The Matter at Hand: A Case of Difficult‐to‐Treat Arthritis

A 12-year-old boy with a history of longstanding oligoarticular juvenile idiopathic arthritis (JIA) presented to a new pediatric rheumatology clinic to establish care following a 2-year gap in access. He originally presented with right wrist pain and stiffness without associated swelling when he was age 4 years, and he was diagnosed with antinuclear antibody (ANA)–negative oligoarticular JIA. Shortly after his initial diagnosis, he underwent an intra-articular corticosteroid injection without subsequent improvement to his pain. He failed trials of several systemic therapies, including oral prednisolone, methotrexate, and, subsequently, adalimumab. Despite these therapies, he had no symptomatic improvement and developed progressive loss of range of motion of the right wrist. No additional joints were involved. He did not have evidence of uveitis on screening eye examinations. Over time, he and his mother noted that his right upper extremity appeared smaller than his left upper extremity. He was evaluated for brachial neuritis by both a neurologist and a physical medicine and rehabilitation specialist. However, an electromyography test was unremarkable, and a magnetic resonance imaging (MRI) scan of his brachial plexus demonstrated no abnormalities. Upon re-establishing care, he reported resolution of his right wrist pain despite discontinuing all medications over the prior 2 years. However, he had developed worsening decreased range of motion of the right wrist, with associated weakness and difficulty with manual activities, such as opening water bottles. He denied joint swelling or morning stiffness. Consent for the use of patient data and images was obtained from the patient's parent. This case report was exempt from institutional review board approval. The patient and his mother denied any previous medical diagnoses other than JIA. He had never had any surgeries. He had never had any fractures or serious injuries. The patient was in the sixth grade and performing well in school. There was no family history of rheumatic diseases, including in two older siblings. Specifically, there was no history of JIA or other inflammatory arthropathies, known genetic disorders, or individuals with similar symptoms as the proband. The patient and his mother denied any history of recurrent or persistent unexplained fevers, fatigue, or weight loss. He did not have any numbness or tingling. They denied any visual disturbances, eye redness or pain, or photophobia. They denied any rashes or skin changes. They denied any gross hematuria or peripheral edema. He had met all developmental milestones appropriately. A complete review of systems was otherwise unremarkable. The patient's height was at the 93rd percentile, and his weight was at the 92nd percentile. He had upper extremity asymmetry, with muscle atrophy and shorter length of his right hand and wrist. The range of motion of his right wrist was severely restricted in both flexion and extension (Figure 1). Notably, he did not have overt swelling or tenderness to palpation of the right wrist. His comprehensive joint examination was otherwise normal, with no synovitis, effusions, joint tenderness, or reduced range of motion in any other joints. A basic laboratory work-up was unremarkable, including negative rheumatoid factor, negative anticyclic citrullinated peptide, and normal markers inflammation (Table 1). An x-ray of his right wrist was notable for irregularity with collapse and sclerotic changes of his carpal bones, with marked joint-space narrowing. His metacarpal and phalangeal bones were normal in appearance. Similarly, a right wrist MRI scan demonstrated extensive erosive changes, decreased size, and abnormal configuration of the carpal bones with synovitis (Figure 2). The patient is a 12-year-old boy with a longstanding history of ANA-negative oligoarticular JIA refractory to multiple therapies presenting to re-establish rheumatology care. He was found to have severely restricted range of motion of his right wrist, with extensive collapse, sclerotic changes, and abnormal configuration of his right carpal bones noted on imaging studies but without other joint involvement. This patient presented with a reported history of persistent oligoarticular JIA. According to the International League of Associations for Rheumatology JIA classification, oligoarticular JIA involves four or fewer joints in the first 6 months. Patients are considered to have persistent oligoarticular JIA if the disease does not extend to involve more than four joints after the first 6 months.1 Much like our patient, most patients with oligoarticular JIA present before age 6 years with persistent joint swelling.2 Patients who are inadequately treated can develop destructive joint disease over time. The patient's carpal bone abnormalities could, therefore, be the sequelae of chronic, untreated arthritis. However, several elements of his presentation and response to therapy were atypical for JIA. Monoarticular wrist involvement is not common.3, 4 In fact, wrist involvement on presentation is often considered a risk factor for the development of polyarticular disease.5 The intensity of his disease, with destructive monoarticular wrist involvement, was also unusual. His imaging findings, including the near-total collapse of his carpal bones, were striking in their severity. Finally, his lack of response to multiple anti-inflammatory agents, including intra-articular and systemic glucocorticoids, raises consideration of noninflammatory conditions affecting the joint. Given that his chronic disease course made infections and malignancies less likely, genetic and metabolic JIA mimics were considered next on the differential diagnosis. Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia caused by heterozygous pathogenic variants in MAFB and characterized by osteolysis of the carpal and/or tarsal bones. Less often, the bones in the shoulders, elbows, or knees can also be affected. Osteolysis is typically observed in more than one location (ie, it is multicentric) and is usually symmetric. Subtle craniofacial differences, such as triangular face, micrognathia, and exophthalmos, have also been described but are not always present.6 Ocular and renal disease have been reported.6, 7 Patients with MCTO often present with joint swelling and stiffness in early childhood, and they can be misdiagnosed with JIA.6, 7 Although this patient did not have multifocal disease on clinical assessment, at least one case of unifocal disease had been reported.8 Farber disease (FD) is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the gene-encoding acid ceramidase, ASAH1.9 Acid ceramidase deficiency leads to accumulation of ceramide in tissues. There are multiple distinct subtypes of FD with different patterns of organ involvement ranging from progressive neurologic deterioration to interstitial pneumonia. Type 1 FD is considered a genetic mimic of JIA. The classic triad of manifestations of Type 1 FD includes joint involvement, subcutaneous skin nodules near joints or over points of mechanical pressure, and progressive hoarseness owing to laryngeal involvement. Patients often first present in infancy and develop joint contractures and severe joint deformities over time.10 This patient did not have polyarticular involvement, as would have been expected with FD. He also lacked other classic manifestations, particularly nodules. Although patients can sometimes present initially with joint disease alone and develop other manifestations over time, it would be unusual to have no other manifestations by age 12 years. Progressive pseudorheumatoid dysplasia (PPRD) is an autosomal recessive skeletal dysplasia caused by biallelic pathogenic variants in CCN6 that lead to altered cartilage homeostasis. Patients with PPRD are typically healthy at birth. They first present in childhood with enlarged interphalangeal joints, gait abnormalities, and joint stiffness, most often of the interphalangeal joints, knees, and hips. They can therefore be misdiagnosed with JIA. This skeletal disease is progressive, and, by adulthood, most patients have kyphoscoliosis, short stature with a short trunk, diffuse joint contractures with restricted range of motion of most joints, and camptodactyly.11 Although most joints end up affected with progressive disease in PPRD, wrist involvement at onset, as seen in this patient, is not typical.11 Although this patient had restricted range of motion of his right wrist, he had normal range of motion of all other joints, normal gait, and normal growth. Type II collagen disorders are a spectrum of diseases caused by heterozygous pathogenic variants in COL2A1, which encodes the alpha-1 chain of type II collagen. These disorders are generally characterized by skeletal dysplasia, eye disease, and hearing impairment. However, their manifestations are diverse, ranging from severe disorders that are often lethal in the perinatal period to milder disorders that present with early-onset osteoarthritis in adolescence or adulthood.12 As type II collagen is a component of cartilage, it is perhaps not surprising that type II collagen disorders can present with joint dysfunction. Patients with Stickler syndrome type 1, which can present with a range of manifestations and severities, can develop early-onset arthropathy. This patient is less likely to have Stickler syndrome without associated hearing loss, cleft palate, or ocular manifestations, such as myopia, retinal detachment, and early-onset cataracts.12 Following his initial evaluation, the patient was started on tocilizumab for management of presumed uncontrolled JIA, as he had not previously been tried on interleukin (IL)-6 inhibition. He was also referred to hand surgery for assistance with management of his restricted range of motion, which interfered with his activities of daily living. He underwent right forearm tendon lengthening followed by serial casting and occupational therapy (OT). He reported functional improvement following his procedure and course of OT. Finally, he was referred to genetics to be evaluated for genetic and metabolic mimics of JIA. A commercially available skeletal dysplasia genetic panel identified a heterozygous MAFB pathogenic variant (NM_005461.4:c.187C>T, p.Pro63Ser), diagnostic of MCTO. Parental testing confirmed that this variant was de novo. Following his genetic diagnosis, a skeletal survey was performed and did not demonstrate any additional skeletal abnormalities. His tocilizumab was discontinued, and he did not have any changes in his clinical status following drug discontinuation. He was started on vitamin D supplementation to optimize his bone health. Screening for additional organ involvement, including an ophthalmologic examination and a renal evaluation, was unremarkable. He will continue to have annual follow-up visits for surveillance. He was referred to physical therapy to help prevent additional muscle atrophy from disuse. We have presented the case of a 12-year-old boy with a presumed history of longstanding ANA-negative oligoarticular JIA refractory to multiple therapies who was found instead to have a genetic mimic of JIA, MCTO. Patients with MCTO typically present in early childhood with joint pain, swelling, and stiffness, symptoms that often lead to a misdiagnosis of JIA. They develop progressive osteolysis of the carpal and/or tarsal bones. Other joints, such as the shoulders, elbows, and knees, are variably affected.6, 7 Over time, focal joint destruction can lead to impaired growth and functional impairment of the affected area. This patient's presentation was atypical for MCTO in that he did not have multicentric disease. Nevertheless, he has a molecular confirmation, and unifocal disease has been previously reported.8 There is significant clinical heterogeneity in the cases of MCTO described in the literature, with different degrees of skeletal involvement and functional impairment.13 In most cases, progressive skeletal deformities occur during childhood and adolescence, but case reports describing long-term follow-up into adulthood are limited. MCTO results from heterozygous pathogenic variants in the MAFB gene,7, 14 but the pathogenesis is not completely understood. The gene encodes a transcription factor, MafB, that has multiple roles, including negative regulation of osteoclast differentiation.15 It is still unclear, however, why the osteolysis of MCTO is most prominent in the carpal and tarsal bones. A component of altered bone formation at these sites, in addition to osteolysis, has been hypothesized.7 Indeed, differential expression of the transcription factor MafB in wrist bones during endochondral ossification has been demonstrated in healthy mice, supporting the notion that distinct mechanisms of bone formation in the wrist may be responsible for the distribution of bone involvement in MCTO.16 The role of inflammation in this disease is also unclear. However, the fact that MCTO mimics JIA and that MRI findings of joint inflammation have been documented17, 18 suggests that it may play a role. Interestingly, this patient's wrist MRI scan demonstrated synovitis. Once this patient's genetic diagnosis was made, it was necessary to decide whether to continue his tocilizumab, which had been prescribed for presumed JIA. Just as a role for inflammation in the pathogenesis of MCTO has not yet been elucidated, the role of anti-inflammatory agents in the management of MCTO remains unclear. Although some patients have reported symptomatic improvement with anti–tumor necrosis factor and anti–IL-6 agents, evidence that it deters further osteolysis is lacking.17, 18 Given his lack of response to therapy, the lack of strong evidence to support benefit in the context of immune suppression, and the need for ongoing safety monitoring, his tocilizumab was discontinued. Although he was started on vitamin D supplementation to optimize bone health, our patient was not started on any additional systemic therapies following his diagnosis. There is currently no standard of care for MCTO. Antiresorptive agents, such as bisphosphonates and denosumab, have been attempted for MCTO management. However, as with anti-inflammatory agents, they have had little success in preventing further focal bone destruction.8, 19, 20 They may play a role in addressing generalized osteopenia, which can be observed in patients with MCTO.8, 19 Surgical interventions can be considered in some situations and may offer both symptomatic relief and improved function.21 A multidisciplinary approach to care for patients with MCTO is recommended, as they require surveillance for disease complications. Up to two-thirds of patients with MCTO develop kidney disease (focal segmental glomerulosclerosis), and approximately half of those can progress to kidney failure.6 This may be because the transcription factor MafB regulates podocyte survival in the kidneys.22, 23 Ocular complications, such as corneal opacities, have also been reported.6 There are no current guidelines for renal and ophthalmologic screening of patients with MCTO. This patient has had normal renal and ophthalmologic evaluations. Nevertheless, he continues to follow serially with his pediatric rheumatologist, nephrologist, ophthalmologist, and clinical geneticist. He undergoes yearly screening urinalyses and chemistry panels. This case illustrates features of MCTO, a skeletal dysplasia that mimics JIA. It highlights that a diagnosis of MCTO should be considered in patients with localized destruction of the carpal and/or tarsal bones, especially, although not exclusively, when in association with kidney disease and/or craniofacial differences. More broadly, this case also supports the need to consider genetic and metabolic JIA mimics (Table 2) when evaluating patients with treatment-refractory disease. Genetic testing should be considered early in patients with atypical joint disease that does not respond to conventional therapies, as timely identification of genetic diagnoses can guide therapy, surveillance for complications, and genetic counseling for the patient and family. Multicentric carpotarsal osteolysis syndrome All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Pereira confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements. Disclosure form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.