Vara-pericarditis Syndrome Research Articles

OA23 A complex case of psoriatic juvenile idiopathic arthritis

Abstract Introduction This patient demonstrates many of the challenges that can be faced when treating juvenile idiopathic arthritis (JIA). The combination of difficult to treat disease, together with her social situation has made her case a particularly challenging one. Her case outlines the necessity of a multidisciplinary, and multi-agency, approach to treatment to ensure patient’s needs are met. Case description This patient presented at five years old with a several year history of swelling in her knees and feet. On examination she had a polyarthritis affecting bilateral metacarpal-phalangeal joints, both wrists, both elbows, and both knees. She is ANA negative and RF negative. She was initially treated with intravenous methylprednisolone (IVMP), methotrexate and joint injections. This patient’s disease has been very difficult to treat, with inadequate response to multiple medications (see table 1). She has had multiple flares, required 12 General anaesthetics for joint injections, as well as several pulses of IVMP to help control her inflammation. The patient has persistent effusion of her knees, not responsive to intra-articular steroids and the presence of significant crepitus. An MRI of her right knee showed 14 mm loose bony fragment, in addition to synovitis and effusion. The orthopaedic team were not keen to manage this surgically. She was discussed with other centres, following which combination of biologics / biologic with small molecule (JAK inhibitors) was felt to be the next option. Adalimumab was added to Tofacitinib in June 2024 due to inadequate control. Discussion The difficulty in treating this patient have made us consider alternative diagnosis. MRI scans of her hips done in April 2023 showed bilateral coxa vara. This, along with no evidence of erosions and poor response to treatment, raised the possibility of Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. However, she did not have camptodactyly, her echocardiogram did not show pericardial effusion and the genetic testing was negative. This patient has a complex social background. She lives with her mother, and no longer has contact with her father, or his side of the family. Her mother was involved in a car accident many years ago and due to a traumatic brain injury has difficulty with memory. Her mother has also suffered with depression. This, together with financial difficulties, have led to many missed appointments and concerns around compliance, despite continuous support from our specialist nursing team. The patient has poor school attendance- more than can be accounted for by her disease. Her current school are very supportive. They give reminders about appointments, and a teacher collects her from home and takes her to school each day. When she starts secondary school this level of support will not be available. Providing psychological support has been challenging due to her age and available resources. However, now she is 11 years old she will be able to get involved with our youth team. She struggles with needle phobia, and is very self-conscious about her swollen knees, and the sound they make when she moves. At various times, safeguarding referrals have been made to try to support the family, none of which were accepted. Her mother’s reluctance to accept support from social services did not help either. This has presented the team with many challenges. Key learning points • This is a challenging case of psoriatic JIA, unresponsive to multiple biologic agents, complicated by difficult social situation influencing care decisions. Non-attendance to clinics has contributed to delay in escalation of treatment at times. She was discussed at various regional and national MDT meetings, both in terms of diagnosis and management plans. Other differential diagnoses were considered and ruled out. • The importance of addressing all the biopsychosocial aspects of care are highlighted in this case. The difficulty of balancing ongoing rapport and trust with the family, and ensuring safeguarding for the patient has been challenging. Learning points: • Importance of multi-agency and multi-centre working in management of patients with complicated JIA. • Importance of difficult social situation affecting timely management decisions and the role of family support in optimising medical care. • Even with newer treatments being approved on regular basis for JIA, it is important to recognise there are patients who prove resistant to many of these and more evidence is needed for combining biologics in such patients.

Jammed joints and constricted heart: The science of tribology and missing lubricin. A case report on camptodactyly-arthropathy-coxa vara-pericarditis syndrome

ABSTRACT An autosomal recessively inherited noninflammatory arthropathy known as camptodactyly, arthropathy, coxa vara, and pericarditis (CACP) syndrome was discovered in 1999. It is distinguished by synoviocyte hyperplasia and subcapsular fibrosis of the synovial capsule, which results in a shortage of lubricin production. The resulting lack of joint lubrication induces increased mechanical stress, causing progressive deformities that become evident with weight-bearing and heightened joint activity. Animal models with a lubricin gene knock-out display similar traits, underscoring the impact of mechanical stress on disrupting type II collagen on the articular surface. The gradual development of pericarditis and constriction often results in misdiagnosis as juvenile rheumatoid arthritis with cardiac involvement, but the defining feature remains the noninflammatory nature of the disease. Early recognition is pivotal, as interventions such as pericardiectomy and recombinant human lubricin hold promise for altering the disease’s natural course. In our familial case of CACP, two siblings exhibited distinct phenotypic variations – one with fibrosis-dominant features and pericardial constriction and the other displaying synovial hyperplasia without pericardial involvement.

Thirteen Indians with camptodactyly-arthropathy-coxa vara-pericarditis syndrome

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome (MIM# 208250) is a rare monogenic disorder, characterized by early onset of camptodactyly, progressive coxa vara, bilateral arthropathy and constrictive pericarditis. The syndrome is caused by biallelic loss-of-function variants in PRG4. Deficiency of PRG4 results in progressive worsening of joint deformity with age. Thirteen individuals with CACP syndrome from eight consanguineous Indian families were evaluated. We used exome sequencing to elucidate disease-causing variants in all the probands. These variants were further validated and segregated by Sanger sequencing, confirming the diagnosis of CACP syndrome in them. Seven females and six males aged 2–23 years were studied. Camptodactyly (13/13), coxa vara (11/13), short femoral neck (11/13) and arthritis in large joints (12/13) [wrists (11/13), ankle (11/13), elbow (10/13) and knee (10/13)] were observed commonly. Five novel disease-causing variants (c.3636G>T, c.1935del, c.1134dup, c.1699del and c.962T>A) and two previously reported variants (c.1910_1911del and c.2816_2817del) were identified in homozygous state in PRG4. We describe the phenotype and mutations in one of the large cohorts of patients with CACP syndrome, from India.

An adult with cystathionine beta-synthase deficiency, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, and deafness: A case report.

Massive sequencing platforms allow the identification of complex clinical phenotypes involving more than one autosomal recessive disorder. In this study, we report on an adult patient, born to a related couple (third degree cousins), referred for genetic evaluation due to ectopia lentis, deafness and previous diagnosis of juvenile idiopathic arthritis. He was biochemically diagnosed as having Classic Homocystinuria (HCU); Sanger sequencing of the CBS gene showed the genotype NM_000071.2(CBS):c.[833T>C];[833T>C], compatible with the diagnosis of pyridoxine-responsive HCU. As he also had symptoms not usually associated with HCU, exome sequencing was performed. In addition to the variants found in the Sanger sequencing, the following variants were identified: NM_001256317.1(TMPRSS3):c.[413C>A];[413C>A]; and the NM_005807.6(PRG4):c.[3756dup]:[3756dup], confirming the diagnosis of autosomal recessive nonsyndromic deafness and Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome (CACP), respectively. Genomic analysis allowed the refinement of the diagnosis of a complex case and improvement of the patient's treatment.

A novel mutation in the proteoglycan 4 gene causing CACP syndrome: two sisters report

BackgroundCamptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome, caused by biallelic pathogenic mutations in the proteoglycan 4 (PRG4) gene, is characterized by early-onset camptodactyly, noninflammatory arthropathy, coxa vara deformity, and rarely, pericardial effusion. This syndrome can mimic juvenile idiopathic arthritis. CACP syndrome is caused by mutations in the proteoglycan 4 (PRG4) gene. To date, only 36 pathogenic mutations have been reported in this gene, but none have been reported from Azerbaijan.Case presentationHerein, we report two siblings presented with chronic polyarthritis, had a prior diagnosis of juvenile idiopathic arthritis, but was subsequently diagnosed as CACP syndrome with novel mutation in the PRG4 gene.ConclusionOur report expands the knowledge of PRG4 mutations, which will aid in CACP patient counseling.

Recombinant lubricin improves anti-adhesive, wear protection, and lubrication of collagen II surface

Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a joint disease caused by a lack of lubricin, resulting in failed lubrication and abnormal deposition at the cartilage surface. Injection of recombinant lubricin (R-LUB) is a promising approach to improve the symptoms of the disease. However, the antifouling and lubrication properties of R-LUB on cartilage surfaces have not yet been studied. Here, the adsorption and lubrication behavior of a type II collagen (COL II) mimicking the cartilage surface upon R-LUB injection was followed by surface plasmon resonance spectroscopy and surface forces apparatus. The results indicated R-LUB can bind well on a COL II surface and COL II/R-LUB complex layer exhibited ultralow nonspecific adsorption of BSA (3.25 ng/cm2) and LYS (0.26 ng/cm2) compared to those of the COL II layer (32.7 ng/cm2, 7.26 ng/cm2). Normal force measurements indicated there was always a repulsive force between COL II/R-LUB complex and different surfaces with -COO-, -NH3+, and -CH3 groups. Likewise, COL II had a high coefficient of friction (∼0.48) with surface damage at 2 µm/s and a wear pressure of 1.56 MPa, while that of COL II/R-LUB complex was down to ∼0.008–0.13 with surface damage at 13 µm/s and a wear pressure of 11.96 MPa, which was 7.7 times higher than for COL II. Hence, R-LUB may act as an anti-adhesive and lubrication layer adsorbed on COL II surfaces to prevent direct contact. Our findings provide fundamental insights into the adsorption and lubrication behavior for understanding biological lubrication, especially the potential supplementation of R-LUB for treating CACP disease.

Monogenic disorders as mimics of juvenile idiopathic arthritis

BackgroundJuvenile idiopathic arthritis is the most common chronic rheumatic disease of childhood. The term JIA encompasses a heterogenous group of diseases. The variability in phenotype of patients affected by the disease means it is not uncommon for mimics of JIA to be misdiagnosed.Case presentationWe present four cases who were treated in single tertiary rheumatology centre for JIA who were subsequently diagnosed with a rare monogenic disease. All four patients shared the unifying features of presenting in early childhood and subsequently suffered with refractory disease, not amenable to usual standards of treatment. Multicentric Carpotarsal Osteolysis Syndrome and Camptodactyly-arthropathy-coxa vara-pericarditis syndrome are non-inflammatory conditions and patients typically present with arthropathy, normal inflammatory markers and atypical radiological features. Blau syndrome is an autosomal dominant condition and patients will typically have symmetrical joint involvement with a strong family history of arthritis, signifying the genetic aetiology.ConclusionsWe share our learning from these cases to add to the growing portfolio of JIA mimics and to highlight when to consider an alternative diagnosis. In cases of refractory disease and diagnostic uncertainty further imaging and genetic testing can play a crucial role in establishing the aetiology. In all of these cases the correct diagnosis was made due to careful, longitudinal clinical phenotyping and a close working relationship between rheumatology, radiology and clinical genetics; highlighting the importance of the multidisciplinary team in managing complex patients.

Quadruped Gait and Regulation of Apoptotic Factors in Tibiofemoral Joints following Intra-Articular rhPRG4 Injection in Prg4 Null Mice.

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome leads to diarthrodial joint arthropathy and is caused by the absence of lubricin (proteoglycan 4—PRG4), a surface-active mucinous glycoprotein responsible for lubricating articular cartilage. In this study, mice lacking the orthologous gene Prg4 served as a model that recapitulates the destructive arthrosis that involves biofouling of cartilage by serum proteins in lieu of Prg4. This study hypothesized that Prg4-deficient mice would demonstrate a quadruped gait change and decreased markers of mitochondrial dyscrasia, following intra-articular injection of both hindlimbs with recombinant human PRG4 (rhPRG4). Prg4−/− (N = 44) mice of both sexes were injected with rhPRG4 and gait alterations were studied at post-injection day 3 and 6, before joints were harvested for immunohistochemistry for caspase-3 activation. Increased stance and propulsion was shown at 3 days post-injection in male mice. There were significantly fewer caspase-3-positive chondrocytes in tibiofemoral cartilage from rhPRG4-injected mice. The mitochondrial gene Mt-tn, and myosin heavy (Myh7) and light chains (Myl2 and Myl3), known to play a cytoskeletal stabilizing role, were significantly upregulated in both sexes (RNA-Seq) following IA rhPRG4. Chondrocyte mitochondrial dyscrasias attributable to the arthrosis in CACP may be mitigated by IA rhPRG4. In a supporting in vitro crystal microbalance experiment, molecular fouling by albumin did not block the surface activity of rhPRG4.

Syndrome of progressive deforming non-inflammatory arthritis of childhood: two patients of camptodactyly-arthropathy-coxa vara-pericarditis syndrome

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a rare familial arthropathy of childhood, commonly misdiagnosed as juvenile idiopathic arthritis. It is characterized by non-inflammatory arthropathy, coxa vara deformity, and sterile pericarditis. We describe two children with CACP syndrome who were referred to the rheumatology clinic for the suspicion of inflammatory arthritis. A literature search was carried out using PubMed/ Medline and Embase databases. English language reports of mutation-proven cases of CACP syndrome reported until 31 March 2020 were retrieved and analysed. Both the children had a delay in diagnosis (age at diagnosis- 12 and 13years, respectively) and had received immunomodulatory therapy for suspected inflammatory arthritis. Presence of symmetrical arthropathy of large joints, camptodactyly, and normal inflammatory parameters are clues that indicated CACP syndrome. One child with a novel variant in PRG4 also had associated mitral valve prolapse and regurgitation. Both had severe constrictive pericarditis requiring pericardiectomy. On literature review, a total of 98 mutation-proven cases of CACP syndrome have been reported till date. Arthropathy in CACP syndrome mainly involves knees, wrists, ankles, and hips. Pericarditis is usually mild, however, can present rarely with severe symptoms requiring surgical intervention. CACP syndrome can closely mimic inflammatory arthritis and early clinical recognition is important to avoid misdiagnosis. Molecular confirmation is essential for early diagnosis and future genetic counselling for affected families.

FAMILIAL CAMPTODACTYLY COXA VARA PERICARDITIS SYNDROME MASQUARADING AS JUVUNILE IDIOPATHIC ARTHRITIS

ABSTRACTThe camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive disease characterized by congenital or early-onset camptodactyly, childhood-onset non-inflammatory arthropathy associated with synovial hyperplasia, constrictive pericarditis and coxa vara. This rare disease is caused by mutations in PRG4 Gene which encodes for lubricin, a protein present in synovial fluid responsible for lubrication.The case we are reporting is of 9 and half years old boy who presented to us in pediatric Out Patient Department with early onset camptodactyly and non-inflammatory arthropathy. Synovial biopsy shows synovial hyperplasia with numerous CD68 positive multinucleated giant cells. He was discharged and physiotherapy was advised with regular follow ups.KEY WORDS: Coxa Vara (MeSH); Lubricin (MeSH); Joint Diseases (MeSH); Arthropathy (MeSH); Osteoarthritis (MESH); Pericarditis (MeSH); Synovial Membrane (MeSH).

293 Comparison of cell populations between juvenile idiopathic arthritis (JIA) and camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) patients

293 Comparison of cell populations between juvenile idiopathic arthritis (JIA) and camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) patients

Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome.

BackgroundThe camptodactyly–arthropathy–coxa vara–pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage.MethodsIn the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations.ResultsWe found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4 years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20 years old. All patients presented developmental coxa vara and seven patients (~22%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene.ConclusionWith this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense‐mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis.

046. Comparison of basic cell populations between Juvenile Idiopathic Arthritis (JIA) and Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) patients

046. Comparison of basic cell populations between Juvenile Idiopathic Arthritis (JIA) and Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) patients

Friction-Induced Mitochondrial Dysregulation Contributes to Joint Deterioration in Prg4 Knockout Mice.

Deficiency of PRG4 (lubricin), the boundary lubricant in mammalian joints, contributes to increased joint friction accompanied by superficial and upper intermediate zone chondrocyte caspase-3 activation, as shown in lubricin-null (Prg4−/−) mice. Caspase-3 activity appears to be reversible upon the restitution of Prg4 either endogenously in vivo, in a gene trap mouse, or as an applied lubricant in vitro. In this study we show that intra-articular injection of human PRG4 in vivo in Prg4−/− mice prevented caspase-3 activation in superficial zone chondrocytes and was associated with a modest decrease in whole joint friction measured ex vivo using a joint pendulum method. Non-lubricated Prg4−/− mouse cartilage shows caspase cascade activation caused by mitochondrial dysregulation, and significantly higher levels of peroxynitrite (ONOO− and −OH) and superoxide (O−2) compared to Prg4+/+ and Prg4+/− cartilage. Enzymatic activity levels of caspase 8 across Prg4 mutant mice were not significantly different, indicating no extrinsic apoptosis pathway activation. Western blots showed caspase-3 and 9 activation in Prg4−/− tissue extracts, and the appearance of nitrosylated Cys163 in the active cleft of caspase-3 which inhibits its enzymatic activity. These findings are relevant to patients at risk for arthrosis, from camptodactyl-arthropathy-coxa vara-pericarditis (CACP) syndrome and transient lubricin insufficiency due to trauma and inflammation.

Camptodactyly Arthropathy CoxaVara Pericarditis Syndrome: Early diagnosis prevents unnecessary and harmful treatment

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a genetic disorder caused by mutation in the Proteoglyacn PRG4 gene on chromosome 1. The syndrome is characterized by congenital or early onset camptodactyly and childhood-onset of non-infl ammatory arthropathy, coxa vara deformity, or other dysplasia associated with progressive hip disease and non-infl ammatory pericardial effusion.

The Efficacy of Yttrium-90 Radiosynovectomy in Patients with Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome.

Objective:Camptodactyly-arthropathy-coxa-vara-pericarditis (CACP) syndrome is an autosomal recessive disorder caused by mutations in PRG4 gene that encodes for proteoglycan 4, the main lubricant for joints and tendon surfaces. It is a non-inflammatory arthropathy, characterized by joint effusions and synovial hypertrophy. So far, there is no effective treatment for this disorder. To evaluate the effectiveness of yttrium-90 radiosynovectomy in arthropathy of patients with CACP syndrome.Methods:Consecutive patients with CACP syndrome were prospectively evaluated at the enrollment and 3 months after the right knee injection with yttrium-90. The outcome variables were patient/parent and physician’s global assessment measured by a 3-point scale, right knee swelling and range of motion on a 3-point scale, in addition to magnetic resonance imaging (MRI) assessment of the right knee for bone, cartilage, fluid, synovial hypertrophy and soft tissue changes.Results:Six (three boys, three girls) patients with a mean age of 12 years and mean follow-up duration of 8.5 years completed a single right knee intra-articular yttrium-90 injection with 5 mCi. The procedure was well tolerated without adverse events apart from mild and transient joint pain in two patients. There was a minimal radioisotope leakage to soft tissue in two patients. During the 3-month follow-up interval, there was no improvement in the outcome variables. Patients and parents did not notice favorable therapeutic effects and global physician assessment was unsatisfactory. There was no difference in knee joint swelling or range of motion. Furthermore, MRI findings were unchanged. However, there was a minimal increase in synovial fluid post injection.Conclusion:Yttrium-90 radiosynovectomy seems to be a safe and well tolerated procedure, however, it did not show a beneficial therapeutic effect in arthropathy of CACP syndrome with the given dosage and interval. Studies including a larger number of patients and probably repeated injections are needed to derive satisfactory results about the effectiveness of yttrium-90 in CACP syndrome patients.

Brothers with constrictive pericarditis – A novel mutation in a rare disease

Familial constrictive pericarditis is extremely rare. We report a case of two brothers both suffering constrictive pericarditis along with having multiple painless joint deformities. Genetic workup confirmed the clinical diagnosis of camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome CACP syndrome and also revealed a rare mutation in the causative gene.

Anti-lubricin monoclonal antibodies created using lubricin-knockout mice immunodetect lubricin in several species and in patients with healthy and diseased joints.

Lubricin, encoded by the gene PRG4, is the principal lubricant in articulating joints. We immunized mice genetically deficient for lubricin (Prg4-/-) with purified human lubricin, and generated several mAbs. We determined each mAb’s binding epitope, sensitivity, and specificity using biologic samples and recombinant lubricin sub-domains, and we also developed a competition ELISA assay to measure lubricin in synovial fluid and blood. We found the mAbs all recognized epitopes containing O-linked oligosaccharides conjugated to the peptide motif KEPAPTTT. By western blot, the mAbs detected lubricin in 1 μl of synovial fluid from several animal species, including human. The mAbs were specific for lubricin since they did not cross-react with other synovial fluid constituents from patients with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), who genetically lack this protein. The competition ELISA detected lubricin in blood samples from healthy individuals but not from patients with CACP, indicating blood can be used in a diagnostic test for patients suspected of having CACP. Lubricin epitopes in blood do not represent degradation fragments from synovial fluid. Therefore, although blood lubricin levels did not differentiate patients with inflammatory joint disease from healthy controls, epitope-specific anti-lubricin mAbs could be useful for monitoring disease activity in synovial fluid.

Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome: Important Differential for Juvenile Idiopathic Arthritis

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an inherited disorder characterized by congenital or early-onset flexion camptodactyly, childhood-onset of non-inflammatory arthropathy, often associated with non-inflammatory pericarditis or pericardial effusion and progressive coxa vara. The causative gene is located on chromosome band 1q25-31. This gene encodes for “proteoglycan-4” (PRG-4), which is a surface lubricant for joints and tendons. This syndrome has distinct radiological and histological features, which are important to recognize since it may clinically mimic juvenile idiopathic arthritis and mutation studies may not be easily available. We describe a case of a 3-year 3-month-old female with features of CACP syndrome.

CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort

Camptodactyly-Arthropathy-Coxa vara-Pericarditis (CACP) syndrome is a rare autosomal recessive disorder caused by mutations in PRG4 gene that encodes for proteoglycan 4, a mucin-like glycoprotein that is the major lubricant for joints and tendon surfaces. The molecular studies reported so far have described the identification of 15 mutations associated with this syndrome and the majority of them were found in families of Arabian origin. Here we report the molecular investigation of the largest European cohort that comprises 13 patients, and allowed the identification of 5 novel mutations and of the first case of CACP syndrome resulting from uniparental disomy of chromosome 1.