Antibodies to cytokeratins in inflammatory arthropathies.

OBJECTIVES: Cytokeratins are a major constituent of the cytoskeleton in eukaryotic cells and are vital for the maintenance of cell structure and function. Identification of increased levels of IgA antibodies to these intracellular structures has prompted increasing interest in the potential role between the gut and the immune system in the pathogenesis of inflammatory arthritis. This review examines the salient features of cytokeratin (CK) antibodies that are relevant to inflammatory arthropathies and discusses the meaning and potential applications of these findings in the context of the different arthropathies. METHODS: Review of the literature on antibodies to cytokeratins in inflammatory arthropathies, using MEDLINE and the key words (cyto)keratin and arthritis. The studies were interpreted and critiqued. RESULTS: Increased levels of IgA antibodies to CK-18 and epidermal keratins have been shown by enzyme-linked immunosorbent assay (ELISA) in rheumatoid arthritis and psoriatic arthritis. Levels were not increased in osteoarthritis or reactive arthritis. CONCLUSIONS: CK-18 is present within endothelial cells lining synovial blood vessels in patients with various rheumatic conditions, including rheumatoid arthritis, as well as in normal controls. Damage to synovial endothelial cells may lead to increased production of antibodies to CK-18. The CK antibody response is independent of the polyclonal immunoglobulin expansion typical of RA and is not specific for RA because an increased IgA response to CK-18 also has been shown in psoriasis and in psoriatic arthritis. Damage to synovial endothelial cells does not explain the increased autoantibody production in other conditions such as psoriasis. In this condition, damage to epithelial tissues in other regions of the body (e.g, skin, gut, kidney) may lead to production of keratin antibodies that recognize epitopes common to all CK, including CK-18. The reason for an elevated IgA anti-CK response rather than an IgG or IgM response is not clear. It cannot be explained by a general increase in serum IgA levels. Most of the conditions in which raised levels of these antibodies were found have been associated to different degrees with abnormalities of the gut mucosa or mucosal immune system. It appears that the nature of autoantibodies to CK-18 is probably natural rather than pathogenic. Currently there are no data on the source of the IgA antibodies to cytokeratins (i.e., mucosal or central immune system). Indeed, it may depend on the disease.

Use of the Stoke Index to differentiate between disease-modifying agents and non-steroidal anti-inflammatory drugs in rheumatoid arthritis.

The Stoke Index is a validated composite algorithm that has been designed to give a global measure of disease activity in rheumatoid arthritis (RA). The use of this single measure of disease activity in RA simplifies the critical evaluation of drug therapy. 368 patients with RA of varying duration and severity, entered into comparative drug trials between 1980 and 1987, had the algorithm calculated four weeks prior to therapy, at the start of treatment, and bi-monthly to six months. The index score was significantly improved by drugs with known slow acting anti-rheumatic drug (SAARD) activity and improvement could be seen as early as two months after the beginning of treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) did not improve the score. The index differentiates between treatments in patients with minor or major disease activity. We conclude that this composite index of disease activity provides a sensitive, meaningful measure for the evaluation of therapy in RA.

BRCA1 and BRCA2 mutations in ovarian cancer: Covariation with specific cytogenetic features.

We analyzed 37 primary invasive carcinomas for BRCA1 and BRCA2 mutations by screening the entire coding regions of both genes. Seven predicted truncating mutations (four in BRCA1 and three in BRCA2) and one novel BRCA1 missense variant (S1542C) were identified (8/37, 22%). Two of the BRCA1 mutations were somatic changes, whereas the remaining three BRCA1 changes and all mutations of BRCA2 were found to be of germline origin. All eight BRCA-positive tumors were serous or seropapillary carcinomas (8/27 serous tumors, 30%), and all but one were poorly differentiated. The correlation between tumor karyotype and BRCA status showed that clonal chromosomal aberrations were present in all BRCA-positive tumors (8/8) compared with 20 of 29 BRCA-negative ones. The most consistently affected region in BRCA-positive tumors was the long arm of chromosome 6; alterations within this arm with a breakpoint in band 6q21 were seen in four of five BRCA1-positive and in two of three BRCA2-positive tumors, but only in four of 20 karyotypically abnormal tumors without BRCA mutations, suggesting that the genetic pathways of tumor progression differ in the two groups. The high frequency of germline BRCA mutations detected in this pilot study (16% of 37 invasive carcinomas) points to the need for more extended analyses of population-based series of patients to determine the true contribution of these predisposing genes to the overall incidence of ovarian cancer in this population.

Synovial sarcoma manifesting as a single joint flare in rheumatoid arthritis.

A 69-year-old female recently diagnosed as suffering from rheumatoid arthritis presented with a general flare-up of disease including a swollen left ankle. Investigation revealed the swelling to be due to a synovial sarcoma. This unusual cause should be considered in all cases of local joint flares in rheumatoid arthritis.

Human parvovirus B19 and rheumatoid arthritis.

Human parvovirus B19 infections have been linked with the development of a short-lived symmetrical polyarthritis and, rarely, a more persistent arthritis. We prospectively looked for serological evidence of recent B19 infection in 25 early synovitis patients presenting within 12 weeks of symptom onset and compared them with 21 controls seen over the same time period. None of the control patients had evidence of recent B19 infection while 3 of the early synovitis patients had raised IgM anti-B19 antibody levels. Two had a transient arthritis and 1 developed persistent seropositive rheumatoid arthritis.

Combination therapy for rheumatoid arthritis and drug-induced systemic lupus erythematosus.

Development of drug-induced systemic lupus erythematosus (SLE) is an uncommon complication of the use of D-penicillamine and sulphasalazine. We report two cases of patients with rheumatoid arthritis (RA) who developed symptoms and signs of SLE and suggest that increasing use of these two agents as combination therapy in RA may cause an additive risk to the occurrence of this complication.

Reflex sympathetic dystrophy syndrome: diagnosis and treatment.

The reflex sympathetic dystrophy syndrome is a very common, poorly recognized syndrome which is associated with marked disability in some cases. The historical aspects, current ideas about the pathogenesis and pathophysiology, clinical features and staging are discussed. Early recognition and appropriate intervention are the cornerstone of successful treatment and are also discussed.

Yersinia-related arthritis in the United Kingdom. A report of 12 cases and review of the literature.

Reactive arthritis following infection with Yersinia is endemic in Scandinavian countries; the prevalence is low in the UK, however. We have reviewed the literature pertaining to Yersinia-related reactive arthritis in the UK and describe 12 patients who presented over a 3-year period with an asymmetrical seronegative polyarthropathy and serological evidence of recent Yersinia infection. Five patients recalled having a diarrhoeal illness prior to the onset of the arthropathy. None had a prior history of psoriasis, inflammatory bowel disease or ankylosing spondylitis. A history of urethral discharge was elicited from one patient. Extra-articular manifestations were seen in three patients (iritis in two, erythema nodosum in another). Four patients developed chronic joint disease after periods of 4, 6, 8, and 18 months, respectively. The prevalence of Yersinia-related arthritis in the UK may be higher than previously thought.

Increased levels of IgA antibodies to cytokeratin-18 and epidermal keratin in rheumatoid arthritis.

OBJECTIVE: To investigate whether levels of antibodies to cytokeratin-18 (CK-18) and epidermal keratin (EPK) were raised in patients with rheumatoid arthritis (RA). METHODS: We measured antibodies to CK-18 and EPK in patients with RA and in patients with osteoarthritis (OA), as well as in normal control subjects by means of an enzyme-linked immunosorbent assay. RESULTS: IgA antibodies to both CK-18 and EPK were significantly increased in patients with RA compared with the controls and with patients with OA (P < 0.0001). No difference was noted in the levels of IgG or IgM antibodies to CK-18 or EPK between controls and patients with OA or RA. CONCLUSION: Raised levels of IgA autoantibody to CK-18 and EPK may reflect damage to cytokeratin-containing cells (e.g., in synovial endothelium) and could be a useful disease marker in RA.

Increased IgA antibodies to cytokeratins in the spondyloarthropathies.

OBJECTIVES: Increased levels of IgA antibodies to cytokeratin-18 (CK-18) and epidermal keratins (EpK) in the sera of patients with rheumatoid arthritis (RA) have been demonstrated previously. In the present study investigations were carried out to determine whether levels of these autoantibodies were also raised in the spondyloarthropathies, and whether there was any association with particular disease manifestations. METHODS: Using specific enzyme linked immunosorbent assays (ELISA) measurements were taken of IgA, IgG and IgM antibodies to EpK and to CK-18 in the sera of patients with psoriatic arthropathy, ankylosing spondylitis (AS), Reiter's syndrome, psoriasis and in normal subjects. RESULTS: IgA antibodies to both EpK and CK-18 were significantly increased in sera from patients with psoriasis and psoriatic arthropathy but not in the sera from the patients with AS or Reiter's syndrome, or in the controls. In psoriatic arthritis, however, these levels were significantly higher only in those patients with peripheral joint disease and not in those with axial arthritis alone. There was no significant increase in antibody levels in patients with AS or Reiter's syndrome. There were no differences in the levels of IgG or IgM antibodies to CK-18 or EpK between the patient groups and controls. CONCLUSIONS: Raised levels of IgA antibodies to CK-18 and EpK in psoriatic arthropathy and psoriasis probably reflect exposure of intracellular cytokeratin antigens to the immune system after damage to cytokeratin containing cells, and suggests a common pathogenic mechanism in these conditions which involves production of cytokeratin autoantibodies. In patients with psoriatic arthropathy, such a mechanism appears only to be operating in patients with peripheral joint involvement and not in those with axial arthritis.

Measurement and prediction of radiological progression in early rheumatoid arthritis.

OBJECTIVE: To compare radiological scoring systems in early RA, and then to determine if the rate of radiological progression in the first year of disease (RRP01) predicts the subsequent rate of progression up to 8 years (RRP1-8). METHODS: Hand and feet radiographs were performed at 0, 1, 2 and 8 years in 65 patients presenting with nonerosive RA and symptoms for less than 3 years. All films were scored by Sharp's method; Sharp, Larsen and carpometacarpal (CMC) ratio methods were compared in 23 patients. RESULTS: Significant change in score was detected over the first year using Sharp (median of 15.5 vs 7.5, p < 0.00002) and Larsen (30.5 vs 22.5, p < 0.0002), but not CMC ratio (1.13 vs 1.14, p = 0.07). Sharp had greater range and sensitivity of change, and had better inter and intraobserver reproducibility. RRP01 showed a skewed distribution (median 0.7 units/month; range -0.3 to +6.1). Spearman correlation between RRP01 and RRP1-8 was r = 0.57, p < 0.001. CONCLUSION: Both Sharp and Larsen indices are sensitive to change in the first year of RA, but Sharp has advantages of greater sensitivity and reproducibility: CMC ratio is not useful. Radiological progression rate in the first year correlates only moderately with subsequent rate of progression up to 8 years. This suggests that radiological progression is nonuniform and that different patterns of progression over time may exist.

Persistent monoarthritis and occult coeliac disease.

Arthritis is a recognized complication of untreated coeliac disease. Symptoms and signs usually respond to the institution of a gluten-free diet. We report a case of occult coeliac disease presenting as a monoarthritis. Severe and progressive erosive damage has occurred in his talo-navicular joint despite a response to the institution of a gluten-free diet.

Radiographic patterns and response to corticosteroid hip injection.

OBJECTIVES: A prospective, open study of corticosteroid hip injection (CHI) was performed to determine if different radiological patterns of arthritis vary in their response. METHODS: Forty five patients (15 with rheumatoid arthritis, 27 with osteoarthritis, and three with anklyosing spondylitis) underwent hip injection with 80 mg methylprednisolone and lignocaine under x ray control. Outcome was assessed at two, 12, and 26 weeks for pain, range of hip movement, and graded functional questionnaire. Patients estimated their pain in four components, night pain, rest pain, weight bearing, and referred pain, each measured by 10 cm visual analogue score and summed to give a total score out of 40 cm. Hip radiographs were evaluated blindly for pattern and severity of arthritis, as well as for progression between 0 and 26 weeks. RESULTS: Median total pain score decreased from 29 cm at baseline to 22 cm at two weeks (p = 0.0001), 24 cm at 12 weeks (p = 0.03), but had returned nearly to baseline by 26 weeks (25 cm, p = 0.3). Greatest improvement was seen for night pain. Mean range of internal rotation increased from 16 to 28 degrees at two weeks (p = 0.03) and 21 degrees at 12 weeks (p = 0.06). Functional ability did not change. Hips with an atrophic pattern of arthritis on plain radiography gained negligible pain relief at two weeks compared with hips with a hypertrophic or mixed bone response (p = 0.04). The degree of pain relief was similar in patients with OA and RA, and was not influenced by radiographic severity or by the direction of migration of the femoral head. CONCLUSION: Pain and internal rotation improve for up to 12 weeks after CHI. CHI offers a useful and safe therapeutic option for patients with hip arthritis, with the exception of those with a purely atrophic radiological pattern.

Rifampicin in early rheumatoid arthritis.

Sixteen patients with definite or classical Rheumatoid Arthritis (RA) of less than twelve months duration were recruited into a randomised, open twelve month study comparing Rifampicin 600 mg daily (9 patients) with Hydroxychloroquine (HCQ) 400 mg daily (7 patients). Ten patients completed twelve months of treatment (4 Rifampicin, 6 HCQ). Five patients were withdrawn from the study due to lack of efficacy (1 HCQ, 4 on Rifampicin). One further patient on rifampicin was withdrawn due to development of abnormal liver function tests. Significant improvement (p < 0.03) was noted in the Stoke Index (SI) at six and twelve months in the HCQ group which was not seen in the rifampicin group. In both groups there was no significant improvement in the single variables (Ritchie index, morning stiffness, grip strength, synovitis score, ESR, CRP). The results fail to confirm that Rifampicin may be useful in the treatment of RA in early stages of disease.