TCM nonpharmacological interventions for ankylosing spondylitis: A protocol for systematic review and network meta-analysis.

BACKGROUND: Ankylosing spondylitis (AS) is a common infammatory rheumatic disease that affects the axial skeleton. Traditional Chinese medicine (TCM) nonpharmacological interventions are gaining an increasing popularity for AS. Nevertheless, the evidence of efficacy and safety of random controlled trials (RCTs) remains controversial. This study aims to evaluate the efficacy and acceptability of different TCM nonpharmacological therapies by systematic review and network meta-analysis. METHODS: According to the strategy, the authors will retrieve a total of 7 electronic databases by December 2020, including PubMed, the Cochrane Library, EMbase, China National Knowledge Infrastructure, China Biological Medicine, Chongqing VIP, and Wan-fang databases After a series of screening, 2 researchers will use Aggregate Data Drug Information System and Stata software to analyze the data extracted from the randomized controlled trials of TCM nonpharmacological interventions for AS. The primary outcome will be the improvement of Pain intensity and functional status/disability and the secondary outcomes will include lobal improvement, health-related quality of life, satisfaction with treatment, and adverse events. Both classical meta-analysis and network meta-analysis will be implemented to investigate direct and indirect evidences on this topic. The quality of the evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation instrument. RESULTS: This study will provide a reliable evidence for the selection of TCM nonpharmacological therapies in the treatment of AS. CONCLUSION: This study will generate evidence for different TCM nonpharmacological therapies for AS and provide a decision-making reference for clinical research. ETHICS AND DISSEMINATION: This study does not require ethical approval. The results will be disseminated through a peer-reviewed publication. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/FHD2U.

Wnt Signaling and Biological Therapy in Rheumatoid Arthritis and Spondyloarthritis.

The Wnt signaling pathway plays a key role in several biological processes, such as cellular proliferation and tissue regeneration, and its dysregulation is involved in the pathogenesis of many autoimmune diseases. Several evidences support its role especially in bone complications of rheumatic diseases. In Rheumatoid Arthritis (RA), the Wnt signaling is implicated in systemic and localized bone loss, while available data of its role in Spondyloarthritis (SpA) are conflicting. In the last few decades, the quality of life of rheumatic patients has been dramatically improved by biological therapy, targeting cytokines involved in the pathogenesis of these diseases like tumor necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-17. In this review, we reviewed the role of Wnt signaling in RA and SpA, focusing on the effect of biological therapy on this pathway and its possible clinical implications.

Ankylosing spondylitis: antiquity and differential diagnosis - a case study of a Bronze Age skeleton from Norabak, southeastern Armenia.

An excavation of a burial mound at Norabak site (Southeast Armenia) unearthed four burial chambers, the central one contained a single skeleton radiocarbon dated to about 1400-1200 BCE. The skeleton was observed to have a polyarticular erosive arthropathy, primarily affecting the spine, with diagnostic features of ankylosing spondylitis. The antiquity of ankylosing spondylitis is questioned in the literature, because there are few reliable and descriptive reports from prehistoric sites. Excellent preservation of the skeleton from Norabak made it possible to perform a detailed analysis of the pathologic changes and to support the diagnosis of ankylosing spondylitis in this 3000-years-old individual. Apart from the main pathology, the skeleton had a dens axis fracture of the C2 vertebra a few days before death, as well as a likely associated fracture of the C1 vertebra. This type of fracture has a high risk of displacement into the vertebral canal with severe neurological consequences. Thus, we were presented with an opportunity to reconstruct a possibly fatal event in the life of this individual. The described case provides further evidence that ankylosing spondylitis is a disease of fairly great antiquity.

Emodin induces apoptosis and autophagy of fibroblasts obtained from patient with ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a type of rheumatoid disease, which has been reported to be associated with the excessive proliferation of fibroblasts recently. Emodin, a single component from a traditional Chinese medicine Rheum palmatum, exerts anti-inflammation and antirheumatic arthritis activities. However, could emodin be used to treat AS remains unclear? Thus, this study aimed to investigate the effect of emodin on AS. METHODS: Fibroblasts obtained from patients with AS were used in the current study. In addition, multiple cellular and molecular biology techniques such as Cell Counting Kit-8, Western blotting, flow cytometry, monodansylcadaverine staining, and immunofluorescence assay were applied as well. RESULTS: Emodin-induced apoptosis of fibroblasts obtained from patient with AS via increasing active caspase-9, active caspase-3, and Bax levels and downregulating Bcl-2. Meanwhile, emodin enhanced autophagy in fibroblasts via upregulation of the expression of Atg12, Atg5, and Beclin 1, which was further confirmed by monodansylcadaverine staining. As expected, autophagy inhibitor 3-methyladenine (3MA) completely reversed emodin-induced autophagy in fibroblasts. Moreover, 3MA significantly increased emodin-induced apoptosis of fibroblasts obtained from patient with AS by increasing the levels of γH2AX, active caspase-9, active caspase-3, and cleaved poly ADP-ribose polymerase. CONCLUSION: Our results indicated that emodin effectively induced apoptosis and autophagy of fibroblasts obtained from patient with AS. In addition, suppression of autophagy enhanced emodin-induced apoptosis in fibroblasts. Therefore, we proposed that combination of emodin with autophagy inhibitor might be a potent strategy for improving the symptoms of AS in the future.

Polydatin Regulates the Apoptosis and Autophagy of Fibroblasts Obtained from Patients with Ankylosing Spondylitis.

The development of ankylosing spondylitis (AS) occurs due to excessive proliferation of fibroblasts. Polydatin, a monomeric compound isolated from a traditional Chinese medicine Polygonum cuspidatum, exhibits anti-inflammatory and anti-arthritic effects. However, the mechanisms underlying the regulatory effects of polydatin on the proliferation, apoptosis and autophagy of fibroblasts obtained from patients with AS remain unclear. The aim of this study was to investigate the therapeutic effects of polydatin on symptoms associated with AS. Multiple cellular and molecular biology experiments were performed in the present study, such as cell viability assay, Western blotting, flow cytometry, monodansylcadaverine (MDC) staining and immunofluorescence assays. In the present study, the results revealed that polydatin induced the apoptosis of fibroblasts isolated from patients with AS by upregulating the expression of active caspase-3 and Bax, and downregulating the expression of Bcl-2. Meanwhile, polydatin was revealed to enhance the autophagy of fibroblasts by increasing the expression levels of LC3II, Beclin 1 and Atg5. The results of MDC and immunofluorescence assays further demonstrated that polydatin significantly induced the formation of autophagosomes in fibroblasts. Furthermore, polydatin-induced apoptosis and autophagy were markedly inhibited following treatment with the autophagy inhibitor, 3-methyladenine (3-MA). In conclusion, the results of the present study indicated that polydatin induces the apoptosis and autophagy of fibroblasts obtained from patients suffering from AS, and that polydatin may represent a therapeutic agent for the future treatment of patients with AS.

Bushen Qiangji Granule () medicated serum inhibits osteogenic differentiation of fibroblasts in ankylosing spondylitis by inhibiting the BMP/Smads signal pathway in vitro.

OBJECTIVE: To explore the mechanism of Bushen Qiangji Granule (, BSQJ) in restraining the osteogenic differentiation of ankylosing spondylitis (AS) fifibroblasts. METHODS: Hip joint capsules were obtained from AS patients (n=10) receiving total hip replacement and healthy hip joint capsules from patients with hip fracture (n=10) receiving surgery as a control. Finite fifibroblast lines were established from these tissue samples to observe the effect of BSQJ on suppressing osteogenic differentiation of fifibroblasts. The expression of osteogenic marker gene corebinding factor a1 (Cbfa1) and Smad family proteins were examined by Western blot and real-time quantitative polymerase chain reaction (qPCR). RESULTS: The mRNA expression level of Cbfa1 was significantly higher in AS fibroblasts than that in normal fibroblasts and the expression of pSmad1, pSmad5, Smad4 and Cbfa1 in AS fibroblasts was also higher, demonstrating the activation of the BMP/Smads signal pathway in AS fifibroblasts. BSQJ-medicated serum not only restrained the mRNA and protein expression levels of Cbfa1 and inhibited protein expression level of Smad4 but also decreased the expression quantities of pSmad1 and pSmad5. CONCLUSIONS: BSQJ can inhibit osteogenic differentiation of AS fifibroblasts in vitro by suppressing the activation of the BMP/Smads signal pathway. This may be the important molecular mechanism of BSQJ in regulating AS ossifification.

Celastrol inhibits prostaglandin E2-induced proliferation and osteogenic differentiation of fibroblasts isolated from ankylosing spondylitis hip tissues in vitro.

BACKGROUND: Heterotopic ossification on the enthesis, which develops after subsequent inflammation, is one of the most distinctive features in ankylosing spondylitis (AS). Prostaglandin E2 (PGE-2) serves as a key mediator of inflammation and bone remodeling in AS. Celastrol, a well-known Chinese medicinal herb isolated from Tripterygium wilfordii, is widely used in treating inflammatory diseases, including AS. It has been proven that it can inhibit lipopolysac-charide-induced expression of various inflammation mediators, such as PGE-2. However, the mechanism by which celastrol inhibits inflammation-induced bone forming in AS is unclear. OBJECTIVE: To investigate whether celastrol could inhibit isolated AS fibroblast osteogenesis induced by PGE-2. METHODS: Hip synovial tissues were obtained from six AS patients undergoing total hip replacement in our hospital. Fibroblasts were isolated, primarily cultured, and then treated with PGE-2 for osteogenic induction. Different doses of celastrol and indometacin were added to observe their effects on osteogenic differentiation. Cell proliferation, osteogenic markers, alizarin red staining as well as the activity of alkaline phosphatase were examined in our study. RESULTS: Celastrol significantly inhibits cell proliferation of isolated AS fibroblasts and in vitro osteogenic differentiation compared with control groups in a time- and dose-dependent manner. CONCLUSION: Our results demonstrated that celastrol could inhibit isolated AS fibroblast proliferation and in vitro osteogenic differentiation. The interaction of PI3K/AKT signaling and Wnt protein may be involved in the process. Further studies should be performed in vivo and animal models to identify the potential effect of celastrol on the bone metabolism of AS patients.

[Acupuncture assisted by dynamic moxibustion for adult ankylosing spondylitis at early-to-mid stage].

OBJECTIVE: To observe the clinical efficacy differences between acupuncture combined with dynamic moxibustion and acupuncture alone for adult ankylosing spondylitis (AS) at early-to-mid stage based on medication. METHODS: Fifty-five cases of adult AS were randomly divided into an acupuncture-moxibustion group (28 cases) and an acupuncture group (27 cases). The two groups were treated with oral administration of sulfasalazine tablets. In addition, the acupuncture-moxibustion group was treated with acupuncture at Jiaji (EX-B 2), Shenshu (BL 23), Dachangshu (BL 25), Weizhong (BL 40) as well as dynamic moxibustion at the first line of bladder meridian of foot-taiyang and governor vessel from Dazhui (GV 14) to Yaoshu (GV 2). The acupuncture group was treated with acupuncture, the acupoints and manipulation of which were identical to acupuncture-moxibustion group. The treatment was given once a day, five days per week; one session was consisted of one-month treatment, and totally three sessions were given. The bath ankylosing spondylitis functional index (BAFI) and bath ankylosing spondylitis disease activity index (BASDAI) were compared before and after treatment in the two groups; also the clinical effective rates were compared between the two groups. RESULTS: The total effective rate was 96.4% (27/28) in the acupuncture-moxibustion group, which was superior to 88.9% (24/27) in the acupuncture group (P<0.05). Compared before treatment, the BASFI and BASDAI were reduced after treatment in the two groups (all P<0.05), which were more significant in the acupuncture-moxibustion group (both P<0.05). CONCLUSIONS: Based on medication, acupuncture combined with dynamic moxibustion could improve the clinical symptoms of AS, which is superior to simple acupuncture.

The Effect of SHH-Gli Signaling Pathway on the Synovial Fibroblast Proliferation in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by chronic synovitis. This study aims to investigate the role of sonic hedgehog (SHH)-Gli signaling pathway in synovial fibroblast proliferation in rheumatoid arthritis. The expression of serum SHH in RA patients group was significantly increased compared with the systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and healthy subject (healthy control, HC) groups, respectively; serum SHH expression of RA patients was positively correlated with rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP Ab), while there was no significant correlation between SHH expression and erythrocyte sedimentation rate (ESR). SHH, Ptch, Smo, and Gli molecules were highly expressed in rat RA-synovial fibroblast (RA-SF); after blocking the SHH-Gli signaling pathway with a Gli specific inhibitor, Gli-antagonist 61 (GANT61), RA-SF proliferation was inhibited in a dose-dependent manner and the apoptosis rate of RA-SF was increased as well; the expression levels of fibroblast growth factor receptor 1 (FGFR1) and FGFR3 declined in SF cells after GANT61 treatment. Our results suggest that SHH-Gli pathway is involved in the pathogenesis of RA, and blocking SHH-Gli pathway inhibits RA-SF cell proliferation and increases cell apoptosis, which may shed light on developing new ideas for RA treatment.

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses.

Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.

Effects of icariin on cytokine-induced ankylosing spondylitis with fibroblastic osteogenesis and its molecular mechanism.

The aim of this study is to explore the effects of icariin on cytokine induced ankylosing spondylitis fibroblast osteogenesis type expression and its molecular mechanism. The normal fibroblasts were collected as normal control group, and the fibroblasts of hip joint capsule of AS patients were collected, which were respectively added in fetal bovine serum (group AS), fetal bovine serum and cytokines (BMP-2+TGF-beta 1) (group AS), and cell factor solution (icariin group), and observed of the osteogenic expression of fibroblast, to evaluate the impact of Icariin on it. The ALP activity, the content of collagen, osteocalcin content and cbfa1mRNA and OCmRNA of fibroblast of AS group increased compared to the normal control group and AS control group (P < 0.01), indicating that icariin can significantly inhibit the above changes (P < 0.01). Icariin can inhibit fibroblast further osteogenic differentiation through inhibiting the effect of cytokines on the fibroblast osteogenesis type markers and osteogenic gene expression and osteogenic differentiation.

Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis.

INTRODUCTION: Inflammatory arthritis is associated with increased bone resorption and suppressed bone formation. The Wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Local glucocorticoid production is also significantly increased during joint inflammation. Therefore, we investigated how locally derived glucocorticoids and inflammatory cytokines regulate DKK1 synthesis in synovial fibroblasts during inflammatory arthritis. METHODS: We examined expression and regulation of DKK1 in primary cultures of human synovial fibroblasts isolated from patients with inflammatory arthritis. The effect of TNFα, IL-1ß and glucocorticoids on DKK1 mRNA and protein expression was examined by real-time PCR and ELISA. The ability of inflammatory cytokine-induced expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) to sensitise fibroblasts to endogenous glucocorticoids was explored. Global expression of Wnt signalling and target genes in response to TNFα and glucocorticoids was assessed using a custom array. RESULTS: DKK1 expression in human synovial fibroblasts was directly regulated by glucocorticoids but not proinflammatory cytokines. Glucocorticoids, but not TNFα, regulated expression of multiple Wnt agonists and antagonists in favour of inhibition of Wnt signalling. However, TNFα and IL-1ß indirectly stimulated DKK1 production through increased expression of 11ß-HSD1. CONCLUSIONS: These results demonstrate that in rheumatoid arthritis synovial fibroblasts, DKK1 expression is directly regulated by glucocorticoids rather than TNFα. Consequently, the links between synovial inflammation, altered Wnt signalling and bone remodelling are not direct but are dependent on local activation of endogenous glucocorticoids.

Update on biologic therapies in ankylosing spondylitis: a literature review.

AIM: The present paper aims to review the recent advances in diagnosis and management of ankylosing spondylitis (AS). METHOD: Medline and abstracts submitted to the recent European League Against Rheumatism (EULAR) congress were searched to obtain quality-controlled information on the management of AS. RESULTS: The use of magnetic resonance imaging (MRI) allows the diagnosis of AS to be made in the pre-radiographic stage. The Assessment in Spondylarthritis International Society recommendations for the management of AS have been modified so that patients with non-radiographic spondyloarthritis (SpA) can now be considered for biological therapy. The 'older' anti-tumour necrosis factor (TNF) continued to be effective in longer-term studies. Studies with longer duration of follow-up have shown that some patients with pre-radiographic SpA entered into prolonged drug-free remission. It is likely that in the foreseeable future, more AS patients will be treated with biological therapies at an earlier stage of the disease. New biologic therapies, golimumab and secukinumab, are looking promising in improving the signs and symptoms of AS, at least in the short-term. CONCLUSION: Longer-term studies of AS patients treated with infliximab, etanercept and adalimumab continued to show a good clinical response. There is a need for more long-term studies to examine the longitudinal efficacy of golimumab and secukinumab in AS.

Modic changes and spondylodiscitis at multiple levels of the thoracolumbar spine in a patient with ankylosing spondylitis.

BACKGROUND AND OBJECTIVE: Modic changes (MC) on magnetic resonance imaging (MRI) were described in 1988 by Modic et al. in a study among patients with chronic low back pain. Type 1 changes were shown to represent an acute inflammatory process while type 2 changes were found in chronic lesions. Since mechanical back pain is very common, it is often difficult to differentiate precisely the origin of the back pain in patients with ankylosing spondylitis (AS) based only on clinical assessment, laboratory findings and/or plain imaging. CASE REPORT: We report a male patient with AS who presented with low back pain. MRI revealed MCs and spondylodiscitis, an uncommon manifestation of AS, at multiple levels of the thoracolumbar spine. CONCLUSION: We believe that MRI may provide key information in addition to the clinical, laboratory and plain radiological assessments and can help to guide physicians in decision-making when treating patients with AS.

Biologics in the treatment of rheumatoid arthritis and ankylosing spondylitis.

There are clear differences in the clinical picture and in the pathogenesis between rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Biologic agents targeting TNF-alpha are efficacious in both diseases, with some tendency to work even better in spondyloarthritides (SpA) on a clinical basis. However, anti-TNF therapy was shown to inhibit radiographic progression in RA but not in AS. This is probably due to the outstanding difference in pathogenesis: while in RA osteodestructive lesions such as erosions predominate, AS patients will rather develop osteoproliferative changes such as syndesmophytes. There is some evidence that anti-TNF agents may show longterm efficacy and acceptable safety profiles over 5-10 years. There are some differences between the agents.Whether the recent developments of targeted therapies in RA with agents such as rituximab, abatacept and tocilizumab will also work for AS is unknown at present.

Ankylosing spondylitis in a patient with Turner syndrome: a case report.

Turner's syndrome (TS) is a chromosomal disorder where phenotypic females have either a missing chromosome (45 X0) or a structural aberration of one of the chromosomes. It is possible for TS to accompany such autoimmune diseases as thyroid diseases, inflammatory intestinal diseases, diabetes mellitus, psoriatic arthritis and juvenile rheumatoid arthritis. Herein, we present an unusual case with Ankylosing spondylitis (AS) and autoimmune thyroiditis associated with TS. We suggest that the possibility that TS patients may also develop such other diseases as AS apart from the already known accompanying autoimmune diseases should not be ruled out when monitoring TS patients.

FOXP3 identifies regulatory CD25bright CD4+ T cells in rheumatic joints.

Regulatory T cells have recently been implicated in a number of human diseases, including rheumatoid arthritis. To investigate whether the presence of CD25+CD4+ regulatory T cells is a general finding in arthritic joints, synovial fluid of patients with different rheumatic diseases such as undifferentiated arthritides, systemic rheumatic diseases and reactive arthritis were investigated for the presence of such cells. In 95% of the patients, a higher frequency of CD25(bright)CD4+ T cells was found in synovial fluid as compared with peripheral blood. Both in vitro suppression experiments and FOXP3 mRNA analysis confirmed these cells to be natural regulatory T cells. Together with our previous data, we conclude that arthritic joints, irrespective of precise diagnosis and disease duration, are enriched with natural regulatory T cells. These results suggest that suppressor cells migrate to and/or multiply at the sites of inflammation as part of the immune responses' effort to combat injurious inflammation.

Prehistoric juvenile rheumatoid arthritis in a precontact Louisiana native population reconsidered.

Descriptions of skeletal pathological conditions evident in the prehistoric Tchefuncte adolescent 16ST1-14883b are clarified. The basis is reaffirmed for assigning to the described pathological conditions a diagnostic perspective of juvenile rheumatoid arthritis or juvenile Lyme disease--a disease that mimics juvenile rheumatoid arthritis in its arthritic presentation--rather than of assigning them as representative of juvenile onset ankylosing spondylitis or other juvenile spondyloarthropathies. A hypothesis (Lewis [1994] Am. J. Phys. Anthropol. 93:455-475) is restated that 1) the spirochete Borrelia burgdorferi was the infectious agent responsible for prevalence of adult rheumatoid arthritis in prehistoric southeastern Native American populations, 2) that B. burgdorferi is a possible cause of the arthritis evident in individual 16ST1-14883b, and 3) that antibodies to B. burgdorferi provided partial immunity to the related spirochete Treponema pallidum for the 16ST1 precontact Tchefuncte population from Louisiana, protecting them from severe treponemal response. Given the probable widespread existence of Ixodid tick vectors for B. burgdorferi in prehistoric North America, coupled with the existence of treponematosis, it follows that the transition of Native American hunting-gathering economies to more sedentary economies would predictably be linked to an increased incidence of treponematosis due to the loss of benefits of the above-stated partial immunity. In other words, as prehistoric Native American exposure to tick vectors for B. burgdorferi decreased, susceptibility to treponematosis increased. Inferences regarding biological controls interacting with and influencing prehistoric Native American migration patterns are suggested from the link of B. burgdorferi to an Ixodid tick common to northeast Asia.

[Correct and incorrect paths in the history of ankylosing spondylitis]. / Wege und Irrwege in der Geschichte der Spondylitis ankylosans.

This article retraces the history of ankylosing spondylitis. While the first part takes into consideration the paleopathological aspects of illness, the second part retains the main stages of the research on the subject from the 16th to the 19th century. This part refers to B.O. Connor, who in 1694 was the first to give a complete description of a characteristic skeleton. This part also mentions Benjamin Brodie who in 1850 wrote the first complete clinical description and Charles Fagge who in his work was the first to combine clinical and anatomical elements. The scientific discussion at the end of the 19th century between Adolf Strümpell. Wladimir von Bechterew and Pierre Marie is also part of this paragraph. The last part shows the important discoveries of the 20th century, specially useful for a better understanding of the pathogenesis of the disease.

Paleopathologic evidence for the evolution of rheumatoid arthritis.

A human skeleton recovered from a Sicilian archaeological site and dating from the Hellenistic period (330-210 B.C.) presents a pathological pattern suggesting a transition between ankylosing spondylitis and rheumatoid arthritis, providing evidence in support of the hypothesis that rheumatoid arthritis may have recently evolved out of ankylosing spondylitis.