior, he developed PPP, which gradually spread across both palms and soles and was associated with severe back pain. Until his first visit to our hospital, the patient had been treated with topical steroids and non-steroidal anti-inflammatory drugs (NSAIDs; loxoprofen sodium 180 mg/day) for 2 months. However, these treatments failed to improve his symptoms, and the pain in the thoracic spine persisted. The patient was referred to our hospital for a further examination of thoracic spinal pain and multiple pustular lesions on both palms and soles. His medical history revealed chronic smoking (10 cigarettes/day, 40 years) but no significant familial history. His history was otherwise unremarkable with no dental metal allergy, periodontitis, or tonsillitis.

A skin examination revealed multiple pustular lesions on both palmar and plantar surfaces (Fig. 1). A physical examination revealed tenderness in the thoracic spine that was exacerbated by anteflexion. No swelling or tenderness was observed in the anterior chest wall. Neither sacroiliac joint pain nor peripheral joint pain was noted.

Figure 1.

Cutaneous findings of palmoplantar pustulosis on the palms and soles. Cutaneous findings of palmoplantar pustulosis of the palms and soles. A small number of blisters and pustules and scattered scales on erythematous skin were present on both palms (A) and soles (B) before the start of risankizumab treatment.

A blood analysis (Table) showed an erythrocyte sedimentation rate (ESR) of 51 mm/h and C-reactive protein (CRP) of 2.44 mg/dL (reference range, ＜0.30 mg/dL). The complete blood count and liver and renal function measurements were all within the normal range. Rheumatoid factor, anti-cyclic citrullinated peptide antibody, human leukocyte antigen B27, and antinuclear antibodies were all negative. He had moderate thoracic spinal pain, suggestive of concomitant PAO. Conventional radiography of the sacroiliac joint showed no abnormalities (Fig. 2); therefore, magnetic resonance imaging (MRI) of the thoracic spine was performed. Short-tau inversion recovery MRI of the cervical and thoracic spine revealed a high signal intensity in multiple vertebral lesions (Fig. 3; before), corroborating the presence of spondylitis in multiple vertebral lesions. He fulfilled the diagnostic criteria for PAO (11), and PPP with PAO was diagnosed. The patient stopped smoking after receiving education for smoking cessation.

Table.

Laboratory Findings on Admission.

Peripheral blood				Immunoserological test
Red blood cells	436×104	/μL		C-reactive protein	2.44	mg/dL (<0.30)
Hemoglobin	13.6	g/dL		Erythrocyte sedimentation rate	51	mm/hr (<10)
Hematocrit	40.7	%		IgG	1,162	mg/dL (861-1,747)
Platelet	58.3×104	/μL		IgA	249	mg/dL (110-410)
White blood cells	7,100	/μL		IgM	93	mg/dL (39-190)
Neutrophil	53	%		RF	10	IU/mL (<15)
Eosinophil	5	%		Anti-CCP Ab	2.5	U/mL (<4.5)
Monocyte	10	%		MMP-3	36	ng/mL (<121)
Lymphocyte	32	%		ANA	<40
Basophil	1	%		MPO-ANCA	(-)	(<3.5 IU/mL)
Blood chemistry				PR3-ANCA	(-)	(<2.0 IU/mL)
Total protein	7.4	g/dL (6.6-8.1)		Microbiological test
Total bilirubin	0.4	mg/dL (0.4-1.5)		HBsAg	(-)
Albumin	3.9	g/dL (4.1-5.1)		Anti-HCV Ab	(-)
Aspartate aminotransferase	16	IU/L (13-30)		β-D-glucan	11	pg/mL (<20)
Alanine aminotransferase	14	IU/L (10-42)		Procalcitonin	20	pg/mL (<50)
Lactate dehydrogenase	131	IU/L (124-222)		CMV antigenemia	(0, 0)
Alkaline phosphatase	109	IU/L (106-322)		T-spot	(-)
Creatine kinase	55	IU/L (59-248)
Blood urea nitrogen	6.0	mg/dL (8-20)		Urinalysis	normal
Cr	0.75	mg/dL (0.65-1.07)
Na	140	mEq/L (138-145)
K	3.8	mEq/L (3.6-4.8)
Cl	105	mEq/L (101-108)
Calcium	10.0	mg/dL (8.6-10.1)

ANA: antinuclear antibody, ANCA: anti-neutrophil cytoplasmic antibody, CCP: cyclic citrullinated peptide, CMV: cytomegalovirus, HBsAg: hepatitis B surface antigen, HCV: hepatitis C virus, MMP-3: matrix metalloproteinase-3, MPO: myeloperoxidase, PR3: proteinase 3, RF: rheumatoid factor

Figure 2.

Radiography of sacroiliac joints. Neither joint space narrowing nor subchondral sclerosis were observed in the bilateral sacroiliac joints.

Figure 3.

MRI findings of the cervical and thoracic spine before and after risankizumab treatment. Sagittal T1-weighted (T1WT) and short-tau inversion recovery (STIR) images of the spine displaying high signal intensities on STIR images of anterior vertebral body lesions of the cervical and thoracic spine (white arrows) before risankizumab treatment (Before). Note that the high signal intensities on STIR images resolved 28 weeks after the start of risankizumab treatment (After).

He was treated with bisphosphonates (risedronate 17.5 mg/weekly) and salazosulphapiridine (500 mg/day); however, his thoracic spinal pain gradually worsened, and his serum CRP level was further elevated (8.78 mg/dL). Therefore, risankizumab was initiated. The drug was first administered 3 months after the first visit to our hospital via subcutaneous injection at a standard dose of 150 mg, followed by a second injection 4 weeks later and then 1 injection every 12 weeks. Bilateral cutaneous lesions on the palms and soles showed marked improvement (Fig. 4) after the start of risankizumab injection. Thoracic pain was also resolved 3 months after the start of risankizumab injection in accordance with the normalization of laboratory data (ESR: 5 mm/h and CRP: 0.11 mg/dL). The disease activity was markedly reduced, as evaluated by the Palmoplantar Pustulosis Area Severity Index (PPPASI) (12). The activity at the initiation of risankizumab was as follows: PPPASI, 16.8; and patient global assessment (PtGA), 70 mm. At the last evaluation performed at 28 weeks, the cutaneous symptoms had largely improved (PPPASI=2.3), as had the PtGA (15 mm). Follow-up MRI was performed six months after starting risankizumab therapy and showed the disappearance of abnormal signals in the cervical and thoracic vertebral lesions (Fig. 3), suggesting that risankizumab could be an effective treatment for refractory cases of PAO.

Figure 4.

Cutaneous findings of palmoplantar pustulosis atter risankizumab treatment. Cutaneous findings on the palms (A) and soles (B) 28 weeks after starting risankizumab. Skin lesions of palmoplantar pustulosis were improved.

Discussion

PAO is a significant comorbidity associated with PPP, and Japanese patients with PAO have been reported (13). Although PAO manifests as anterior chest wall lesions, spinal, sacroiliac, and peripheral joint lesions are also known to be affected (14). Synovitis acne pustulosis hyperostosis-osteitis (SAPHO) syndrome is a rare inflammatory osteoarticular disorder that encompasses many diseases, including PAO. Indeed, more than half of Japanese patients with PAO fulfill the diagnostic criteria for SAPHO syndrome (13), and the present case meets Kahn's diagnostic criteria for SAPHO syndrome (17).

Owing to its rarity, therapeutic strategies for PAO have not been standardized and are mostly based on case reports or case series. Generally, NSAIDs and analgesics constitute first-line interventions for pain management in PAO, and disease-modifying antirheumatic drugs (DMARDs) show benefits in certain cases (18). Bisphosphonates have emerged as alternative treatments owing to their inhibitory effects on bone resorption and the potential to alleviate joint symptoms (19). Nevertheless, their efficacy in cutaneous and joint symptoms remains controversial (5). Consistent with the refractory nature of PAO, initial treatments of NSAIDs, salazosulphapiridine, and bisphosphonates failed to yield satisfactory results in the present patient. Although TNF inhibitors have been used for refractory PAO, their efficacy is yet to be demonstrated in randomized controlled trials (20). Notably, IL-23-targeting treatments show promise for managing PPP (1). However, the efficacy of these treatments requires further investigation for real-world applications.

MRI facilitates the early detection of spinal inflammation before structural damage occurs (21). MRI effectively identified spinal inflammation in our patient, which was substantially alleviated following risankizumab treatment, as evidenced by radiological improvement and normalization of the acute-phase reactants. Recent single-cell analyses have highlighted that the inflammatory pathway in PPP involves dendritic cell-mediated IL-23 production and subsequent activation and proliferation of T helper 17 cells (22).

A Japanese phase III RCT comparing the IL-23 p19 inhibitor guselkumab to placebo revealed significant improvements in dermatological symptoms in Japanese patients with PPP (9). A subgroup analysis of PAO patients in this study demonstrated that guselkumab treatment resulted in the improvement of PAO signs and symptoms, suggesting that guselkumab has potential as a novel therapeutic option for treating PAO (23). In addition, guselkumab showed improvement in the articular manifestations evidenced by MRI findings, while a slight decrease in the CRP level was observed in the guselkumab group at week 52 compared to baseline in this subgroup analysis (23). In our case, risankizumab successfully improved the dermatological and spinal involvement of PPP as well as the normalization of CRP and ESR.

Cytokine blockade therapies are valuable in addressing cytokine imbalances in refractory PPP (1). Risankizumab is a human monoclonal IgG1 antibody targeting IL-23p19 (24). A recent randomized phase 3 trial in Japanese patients with moderate-to-severe PPP demonstrated greater improvement in PPPASI change from baseline at week 16 with risankizumab versus placebo (10). Nevertheless, data regarding the effectiveness of risankizumab against PAO remain limited. Risankizumab may improve joint involvement, including spinal lesions of PAO, by inhibiting the IL-23 pathway. To our knowledge, this is the first known report of the effectiveness of risankizumab in achieving both dermatologic disease improvement of PPP as well as the spinal involvement of PAO.

Several limitations associated with the present study warrant mention. First, the effect of methotrexate (MTX) was not evaluated, as MTX seems to be mainly used to treat peripheral arthritis and was not used in this case. Second, we have only reported the findings at one-year follow-up in our case, so long-term observation to conclude the effectiveness of risankizumab against spinal involvement in PAO is needed.

In conclusion, our case underscores the effectiveness of risankizumab in the treatment of refractory PAO with spinal involvement. IL-23p19-targeted therapy appears promising as a novel therapeutic option for refractory PAO patients unresponsive to conventional treatments, including DMARDs and bisphosphonates. Further case accumulation and extended follow-up studies are necessary to validate the long-term efficacy and safety of risankizumab.

Appropriate written consent was obtained from the patient.

The authors state that they have no Conflict of Interest (COI).