Quo vadis reactive arthritis?

PURPOSE OF REVIEW: We provide an overview of recent articles which describe new thinking regarding HLA-B27-associated reactive arthritis (ReA), including those additional infection-related arthritides triggered by microbes that often are grouped under the term ReA. RECENT FINDINGS: With the advent and continuation of the pandemic, an increasing number of cases and case series of post-COVID-19 arthritis have been reported and classified as ReA. Further, arthritis after COVID-19 vaccination is a new entity included within the spectrum of ReA. New causative microorganisms identified in case reports include Clostridium difficile, Mycoplasma pneumoniae, Giardia lamblia, Leptospira , and babesiosis. SARS-CoV-2 is emerging as a significant etiologic agent for apparent ReA. SUMMARY: It is now clear that comprehensive clinical and laboratory investigations, synovial fluid analyses, and close follow-up of patients all are essential to differentiate ReA from diseases that may present with similar clinical attributes. Further, and importantly, additional research is required to define the wide diversity in causative agents, epidemiology, and rare case presentations of these arthritides. Finally, new classification and diagnostic criteria, and updated treatment recommendations, are essential to the advancement of our understanding of ReA.

Psoriatic Spondylitis: A Disease Manifestation in Debate: Evidences to Know for the Clinical Rheumatologist.

ABSTRACT: With the advent of classification criteria for psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), patients with axial manifestations associated with psoriasis, initially described in the l950s as a specific entity termed psoriatic spondylitis (PS), are now categorized within PsA, ankylosing spondylitis (AS), and axSpA. Thus, different terms are used to describe axial disease in patients with PsA including PS, axial psoriatic arthritis (axPsA), and psoriatic spondyloarthritis. Patients with PS may present with inflammatory and/or mechanical back pain, but also may display axial disease on imaging despite not complaining of back pain. Cervical spondylitis has been reported in 35% to 75% of patients with PsA. Axial disease is silent in 20% and 25% of patients with axial PsA and PsA, respectively. The majority of axPsA patients have peripheral arthritis alongside the axial involvement, whereas only 2% to 5% of PsA patients have solely axial arthritis with no peripheral arthritis.A debate is currently underway as to whether inflammatory axial disease and psoriasis represent axSpA with psoriasis or a subset of PsA named axPsA. Studies have recognized that axial disease in PsA patients seems to be different demographically, genetically, clinically, and radiographically when compared with AS with or without psoriasis. This narrative review summarizes current knowledge regarding axial involvement of PsA in terms of history, terminology, classification, epidemiology, clinical presentation, imaging, diagnosis, and treatment, with the aim of providing advice for management of PS in clinical evidence-based practice. Data-driven studies are needed to develop clear, nonoverlapping classification criteria for spinal involvement in PsA.

Reactive Arthritis Update: Spotlight on New and Rare Infectious Agents Implicated as Pathogens.

PURPOSE OF REVIEW: This article presents a comprehensive narrative review of reactive arthritis (ReA) with focus on articles published between 2018 and 2020. We discuss the entire spectrum of microbial agents known to be the main causative agents of ReA, those reported to be rare infective agents, and those reported to be new candidates causing the disease. The discussion is set within the context of changing disease terminology, definition, and classification over time. Further, we include reports that present at least a hint of effective antimicrobial therapy for ReA as documented in case reports or in double-blind controlled studies. Additional information is included on microbial products detected in the joint, as well as on the positivity of HLA-B27. RECENT FINDINGS: Recent reports of ReA cover several rare causative microorganism such as Neisseria meningitides, Clostridium difficile, Escherichia coli, Hafnia alvei, Blastocytosis, Giardia lamblia, Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica/dispar, Strongyloides stercoralis, ß-haemolytic Streptococci, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Mycobacterium bovis bacillus Calmette-Guerin, and Rickettsia rickettsii. The most prominent new infectious agents implicated as causative in ReA are Staphylococcus lugdunensis, placenta- and umbilical cord-derived Wharton's jelly, Rothia mucilaginosa, and most importantly the SARS-CoV-2 virus. In view of the increasingly large spectrum of causative agents, diagnostic consideration for the disease must include the entire panel of post-infectious arthritides termed ReA. Diagnostic procedures cannot be restricted to the well-known HLA-B27-associated group of ReA, but must also cover the large number of rare forms of arthritis following infections and vaccinations, as well as those elicited by the newly identified members of the ReA group summarized herein. Inclusion of these newly identified etiologic agents must necessitate increased research into the pathogenic mechanisms variously involved, which will engender important insights for treatment and management of ReA.

Chlamydia-Induced Reactive Arthritis: Disappearing Entity or Lack of Research?

PURPOSE OF REVIEW: Recent studies regarding the frequency of Chlamydia-induced reactive arthritis (ReA) are reviewed, with a focus on the question of whether the entity is in fact disappearing or whether it is simply being underdiagnosed/underreported. Epidemiological reports indicate diversity in the frequency of Chlamydia-associated ReA in various parts of the world, with evidence of declining incidence in some regions. RECENT FINDINGS: The hypothesis that early effective treatment with antibiotics prevents the manifestation of Chlamydia-associated ReA requires further investigation. For clinicians, it is important to remember that ReA secondary to Lymphogranuloma venereum (LGV) serovars L1-L3 of C. trachomatis is probably underestimated due to a limited awareness of this condition, the re-emergence in Western countries of LGV overall, and the present increasingly rare classical inguinal presentation.

Auguste Renoir, Sculptor With Hired Hands: A Masterful Artistic Cooperation Overshadowed by Legal Issues and Copyright Infringement.

The coping with rheumatoid arthritis of the famous French impressionist painter Pierre-Auguste Renoir (1841-1919) is described in former publications. The heavily handicapped painter has in his last years created sculptures in cooperation with the sculptor Richard Guino (1890-1973). The extraordinary genesis of the sculptures through a masterful artistic cooperation, as well as the resulting legal issues and shameful copyright infringements, is reported. Renoir's decision to create sculptures with the help of Guido can be attributed to his remarkable artistic vision, vitality, optimistic nature, and strong will and is also a further testimonial of creative coping of an artist overcoming the physical handicap due to rheumatoid arthritis of his final years, so far not described in detail in the medical literature.

Causality of Chlamydiae in Arthritis and Spondyloarthritis: a Plea for Increased Translational Research.

Current molecular genetic understanding of the metabolically active persistent infection state of Chlamydia trachomatis and Chlamydia pneumoniae in the synovium in patients with arthritis and spondyloarthritis favors a causal relationship. Here, we examine how adequately the accepted criteria for that etiologic relationship are fulfilled, emphasizing the situation in which these microorganisms cannot be cultivated by standard or other means. We suggest that this unusual situation of causality by chlamydiae in rheumatic disease requires establishment of a consensus regarding microorganism-specific terminology as well as the development of new diagnostic and classification criteria. Recent studies demonstrate the value of molecular testing for diagnosis of reactive arthritis, undifferentiated spondyloarthritis, and undifferentiated arthritis caused by C. trachomatis and C. pneumoniae in clinical practice. Data regarding combination antibiotic therapy is consistent with the causative role of chlamydiae for these diseases. Observations of multiple intra-articular coinfections require more research to understand the implications and to respond to them.

New insights into Chlamydia and arthritis. Promise of a cure?

Chlamydia trachomatis and Chlamydia pneumoniae together comprise the most frequent causative pathogens that elicit reactive arthritis (ReA). Advances in our understanding of the molecular biology/molecular genetics of these organisms have improved significantly the ability to detect chlamydiae in the joint for diagnostic purposes, as well as extending our current understanding of the pathogenic processes they elicit in the joint and elsewhere. An important aspect of the latter is that synovial chlamydiae infect the joint in an unusual but metabolically active state. While some standard treatments can provide a palliative effect on the ReA disease phenotype, many reports have indicated that standard antibiotic treatment does not provide a cure. Of critical importance, however, two recent reports of controlled clinical trials demonstrated that Chlamydia-ReA can be treated successfully using combination antibiotic therapy. These observations offer the opportunity of a cure for this disease, thereby increasing the practical importance of awareness and diagnosis of the spondyloarthritis caused by Chlamydia. In this viewpoint, we provide an overview of recent key findings in the epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of Chlamydia-induced arthritis. Our intention is for these insights to be translated rapidly into clinical practice to overcome misdiagnosis and underdiagnosis of the disease, and for them to stimulate the continued development of a cure.

Influence of Anode Immersion Speed on Current and Power in Plasma Electrolytic Polishing.

Plasma electrolytic polishing (PeP) is mainly used to improve the surface quality and thus the performance of electrically conductive parts. It is usually used as an anodic process, i.e., the workpiece is positively charged. However, the process is susceptible to high current peaks during the formation of the vapour-gaseous envelope, especially when polishing workpieces with a large surface area. In this study, the influence of the anode immersion speed on the current peaks and the average power during the initialisation of the PeP process is investigated for an anode the size of a microreactor mould insert. Through systematic experimentation and analysis, this work provides insights into the control of the initialisation process by modulating the anode immersion speed. The results clarify the relationship between immersion speed, peak current, and average power and provide a novel approach to improve process efficiency in PeP. The highest peak current and average power occur when the electrolyte splashes over the top of the anode and not, as expected, when the anode touches the electrolyte. By immersion of the anode while the voltage is applied to the anode and counterelectrode, the reduction of both parameters is over 80%.

Easy probability estimation of the diagnosis of early axial spondyloarthritis by summing up scores.

OBJECTIVES: Several sets of criteria for the diagnosis of axial SpA (including non-radiographic axial spondyloarthritis) have been proposed in the literature in which scores were attributed to relevant findings and the diagnosis requests a minimal sum of these scores. To quantitatively estimate the probability of axial SpA, multiplying the likelihood ratios of all relevant findings was proposed by Rudwaleit et al. in 2004. The objective of our proposal is to combine the advantages of both, i.e. to estimate the probability by summing up scores instead of multiplying likelihood ratios. METHODS: An easy way to estimate the probability of axial spondyloarthritis is to use the logarithms of the likelihood ratios as scores attributed to relevant findings and to use the sum of these scores for the probability estimation. RESULTS: A list of whole-numbered scores for relevant findings is presented, and also threshold sum values necessary for a definite and for a probable diagnosis of axial SpA as well as a threshold below which the diagnosis of axial spondyloarthritis can be excluded. In a diagram, the probability of axial spondyloarthritis is given for sum values between these thresholds. CONCLUSION: By the method proposed, the advantages of both, the easy summing up of scores and the quantitative calculation of the diagnosis probability, are combined. Our method also makes it easier to estimate which additional tests are necessary to come to a definite diagnosis.

Cost-effectiveness simulation model of biologic strategies for treating to target rheumatoid arthritis in Germany.

OBJECTIVES: The treatment of active rheumatoid arthritis (RA) usually requires different therapeutic options used sequentially in case of an insufficient response (IR) to previous agents. Since there is a lack of clinical trials comparing biologic treatment sequences, simulation models might add to the understanding of optimal treatment sequences and their cost-effectiveness. The objective of this study was to assess the cost-effectiveness of different biologic treatment strategies in patients with an IR to anti-TNF agents, based on levels of disease activity from the German public payer's perspective. METHODS: A cost-effectiveness sequential model was developed in accordance with local RA treatment strategies, using DAS28 scores as dichotomous effectiveness endpoints: achieving remission/no remission (RS/no RS) or a state of low disease activity (LDAS/no LDAS). Costs were estimated using resource utilisation data obtained from a large observational German cohort. Advanced simulations were conducted to assess the cost-effectiveness over 2 years of four sequential biologic strategies composed of up to 3 biologic agents, namely anti-TNF agents, abatacept or rituximab, in patients with moderate-to-severe active RA and an IR to at least one anti-TNF agent. RESULTS: Over two years, the biological sequence including abatacept after an IR to one anti-TNF agent appeared the most effective and cost-effective versus (vs.) use after two anti-TNF agents (€633 vs. €1,067/day in LDAS and €1,222 vs. €3,592/day in remission), and vs a similar sequence using rituximab (€633 vs. €728/day in LDAS and €1,222 vs. €1,812/day in remission). The sequence using a 3rd anti-TNF agent was less effective and cost-effective than the same sequence using abatacept (€2,000 vs. €1,067/day in LDAS and €6,623 vs. €3,592/day in remission). All differences were statistically significant (p<0.01). CONCLUSIONS: The results suggest that in patients with an IR to at least one anti-TNF agent, biologic sequences including abatacept appear more efficacious and cost-effective than similar sequences including rituximab or only cycled anti-TNF agents.

Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis.

OBJECTIVE: To assess prospectively the rates and to explore predictors of spinal radiographic progression over 2 years in a cohort of patients with early axial spondylarthritis (SpA). METHODS: Two hundred ten patients with axial SpA from the German Spondyloarthritis Inception Cohort were selected for this analysis based on the availability of radiographs at baseline and after 2 years of followup. Spinal radiographs were scored by 2 trained readers in a blinded, randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Spinal radiographic progression was defined as worsening of the mean mSASSS by ≥2 units over 2 years. RESULTS: Among the patients with axial SpA, 14.3% showed spinal radiographic progression after 2 years (20% of those with AS and 7.4% of those with nonradiographic axial SpA). The following parameters were independently associated with spinal radiographic progression: presence of syndesmophytes at baseline (odds ratio [OR] 6.29, P < 0.001), elevated levels of markers of systemic inflammation (for the erythrocyte sedimentation rate, OR 4.04, P = 0.001; for C-reactive protein level time-averaged over 2 years, OR 3.81, P = 0.001), and cigarette smoking (OR 2.75, P = 0.012). These associations were confirmed by multivariate logistic regression analysis. No clear association with spinal radiographic progression was observed for HLA-B27 status, sex, age, disease duration, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, presence of peripheral arthritis, enthesitis, psoriasis, treatment with nonsteroidal antiinflammatory drugs, or treatment with disease-modifying antirheumatic drugs at baseline. CONCLUSION: The presence of radiographic damage at baseline (syndesmophytes), elevated levels of acute-phase reactants, and cigarette smoking were all independently associated with spinal radiographic progression in patients with early axial SpA.

Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort.

OBJECTIVE: To investigate the influence of non-steroidal anti-inflammatory drugs (NSAIDs) intake on radiographic spinal progression over 2 years in patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (SpA). METHODS: 164 patients with axial SpA (88 with AS and 76 with non-radiographic axial SpA) were selected for this analysis based on availability of spinal radiographs at baseline and after 2 years of follow-up and the data on NSAIDs intake. Spinal radiographs were scored by two trained readers in a concealed randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) system. An index of the NSAID intake counting both dose and duration of drug intake was calculated. RESULTS: High NSAIDs intake (NSAID index≥50) in AS was associated with lower likelihood of significant radiographic progression defined as an mSASSS worsening by ≥2 units: OR=0.15, 95% CI 0.02 to 0.96, p=0.045 (adjusted for baseline structural damage, elevated C reactive protein (CRP) and smoking status) in comparison with patients with low NSAIDs intake (NSAID index<50). This effect was most pronounced in patients with baseline syndesmophytes plus elevated CRP: mean mSASSS progression was 4.36±4.53 in patients with low NSAIDs intake versus 0.14±1.80 with high intake, p=0.02. In non-radiographic axial SpA, no significant differences regarding radiographic progression between patients with high and low NSAIDs intake were found. CONCLUSION: A high NSAIDs intake over 2 years is associated with retarded radiographic spinal progression in AS. In non-radiographic axial SpA this effect is less evident, probably due to a low grade of new bone formation in the spine at this stage.

Great artists with rheumatoid arthritis. What did their disease and coping teach? Part II. Raoul Dufy and Niki de Saint Phalle.

Raoul Dufy (1877-1953) and Niki de Saint Phalle (1930-2002) were 2 famous artists who suffered from rheumatoid arthritis (RA). Both artists represent an additional outstanding example of successful coping with RA in former times when, for the first time, corticosteroids were available, but nevertheless treatment was very limited in the pre-biological era. Dufy was one of the earliest patients with RA who received corticosteroids and regained his creativity to paint for a few additional years, but finally he died of massive intestinal hemorrhages, the adverse event of the combination of corticosteroid plus aspirin. Niki de Saint Phalle, a self-taught French painter and sculptor, was one of the most significant and unconventional female artists of the 20th century. Her eventful life was full of emotional burdens and lifelong lung disease in addition to RA. Niki de Saint Phalle came out from each physical and emotional crisis with new forces and new artistic ideas. Interestingly, it has been suggested that the occupational exposure to colors contributed to the development of RA in artists, which used significantly more bright and clear colors based on toxic heavy metals such as Renoir and Dufy. Moreover, these 2 were cigarette smokers, a recently described risk factor for developing RA and increasing the severity once it does develop. Niki de Saint Phalle produced her sculptures made of plastic material without protection while she assumed that exposition to polyester and toxic fumes of polystyrene caused severe damage to her lungs, resulting in recurrent health problems.

Great artists with rheumatoid arthritis: what did their disease and coping teach? Part I. Pierre-Auguste Renoir and Alexej von Jawlensky.

The famous artists Pierre-Auguste Renoir (1841-1919) and Alexej von Jawlensky (1864-1941) had rheumatoid arthritis (RA). Both represent an outstanding example of successful coping with RA in former times when treatment was very limited, and these individuals took advantage of creative disease management. The most popular French impressionist painter Renoir used his creativity to develop his own exercises and assistive equipments for painting despite his disability. Thus, Renoir exemplifies an artistic life altered by RA over more than 25 years that he dedicated entirely to his art and the depiction of beauty and happiness testified by his own words: "The pain passes, but the beauty remains." Jawlensky, a Russian from origin, was one of the most important expressionist painter active in Germany and the first painter in the 20th century who created extensive series of paintings especially of human faces. From Jawlensky, we learned that his rapidly progressing, late-onset RA induced depression, disability, financial pressure, and social retreat. But the resulting artistic sublimation contributed to the change in his paintings, which we owe the more than 1000 series of the very unique, small-format "Meditations."For those interested in art, new insight will be opened into the life and work of the artists and increase the appreciation for their contribution to modern art.

A historical perspective of the spondyloarthritis.

PURPOSE OF REVIEW: The history of ankylosing spondylitis, the main representative of the spondyloarthritides, is dating back to several thousand years BC and recently proven for medieval skeleton by HLA-B27 typing with modern molecular techniques. In modern time, the history of spondyloarthritis (SpA) is characterized by fluctuation between lumping and splitting. Actually, the recent advent of new classification criteria demands to discuss the consequences and clinical implications in the historical context of the development of the concept of SpA including the controversy of lumping and splitting. RECENT FINDINGS: The new Assessment of SpondyloArthritis International Society classification criteria for axial and peripheral SpA are primarily developed to provide support for clinical trials with biologicals and other treatment modalities, which intend to cover the whole spectrum, especially early clinical manifestations of spondyloarthritides. New insights into genetics and the evolving etiological role of Chlamydia in SpA including the most recent finding of the effective combination antibiotic therapy are major advances in the evolving history of SpA. SUMMARY: The concept of SpA is well accepted for the classification, diagnosis, and therapeutic management of a high proportion of individuals with inflammatory rheumatic conditions. For further advances research technologies are now available to enlarge the current body of clinical, immunologic, and genetic studies using pivotal microbiologic research and new antimicrobial therapeutic strategies.

Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis.

OBJECTIVE: To assess the progression of radiographic sacroiliitis in a cohort of patients with early axial spondyloarthritis over a period of 2 years and to explore predictors of progression. METHODS: 210 patients with axial spondyloarthritis from the German Spondyloarthritis Inception Cohort have been selected for this analysis based on availability of radiographs at baseline and after 2 years of follow-up. Radiographs were centrally digitised and the sacroiliac joints were scored independently according to the grading system of the modified New York criteria for ankylosing spondylitis (AS) by two trained readers. The readers scored both time points simultaneously but were blinded for the time point and for all clinical data. RESULTS: 115 patients (54.8%) fulfilled the modified New York criteria for AS in their radiographic part in the opinion of both readers at baseline, while 95 patients (45.2%) were classified as non-radiographic axial spondyloarthritis. More patients with non-radiographic spondyloarthritis (10.5%) compared with AS (4.4%) showed an estimated 'true' progression by at least one grade according to both readers, although the difference between the two groups was statistically non-significant. The rate of progression from non-radiographic axial spondyloarthritis to AS was 11.6% over 2 years. An elevated level of C-reactive protein (CRP) at baseline was a strong positive predictor of radiographic sacroiliitis progression in non-radiographic axial spondyloarthritis and AS (OR 3.65 and 5.08, respectively, p<0.05). CONCLUSION: Progression of radiographic sacroiliitis by at least one grade after 2 years occurs only in a small percentage of patients with early axial spondyloarthritis. An elevated level of CRP was found to be a strong positive predictor of sacroiliitis progression.