Large Joint Arthropathy Research Articles

ALKAPTONURIA DIAGNOSED IN A 72 YEAR OLD FEMALE AFTER TOTAL KNEE REPLACEMENT

Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of homogentisic acid oxidase and resulting in accumulation of homogentisic acid in collagenous structures. It is characterized by homogentisic aciduria, bluish-black discoloration of connective tissues (ochronosis) and arthropathy of large joints. Less common manifestations include cardiovascular abnormalities, renal, urethral and prostate calculi. Bone fractures are unusual in ochronosis. In this report, we describe a woman, 72 years of age, with a history of severe arthropathy requiring total joint replacement in both of her hips and left Knee. During the Left Total Knee Replacement, an intra operative observation of a bluish-black discoloration of the knee joint and the surrounding soft tissue raised the diagnosis of Alkaptonuria. We review the etiology, pathogenesis, clinical presentation, diagnosis and treatment of alkaptonuric ochronosis. Early detection is important for prevention and treatment of multiple systems.

Nutritional interventions for patients with alkaptonuria: A minireview.

Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.

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.

Stevens-Johnson syndrome complicating adalimumab therapy in Crohn’s disease

The anti-tumor necrosis factor (TNF)alpha medications demonstrate efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions. With the increasing number of patients receiving anti-TNFalpha agents, however, less common adverse reactions will occur. Cutaneous eruptions complicating treatment with an anti-TNFalpha agent are not uncommon, occurring in around 20% of patients. Adalimumab, a fully humanized antibody against TNFalpha, may be expected to cause minimal immune-mediated skin reactions compared to the chimeric monoclonal antibody, infliximab. We, however, report a case of Stevens-Johnson syndrome that required hospitalization and cessation of adalimumab in a patient with Crohn's disease (CD). In this case report, a 29-year-old male with colonic and perianal CD with associated erythema nodosum and large joint arthropathy developed severe mucositis, peripheral rash and desquamation, fevers and respiratory symptoms concomitant with a second dose of 40 mg adalimumab after a 2 mo break from adalimumab therapy. Skin biopsies of the abdominal wall confirmed erythema multiforme and the patient was on no other drugs and infective etiologies were excluded. The patient responded rapidly to IV hydrocortisone and was able to be commenced on infliximab without recurrence of the Stevens-Johnson syndrome. Desquamating skin reactions have now been described in three of the TNFalpha antagonists (infliximab, etanercept and adalimumab). These reactions can be serious and prescribers need to be aware of the potential mucocutaneous side effects of these agents, especially as Stevens-Johnson syndrome is associated with significant morbidity and mortality.

Do HLA antigens predict the occurrence of extraintestinal manifestations of IBD?

Extraintestinal manifestations are commonly seen in (up to 40%) in patients with either ulcerative colitis (UC) or Crohn’s disease (CD). Many of them are associated with active disease (recurrent mouth ulcers, erythema nodosum, uveitis, Type 1, or reactive large joint arthropathy). Others pursue a clinical course independent of the intestinal disease (sacroiliitis, ankylosing spondylitis, Type 2 or small joint arthropathy, primary sclerosing cholangitis). Pyoderma gangrenosum usually occurs with active intestinal disease but can occasionally occur when the intestinal inflammation is largely in remission. For CD, both groups of these extraintestinal manifestations occur in patients with colonic involvement, and rarely occur when only small intestinal disease is present. Data on the HLA associations are limited both in terms of numbers of studies and numbers of patients studied. However, a particularly strong association has been found between the Class II allele DRB1*0103, and Type 1 arthropathy.1 Of patients with either UC or CD who develop the acute, large joint arthropathy in association with active disease, 38% of them carry this allele, compared with about 8% of UC patients as a whole, and only 2% of the healthy population. It is interesting to note that patients who develop a reactive arthropathy following infection (Salmonella, Campylobacter, Reiter’s syndrome) also have a high carriage rate of this allele. This allele is also associated with the risk of having recurrent mouth ulcers or uveitis, although less strongly compared with Type 1 arthropathy. Uveitis and recurrent mouth ulcers are also associated with HLA B27. Erythema nodosum has a particularly strong association with a polymorphism in the promoter region of the TNF gene (-1031C).2 There are further HLA associations with some of those extraintestinal manifestations that are independent of inflammatory bowel disease (IBD) activity. Ankylosing spondylitis (AS) occurs in 1%–2% of patients with IBD and differs from sporadic AS in having no gender association (compared with a marked male predominance in sporadic AS) and in having a weaker association with HLA B27 (60% compared with 90% in sporadic AS). Nevertheless, the association is highly significant. Patients with sacroiliitis only have a 22% risk of having HLA B27, a percentage that is little different from the normal control population. Patients with Type II arthropathy, a seronegative, symmetrical small joint disease, have a strong association with HLA B44. Data concerning primary sclerosing cholangitis (PSC) are conflicting. Most studies find an association with HLA DR3. In the largest study the haplotype HLA DRB1*0301, DQB1*0201 (the classical autoimmune haplotype) was found in 25% of patients with PSC and colitis, 16% of patients with pancolitis only, and 10% of controls (Cullen S, Chapmann RG, Jewell DP. Submitted). These data clearly indicate that individuals possessing certain HLA alleles are at risk of developing extraintestinal manifestations, should they have the misfortune of developing IBD. In contrast, they are unlikely to occur in patients with IBD who do not possess these alleles. Furthermore, these associations can explain why these manifestations often overlap in a single individual. The outstanding questions concern the mechanisms of pathogenesis. Since the HLA region on the short arm of chromosome 6 is a very gene-dense region, it cannot be assumed that the allelic associations that have been identified are the relevant genes as opposed to having identified an allele which is in linkage disequilibrium with a more relevant polymorphism in a neighboring gene. Until this problem has been overcome, functional studies to explore pathogenic mechanisms cannot sensibly begin.

Secondary prophylaxis in adolescent and adult haemophiliacs.

Progressive arthropathy of large joints of the limbs (knees, ankles, elbows), resulting from recurrent joint bleeds and subsequent long-term degenerative phenomena, is one of the main causes of morbidity and of deterioration of quality of life in adult severe hemophiliacs. While primary prophylaxis (i.e. the regular continuous long-term infusion of factor concentrates started before the age of two years and/or after no more than one joint bleed) is nowadays considered the gold standard for preserving joint function in patients with severe haemophilia, the benefits of secondary prophylaxis (i.e., all the long-term regular treatments not fulfilling the criteria of primary prophylaxis) are still controversial. In this review we present the literature data on secondary prophylaxis, focusing on adolescent and adults haemophiliacs along with clinical experience in Italy. On the whole, the more recently published studies suggest the effectiveness of early and delayed secondary prophylaxis. However, a number of questions are still unanswered, including the optimal dose, dosing interval and duration of secondary prophylaxis. Only large, prospective, long-term, possibly randomized studies will help to definitively assess the clinical impact of this strategy in adolescent and adult hemophiliacs.

Homology of lubricin and superficial zone protein (SZP): products of megakaryocyte stimulating factor (MSF) gene expression by human synovial fibroblasts and articular chondrocytes localized to chromosome 1q25

We have previously identified megakaryocyte stimulating factor (MSF) gene expression by synovial fibroblasts as the origin of lubricin in the synovial cavity. Lubricin is a mucinous glycoprotein responsible for the boundary lubrication of articular cartilage. MSF has a significant homology to vitronectin and is composed of 12 exons. RNA was purified from human synovial fibroblasts and articular chondrocytes grown in vitro from tissue explants obtained from subjects without degenerative joint disease. RT-PCR was used with multiple complimentary primer pairs spanning the central mucin expressing exon 6 of the MSF gene and individual exons on both the N- and C-terminal sides of exon 6. Exons 2, 4 and 5 appear to be variably expressed by synovial fibroblasts and articular chondrocytes. Lubricating mucin, in the form of MSF, is expressed by both chondrocytes and synovial fibroblasts in vitro. Both lubricin and superficial zone protein (SZP), a related proteoglycan, share a similar primary structure but could differ in post-translational modifications with O-linked oligosaccharides which are predominant in lubricin and with limited amounts chondroitin and keratan sulfate found in SZP. Since most of the MSF exons are involved in the expression of lubricating mucin, a strong homology to vitronectin persists. It is therefore appropriate to consider that both SZP and lubricin occupy a new class of biomolecules termed tribonectins. Screening of a human genome bacterial artificial chromsome (BAC) library with a cDNA primer pair complimentary for exon 6 identified two clones. Both clones were complimentary for chromosome 1q25 by in situ hybridization. This same locus was previously implicated in camptodactyl-arthropathy-pericarditis syndrome (CAP) by genetic mapping. It is hypothesized that CAP, a large joint arthropathy, may be associated with ineffective boundary lubrication provided by synovial fluid.

Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history

Background—Peripheral arthropathy is a well-recognised complication of inflammatory bowel disease (IBD). Little is known of its natural history, but a variety of joint involvement has been described, from large joint...

Syndrome of Camptodactyly, Arthropathy and Coxa Vara (Cac Syndrome)

Three Saudi children (two female, one male) are described who presented with familial arthropathy associated with congenital camptodactyly. This rare but recognized clinical entity has a variable clinical presentation and may be associated with pericarditis and coxa vara. Camptodactyly was observed in the neonatal period in all patients, while joint swelling was observed between the third and 11th month. Pericarditis was suspected in the referral hospital in one patient but was not subsequently confirmed at our institution, raising the possibility that pericarditis may be reversible. Radiological examination of the hips showed coxa vara with short femoral neck in all patients. Synovial biopsy in the three patients revealed proliferating synovial epithelium with moderate fibrocollagenous densities and multinucleated giant cells, occasional lymphocytes or neutrophils but no plasma cells were identified. This is the first series of this familial arthropathy with a triad of camptodactyly, arthropathy and coxa vara (CAC syndrome) in Saudi Arabia which is to be considered in patients where more than one family member has juvenile arthritis.

Arthropathy and sacro-iliitis in severe psoriasis.

Fifty consecutive adult patients hospitalized for psoriasis were examined. Persistent low back pain, large joint arthropathy, phalangeal joint arthropathy and radiological sacro-iliitis were frequent findings (18-28%), but were not associated with one another. Chest expansion and spinal mobility were not reduced in the patients who had roentgenological sacro-iliitis. Low back pain at night and large joint arthropathy were positively associated. Peripheral arthropathy and roentgenological sacro-iliitis were associated. There was no sex difference in the frequency of signs or symptoms. Four patients (8%) had ankylosing spondylitis. It was concluded that in psoriatic patients, the different signs of joint affection are only partly related.

Laboratory findings in patients with psoriasis, with special reference to immunological parameters, associations with arthropathy and sacro-iliitis.

Twenty-five male and 25 female consecutive patients hospitalized because of psoriasis were examined. The clinical and radiographical findings are presented in detail elsewhere. Increased serum IgA, C3, C4, and C3PA concentrations were found in patients both with and without arthropathy and/or sacro-iliitis. Increased IgG concentrations were found in patients without arthropathy, and of C1 inhibitor concentrations in patients with arthropathy and/or sacro-iliitis. IgG and IgA concentrations were lower in patients with arthropathy than in those without, the difference being most significant in patients with arthropathy of large joints. An association was found between increased C4 concentration and sacro-iliitis, increased CRP concentration and sacro-iliitis and increased C3 concentration and phalangeal joint arthropathy. C4 and CRP concentrations were not associated. A close association between CRP and SAA was observed. Our results indicate that psoriatic arthropathy is not a single uniform joint disease, but represents different forms of arthropathy.