A Case of Spondyloarthritis with Fulminant Extra-articular Features and Renal Amyloidosis and Difficulties in its Phenotypical Classification
Year: 2025
Type: article
Study design: Case Report
Abstract: INTRODUCTION Spondyloarthritis (SpA) refers to a group of overlapping disorders of ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic arthritis (PsA), arthritis associated with inflammatory bowel disease (IBD), juvenile SpA and undifferentiated SpA. These disorders are broadly classified as either predominantly axial SpA (Ax-SpA), affecting the spine, pelvis and thoracic cage or predominantly peripheral SpA, affecting the extremities. The classification criteria for SpA have evolved over the years. Recently, separate criteria for Ax-SpA and peripheral SpA have been developed by the Assessment of Spondylo-Arthritis International Society (ASAS) to increase the sensitivity of diagnosing SpA, even in its early phase.[1,2] Ax-SpA is often associated with one or more of several articular features, including synovitis, enthesitis and dactylitis. It may also be associated with several non-articular features such as psoriasis, IBD, and uveitis. Peripheral SpA includes cases that only have peripheral involvement (dactylitis, enthesitis, asymmetrical distal oligoarthritis, etc.). This pattern may be seen with psoriasis, ReA, IBD and a subset of patients without established definitions.[1,2] Patients with axial features, even if they have peripheral manifestations of musculoskeletal involvement, cannot be classified as peripheral SpA. Many patients present with one or more SpA features but lack sufficient findings for any one of the preceding diagnoses. These patients were said to have undifferentiated SpA or simply SpA. The diagnosis of undifferentiated SpA was commonly applied to patients with peripheral arthritis and/or enthesitis and to patients with IBD and other SpA features who did meet the radiographic criteria for AS.[2,3] A clear distinction between the clinically defined phenotypes of SpA is often difficult and the diagnosis may change during a patient’s disease course. It has been observed that renal impairment in SpA has a low prevalence (1%–5%).[4] The renal abnormalities include glomerulonephritis (particularly immunoglobulin [Ig] A nephropathy), renal amyloid deposition, microscopic hematuria, microalbuminuria and decreased renal function and creatinine clearance. Amyloidosis is more prevalent in aggressive and active SpA and older patients with longstanding diseases.[5] Hereby, we report the case of SpA with features of multiple phenotypes at different times in the course of the illness that ultimately lead to the development of renal amyloidosis. CASE REPORT Our case is a 35-year-old male, a cook by profession, chronic cigarette smoker (15 pack years, active smoker) and occasional Ganja/Charas (cannabinoids) user. At the age of 18 years, he experienced insidious onset gradually progressive pain and swelling in bilateral knee joints, which was improving with daily activities and getting worse in the morning hours. This pain had an inflammatory nature and was accompanied by a distinct inflammatory low backache. There was no associated history of fever. His symptoms used to subside with over-the-counter painkillers and exercise. In subsequent years, he remained mostly asymptomatic, only requiring on-demand painkillers twice or thrice a month for backache. At the age of 32 years, the patient had developed polyarthritis, erythematous annular penile lesions and scaly plaques over the palms and soles, following which he was diagnosed with ReA and started on oral steroids and methotrexate. After an initial clinical improvement, he discontinued his medications and lost to follow-up further. He now presented to our centre with complaints of joint pain (bilateral knees, shoulders and left wrist), skin and nail lesions for 3 months and diarrhoea for 1 month, with dysentery in the last 5 days. The diarrhoea was insidious in onset, initially 2–3 episodes/day and later worsened to 5–6 episodes/day. The stools were of watery consistency, small volume, mixed with mucous and blood, however, not associated with fever. It was associated with intermittent colicky abdominal pain, urgency, tenesmus and bloating sensation. He had also experienced multiple non-bilious, non-bloody vomiting episodes in the last 10 days, associated with a reduced urine output (~500 mL/day). There was a history of bilateral progressive pedal oedema; however, no history of altered mental status or respiratory distress was present. There was no history of antibiotic usage before the onset of diarrhoea, contact with diarrhoea patients in his home or neighbourhood. There was also no history of steatorrhoea or any history suggestive of intravenous (IV) drug abuse, high-risk sexual behaviour, tattooing or blood transfusion. Possibility of inflammatory diarrhoea and renal dysfunction (pre-renal AKI) were kept at this point. On examination, the patient was conscious, oriented, pale-looking and haemodynamically stable. There were multiple well-defined erythematous hyperkeratotic plaques with scaling over the forearms, hands and lower limbs [Figure 1a and b]. There were multiple erosions of the oral mucosa and characteristic lesions of keratoderma blennorrhagica [Figure 1c] and circinate balanitis [Figure 1d]. Nail changes in the form of proximal onycholysis and subungual hyperkeratosis [Figure 1e] were also present. On musculoskeletal examination, he had swelling and tenderness of both knees and left wrist joints. Bilateral shoulder and distal interphalangeal joints were tender, but no peripheral joint limitation or deformity existed. The patient had reduced metrological parameters, namely the modified Schober test (2 cm), chest expansion (2 cm), lateral lumbar flexion (8 cm each) and intermalleolar distance (60 cm) - suggestive of axial ankylosis. His other systems’ examinations were unremarkable.Figure 1: Images of various skin lesions in the patient, which consist of psoriatic rashes; various erythematous hyperkeratotic plaques with scaling over various body parts–including the forearm, hands, and lower limbs (arrow) (a and b), keratoderma blennorrhagica involving bilateral soles (arrow) (c), circinate balanitis (arrow) (d), and various nail changes including proximal onycholysis, and subungual hyperkeratosis (arrow) (e)Considering the above history and examination findings, the patient was classified as Ax-SpA as per the ASAS criteria. Since the clinical features of circinate balanitis and keratoderma blennorrhagica preceded other cutaneous manifestations, he was initially diagnosed with ReA. Over the course of the illness, the patient developed psoriasiform lesions as well, thereby suggesting a diagnosis of PsA. However, the authors would like to highlight their dilemma as pustular psoriasiform skin lesions may also occur in ReA. At the same time, circinate balanitis may also occur in psoriasis patients and pustular palmoplantar psoriasis may appear similar to keratoderma blennorrhagica visually and histopathologically. Chronic diarrhoea and dysentery suggested a possibility of IBD.[6] The patient had a raised erythrocyte sedimentation rate (ESR) of 121 mm in 1st h (normal range; 0–20 in a male in this age) and C-reactive protein of 174 mg/dL (normal range: 0–6 mg/dL). He had negative rheumatoid factor and anti-citrullinated protein antibodies and a positive HLA-B27 by the polymerase chain reaction. His X-ray of sacroiliac joints showed Grade IV sacroiliitis (New York criteria) [Figure 2a]. The radiographs also showed the typical Dagger sign [Figure 2b], facet joint ankylosis and Bamboo spine [Figure 2c]. Stool routine microscopy examination and stool aerobic cultures were non-suggestive; however, faecal calprotectin levels were significantly raised (3640 μg/g; normal value <50 μg/g). X-ray of the abdomen showed a dilated colon. Colonoscopy showed loss of vascular pattern, cobblestone appearance, mucosal oedema and deep ulcers at the various parts of the large intestine, constituting the picture of IBD-Crohn’s colitis [Figure 3a and b]. Histopathology from the same showed features suggestive of mild active chronic colitis. Cutaneous punch biopsy from the lower limb plaque was suggestive of psoriasiform dermatitis.Figure 2: Various radiological images suggestive of axial spondyloarthritis, like: Grade 4 sacroiliitis in X-ray SI joint - indicated by arrow on right side (a), Ossification of supraspinous and interspinous ligaments leading to ‘Dagger sign’ appearance of the spine (arrow) (b), ‘Bamboo spine’ appearance of thoracolumbar spine as a result of vertebral body fusion by marginal syndesmophytes (arrow) (c). Also, note the presence of facet joint fusion due to chronic facetal arthritisFigure 3: Colonoscopy and histopathology images: Colonoscopy images suggest inflammatory bowel disease (a and b). Histopathology of renal biopsy showing irregular fluffy amorphous material (see arrow) deposition in the mesangial matrix with variable para mesangial expansion, which is weakly positive with Periodic acid-Schiff stain, negative with silver methenamine stain, suggestive of renal amyloidosis (c)He had persistent leucocytosis (30,000–40,000/μL) with a neutrophilic predominance (90%–95%), although he was afebrile and blood/urine cultures were sterile. His peripheral smear and leucocyte alkaline phosphatase score (288) suggested a leukemoid reaction. However, to rule out underlying chronic myeloid leukaemia, BCR-ABL was tested which came to be negative. Subsequently, leucocytosis showed a resolving trend after the starting of immunomodulators. His blood urea nitrogen (60 mg/dL) and serum creatinine (5.6 mg/dL) were elevated. Urine analysis revealed 2+ proteinuria (24-h collection deferred due to oliguria), with 5–6 red blood cell/high-power field. Arterial blood gas analysis revealed a normal anion gap metabolic acidosis (even after correction for hypoalbuminaemia). Bilateral kidney size was found to be normal and a renal biopsy was done, which showed glomerular and vascular AA amyloid deposits [Figure 3c]. The patient was initially managed with IV fluids, oral rehydration solution, probiotics and antibiotics (metronidazole) because of chronic diarrhoea with dysentery. Renal dysfunction was initially managed conservatively with adequate hydration, alkali supplementation and anti-hyperkalemic and hypophosphatemia measures. Later, he required hemodialysis (a total of 5 sessions in 11 days). An oral tramadol-acetaminophen combination was started for pain relief, and arthralgia symptoms improved gradually. A topical clobetasol-salicylic acid combination was started for psoriasiform skin lesions. As the renal dysfunction and diarrhoea persisted, oral steroids (prednisolone – 40 mg/day) were started, and his IBD symptoms improved drastically after that, along with gradual improvement in renal parameters. Later he was discharged on oral steroids, 5-ASA agents (sulphasalazine), and other supportive medications. The patient reported for follow-up 1 month after discharge with an improvement in his joint pain symptoms, skin lesions, IBD symptoms and renal status. Two-weekly adalimumab was advised but the patient lost to follow-up. A telephone inquiry disclosed that the patient passed away 2 months after his last follow-up, presumably due to renal complications. DISCUSSION Most rheumatic diseases do not have unique or specific diagnostic tests, and classification criteria have been developed to identify homogeneous patient populations for the clinical trials. It should be noted that most of the criteria sets in rheumatology have been developed as the classification criteria for clinical research but are widely used as diagnostic aids in daily practice. For spondyloarthropathies, various diagnostic criteria were introduced over time. After the initial European Spondyloarthropathy Study Group and Amor criteria, ASAS criteria were introduced which included radiological and clinical arms for the first time.[2] Over time, ASAS criteria have also undergone various modifications with the aim of early diagnosis of spondyloarthropathies, even before radiological findings. Currently, SpA patients are broadly classified into Ax-SpA and peripheral SpA as per the ASAS classification criteria. Nevertheless, those SpA patients who do not fulfil any such classification or diagnostic-specific criteria remain unclassified and comprise the subgroup of undifferentiated SpA.[3] Overlaps between the various SpA phenotypes are common (for example, AS and psoriasis in the same individual, or PsA, AS and Crohn’s disease in one patient).[3] A meta-analysis of 2236 patients by de Winter et al. showed that peripheral disease (arthritis, enthesitis and dactylitis) and extra-articular disease (uveitis, psoriasis and IBD) manifestations are frequent and, except for uveitis, equally prevalent in AS and non-radiographic Ax-SpA.[7] Results from a national register-based cohort study in Sweden (from 2001 to 2015) showed that anterior uveitis, followed by IBD and psoriasis, is the extra-articular manifestation most strongly associated with AS and uSpA. Amongst the SpA subtypes, AS and uSpA display a similar pattern of extra-articular manifestations, whereas PsA has a considerably weaker association with anterior uveitis and IBD.[8] Here, our patient meets the classification criteria of Ax-SpA (ASAS criteria). Interestingly, he has developed phenotypic features of all four axial adult spondyloarthropathies over time. Initially, his condition manifested as AS, later progressed to ReA, subsequently displaying typical characteristics of PsA (meeting CASPAR criteria), and now finally, presented with features of IBD. The time spectrum of presentation of his various SpA phenotypes in this patient is plotted in Figure 4. Hence, as in our case, it may not be possible to classify the disease into a specific phenotypic form. Even when the diagnosis looks straightforward at one point in time, the patient may evolve into a different phenotype on the follow-up. This has significant implications for the research profile of the patient. As already explained in ‘differential diagnosis’, the patient could ultimately be classified as either ReA or PsA.Figure 4: Timeline of onset of various spondyloarthritis phenotypes in the present case. IBD: Inflammatory bowel diseaseRenal involvement in SpA patients is low in prevalence, as per the various studies. The ASAS-COMPOSA, a cross-sectional study conducted across 22 nations, showed a 5.2% prevalence of renal impairment.[5,9] It includes pathologies such as IgA nephropathy, amyloidosis and analgesic nephropathy. Here, apart from the florid manifestations of the disease, our patient also had renal dysfunction in the form of intrinsic-oliguric renal acute kidney injury, sub-nephrotic range proteinuria, microscopic hematuria and normal anion gap metabolic acidosis. A kidney biopsy revealed renal amyloidosis-AA type. Secondary amyloidosis (AA) is a complication of chronic inflammatory diseases. It is estimated that around 1.1% of AS patients present as amyloidosis in its symptomatic form and 7% in its asymptomatic manifestation, as per the various studies conducted.[10,11] They showed that 1.3% of patients with SpA were diagnosed with amyloidosis, of which 33.3% had AS, 33.3% had IBD-associated SpA, 26.7% had PsA and 6.7% had ReA. They found that symptomatic AA amyloidosis in AS usually occurred in patients with the long-term disease, with significant axial and peripheral involvement, higher ESR and Bath AS Disease Activity Index at the beginning of the disease and lower haemoglobin levels. Amyloidosis was also associated with all the types of SpA; in particular, IBD-associated SpA showed a stronger association. IgA nephropathy is another common form of renal dysfunction seen in SpA.[5,12] The present case demonstrates one or the other characteristic features of each of the phenotypes of SpA in a single patient. It also highlights the difficulties in disease classification/diagnosis in rheumatology and the importance of recognising the patterns of involvement and treating accordingly. In conclusion, the SpA can present with overlapping phenotypes which can evolve as the disease progresses; hence, follow-up is crucial for exact categorization; otherwise, research documentation may be incorrect. In SpA, pattern recognition (axial or peripheral; with or without extra-articular features) may have more therapeutic implications for the patient rather than chasing a specific phenotypic diagnosis. AA amyloidosis should be suspected in patients with longstanding uncontrolled SpA with persistently elevated acute-phase reactants, proteinuria and renal failure. Such a life and organ-threatening complication can be avoided completely with the appropriate control of disease activity. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Declaration of generative AI and AI assisted technologies in the writing process AI tool was not used in preparing this manuscript.
Source: Journal of Medical Evidence
Authors: P. Anantha Krishnan, Shyam Murti Bohare, Prasan Kumar Panda, Rajat Ranka
Institution: All India Institute of Medical Sciences Rishikesh
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4408842881