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| Musculoskeletal disorders | |
|---|---|
| Carpal tunnel syndrome is a common musculoskeletal disorder, and is often treated with a splint. | |
| Specialty | Rheumatology |
Musculoskeletal disorders (MSDs) are injuries or pain in the human musculoskeletal system, including the joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck and back.[1] MSDs can arise from a sudden exertion (e.g., lifting a heavy object)[2], or they can arise from making the same motions repeatedly repetitive strain, or from repeated exposure to force, vibration, or awkward posture.[3] Injuries and pain in the musculoskeletal system caused by acute traumatic events like a car accident or fall are not considered musculoskeletal disorders.[4] MSDs can affect many different parts of the body including upper and lower back, neck, shoulders and extremities (arms, legs, feet, and hands).[5] Examples of MSDs include carpal tunnel syndrome, epicondylitis, tendinitis, back pain, tension neck syndrome, and hand-arm vibration syndrome.[3]
- 1Causes
- 3Prevention
- 4Epidemiology
Causes[edit]
MSDs can arise from the interaction of physical factors with ergonomic, psychological, social, and occupational factors.[6]
Biomechanical[edit]
MSDs are caused by biomechanical load which is the force that must be applied to do tasks, the duration of the force applied, and the frequency with which tasks are performed.[7] Activities involving heavy loads can result in acute injury, but most occupation-related MSDs are from motions that are repetitive, or from maintaining a static position.[8] Even activities that do not require a lot of force can result in muscle damage if the activity is repeated often enough at short intervals.[8] MSD risk factors involve doing tasks with heavy force, repetition, or maintaining a nonneutral posture.[8] Of particular concern is the combination of heavy load with repetition.[8] Although poor posture is often blamed for lower back pain, a systematic review of the literature failed to find a consistent connection.[9]
Individual differences[edit]
People vary in their tendency to get MSDs. Gender is a factor, with women having a higher incidence of MSDs than men.[8] Obesity is also a factor, with overweight individuals having a higher risk of some MSDs, specifically of the lower back.[10]
Psychosocial[edit]
There is a growing consensus that psychosocial factors are another cause of some MSDs.[11] Some theories for this causal relationship found by many researchers include increased muscle tension, increased blood and fluid pressure, reduction of growth functions, pain sensitivity reduction, pupil dilation, body remaining at heightened state of sensitivity. Although there is no consensus at this time,[12] some of the workplace stressors found to be associated with MSDs in the workplace include high job demands, low social support, and overall job strain.[11][13][14] Researchers have consistently identified causal relationships between job dissatisfaction and MSDs. For example, improving job satisfaction can reduce 17-69 per cent of work-related back disorders and improving job control can reduce 37-84 per cent of work-related wrist disorders.[15]
Occupational[edit]
Because workers maintain the same posture over long work days and often several years, even natural postures like standing can lead to MSDs like low back pain. Postures which are less natural, such as twisting of or tension in the upper body, are typically contributors to the development of MSDs due to the unnatural biomechanical load of these postures.[3][16] There is evidence that posture contributes to MSDs of the neck, shoulder, and back.[3] Repeated motion is another risk factor for MSDs of occupational origin because workers can perform the same movements repeatedly over long periods of time (e.g. typing leading to carpal tunnel syndrome), which can wear on the joints and muscles involved in the motion in question.[3] Workers doing repetitive motions at a high pace of work with little recovery time and workers with little to no control over the timing of motions (e.g. workers on assembly lines) are also prone to MSDs due to the motion of their work.[16] Force needed to perform actions on the job can also be associated with higher MSD risk in workers, because movements which require more force can fatigue muscles quicker which can lead to injury and/or pain.[3] Additionally, exposure to vibration (experienced by truck drivers or construction workers, for example) and extreme hot or cold temperatures can affect a worker's ability to judge force and strength, which can lead to development of MSDs.[16] Vibration exposure is also associated with hand-arm vibration syndrome, which has symptoms of lack of blood circulation to the fingers, nerve compression, tingling, and/or numbness.[17]
Diagnosis[edit]
Assessment of MSDs is based on self-reports of symptoms and pain as well as physical examination by a doctor.[3] Doctors rely on medical history, recreational and occupational hazards, intensity of pain, a physical exam to locate the source of the pain, and sometimes lab tests, X-rays, or an MRI[18] Doctors look for specific criteria to diagnose each different musculoskeletal disorder, based on location, type, and intensity of pain, as well as what kind of restricted or painful movement a patient is experiencing.[3] A popular measure of MSDs is the Nordic Questionnaire that has a picture of the body with various areas labeled and asks the individual to indicate in which areas they have experienced pain, and in which areas has the pain interfered with normal activity.[5]
Prevention[edit]
Prevention of MSDs relies upon identification of risk factors, either by self-report, observation on the job, or measurement of posture which could lead to MSDs.[19] Once risk factors have been determined, there are several intervention methods which could be used to prevent the development of MSDs. The target of MSD prevention efforts is often the workplace in order to identify incidence rates of both disorders and exposure to unsafe conditions.[20]
Workplace controls[edit]
Groups who are at particular risk can be identified, and modifications to the physical and psychosocial environment can be made.[20] Approaches to prevention in workplace settings include matching the person's physical abilities to the tasks, increasing the person's capabilities, changing how tasks are performed, or changing the tasks.[21] Employers can also utilize engineering controls and administrative controls to prevent injury happening on the job.[4] Implementation of engineering controls is the process of designing or redesigning the workplace to account for strengths, weaknesses, and needs of the working population- examples would be workstation layout changes to be more efficient or reducing bending over, or moving necessary tools within shorter reach of the worker's station.[4] Employers may also utilize administrative controls like reducing number of hours in a certain position, limiting overtime, or including more breaks during shifts in order to reduce amount of time at risk for each worker.[4]
Ergonomics[edit]
Encouraging the use of proper ergonomics not only includes matching the physical ability of the worker with the correct job, but it deals with designing equipment that is correct for the task.[22] Limiting heavy lifting, training, and reporting early signs of injury are examples that can prevent MSD.[23] Employers can provide support for employees in order to prevent MSD in the workplace by involving the employees in planning, assessing, and developing standards of procedures that will support proper ergonomics and prevent injury.[23]
One focus of ergonomic principles is maintaining neutral postures, which are postures in which muscles are at their normal length and able to generate the most force, while reducing stress and possible injury to muscles, tendons, nerves, and bones- therefore, in the workplace or in everyday life, it is ideal for muscles and joints to maintain neutral positions.[24] Additionally, to prevent hand, wrist, and finger injuries, understanding when to use pinch grips (best for fine motor control and precise movements with low force) and power grips (best for high-force movements done repeatedly) is important for employees and general tasks outside the workplace.[24] The choice of tools should match that of the proper grip and be conducive to neutral postures, which is important for employers to consider when purchasing equipment.[24] In order to reduce injuries to the low back and spine, it is recommended to reduce weight and frequency of lifting cycles as well as decreasing the distance between the body and the load to reduce the torque force on the back for workers and individuals doing repeated lifting to avoid fatigue failure of the spine.[24] The shape of objects being lifted should also be considered, especially by employers, because objects which are easier to grip, lift, and access present less stress on the spine and back muscles than objects which are awkwardly shaped and difficult to access.[24]
The National Institute of Occupational Safety and Health (NIOSH) has published ergonomic recommendations for several industries, including construction, mining, agriculture, healthcare, and retail, among others.[25]
Epidemiology[edit]
Deaths from musculoskeletal diseases per million persons in 2012General population[edit]
MSDs are an increasing healthcare issue globally, being the second leading cause of disability.[8] For example, in the U.S. there were more than 16 million strains and sprains treated in 2004, and the total cost for treating MSDs is estimated to be more than $125 billion per year.[26] In 2006 approximately 14.3% of the Canadian population was living with a disability, with nearly half due to MSDs.[27] Neck pain is one of the most common complaints, with about one fifth of adults worldwide reporting pain annually.[28]
Workplace[edit]
Most workplace MSD episodes involve multiple parts of the body.[29] MSDs are the most frequent health complaint by European, United States and Asian Pacific workers.[30] and the third leading reason for disability and early retirement in the U.S.[13] The incidence rate for MSDs among the working population in 2014 was 31.9 newly diagnosed MSDs per 10,000 full-time workers.[31] In 2014, the median days away from work due to MSDs was 13, and there were 10.4 cases per 10,000 full-time workers in which an MSD caused a worker to be away from work for 31 or more days.[31] MSDs are widespread in many occupations, including those with heavy biomechanical load like construction and factory work, and those with lighter loads like office work.[13] The transportation and warehousing industries have the highest incidence rate of musculoskeletal disorders, with an incidence rate of 89.9 cases per 10,000 full-time workers.[31]Healthcare, manufacturing, agriculture, wholesale trade, retail, and recreation industries all have incidence rates above 35 per 10,000 full-time workers.[31] For example, a national survey of U.S. nurses found that 38% reported an MSD in the prior year, mainly lower back injury.[32] The neck and back are the most common sites of MSDs in workers, followed by the upper limbs and lower limbs.[31] The Bureau of Labor Statistics reports that 31.8 new cases of MSDs per 10,000 full-time workers per year are due to overexertion, bodily reaction, or repetitive motions.[31]
See also[edit]
References[edit]
- ^'CDC - NIOSH Program Portfolio : Musculoskeletal Disorders : Program Description'. www.cdc.gov. Retrieved 2016-03-24.
- ^Kumaraveloo, K Sakthiaseelan; Lunner Kolstrup, Christina (2018-07-03). 'Agriculture and musculoskeletal disorders in low- and middle-income countries'. Journal of Agromedicine. 23 (3): 227–248. doi:10.1080/1059924x.2018.1458671. ISSN1059-924X. PMID30047854.
- ^ abcdefgh'CDC - NIOSH Publications and Products - Musculoskeletal Disorders and Workplace Factors (97-141)'. www.cdc.gov. 1997. doi:10.26616/NIOSHPUB97141. Retrieved 2016-03-24.
- ^ abcdPrevention, Centers for Disease Control and. 'CDC - Workplace Health - Implementation - Work-Related Musculoskeletal Disorders (WMSD) Prevention'. www.cdc.gov. Retrieved 2016-03-24.
- ^ abKuorinka, I.; Jonsson, B.; Kilbom, A.; Vinterberg, H.; Biering-Sørensen, F.; Andersson, G.; Jørgensen, K. (1987). 'Standardised Nordic questionnaires for the analysis of musculoskeletal symptoms'. Applied Ergonomics. 18 (3): 233–7. doi:10.1016/0003-6870(87)90010-x. PMID15676628.
- ^Gatchel, R. J., & Kishino, N. (2011). Pain, musculoskeletal injuries, and return to work. In J. C. Quick & L. E. Tetrick (Eds.), Handbook of occupational health psychology (2nd ed.). Washington, DC: American Psychological Association.
- ^Barriera-Viruet H.; Sobeih T. M.; Daraiseh N.; Salem S. (2006). 'Questionnaires vs observational and direct measurements: A systematic review'. Theoretical Issues in Ergonomics Science. 7 (3): 261–284. doi:10.1080/14639220500090661.
- ^ abcdefBarbe, Mary F; Gallagher, Sean; Massicotte, Vicky S; Tytell, Michael; Popoff, Steven N; Barr-Gillespie, Ann E (2013). 'The interaction of force and repetition on musculoskeletal and neural tissue responses and sensorimotor behavior in a rat model of work-related musculoskeletal disorders'. BMC Musculoskeletal Disorders. 14: 303. doi:10.1186/1471-2474-14-303. PMC3924406. PMID24156755.
- ^Roffey DM, Wai EK, Bishop P, Kwon BK, Dagenais S (January 2010). 'Causal assessment of awkward occupational postures and low back pain: results of a systematic review'. The Spine Journal. 10 (1): 89–99. doi:10.1016/j.spinee.2009.09.003. PMID19910263.
- ^Kerr MS, Frank JW, Shannon HS, Norman RW, Wells RP, Neumann WP, Bombardier C (July 2001). 'Biomechanical and psychosocial risk factors for low back pain at work'. American Journal of Public Health. 91 (7): 1069–75. doi:10.2105/AJPH.91.7.1069. PMC1446725. PMID11441733.
- ^ abSafety, Government of Canada, Canadian Centre for Occupational Health and. 'Musculoskeletal Disorders - Psychosocial Factors : OSH Answers'. www.ccohs.ca. Retrieved 2016-04-07.
- ^Courvoisier DS, Genevay S, Cedraschi C, Bessire N, Griesser-Delacretaz AC, Monnin D, Perneger TV (July 2011). 'Job strain, work characteristics and back pain: a study in a university hospital'. European Journal of Pain. 15 (6): 634–40. doi:10.1016/j.ejpain.2010.11.012. PMID21186129.
- ^ abcSprigg C. A.; Stride C. B.; Wall T. D.; Holman D. J.; Smith P. R. (2007). 'Work characteristics, musculoskeletal disorders, and the mediating role of psychological strain: A study of call center employees'. Journal of Applied Psychology. 92 (5): 1456–1466. doi:10.1037/0021-9010.92.5.1456. PMID17845098.
- ^Hauke A.; Flintrop J.; Brun E.; Rugulies R. (2011). 'The impact of work-related psychosocial stressors on the onset of musculoskeletal disorders in specific body regions: A review and meta-analysis of 54 longitudinal studies'. Work & Stress. 25 (3): 243–256. doi:10.1080/02678373.2011.614069.
- ^Punnett (2004). 'Work-related Musculoskeletal Disorders: The Epidemiologic Evidence and the Debate'. Journal of Electromyography and Kinesiology. 14 (1): 13–23. doi:10.1016/j.jelekin.2003.09.015. PMID14759746.
- ^ abcSafety, Government of Canada, Canadian Centre for Occupational Health and. 'Work-related Musculoskeletal Disorders (WMSDs) - Risk Factors : OSH Answers'. www.ccohs.ca. Retrieved 2016-03-25.
- ^'CDC - NIOSH Publications and Products - Criteria for a Recommended Standard: Occupational Exposure to Hand-Arm Vibration (89-106)'. www.cdc.gov. 1989. doi:10.26616/NIOSHPUB89106. Retrieved 2016-03-25.
- ^'Musculoskeletal Pain: Tendonitis, Myalgia & More Cleveland Clinic'. my.clevelandclinic.org. Retrieved 2016-03-24.
- ^NIOSH [2014]. Observation-based posture assessment: review of current practice and recommendations for improvement. By Lowe BD, Weir PL, Andrews DM. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014–131.
- ^ abCôté, Julie N.; Ngomo, Suzy; Stock, Susan; Messing, Karen; Vézina, Nicole; Antle, David; Delisle, Alain; Bellemare, Marie; Laberge, Marie; St-Vincent, Marie (2013). 'Quebec Research on Work-related Musculoskeletal Disorders'. Relations Industrielles. 68 (4): 643. doi:10.7202/1023009ar.
- ^Rostykus W.; Ip W.; Mallon J. (2013). 'Musculoskeletal disorders'. Professional Safety. 58 (12): 35–42.
- ^'Hospital eTool: Healthcare Wide Hazards - Ergonomics'. www.osha.gov. Retrieved 2016-04-07.
- ^ ab'Safety and Health Topics Ergonomics'. www.osha.gov. Retrieved 2016-04-07.
- ^ abcdeMoore, S.M., Torma-Krajewski, J., & Steiner, L.J. (2011). Practical Demonstrations of Ergonomic Principles. Report of Investigations 9684. NIOSH. Retrieved 24 March 2016.
- ^'CDC - Ergonomics and Musculoskeletal Disorders - NIOSH Workplace Safety and Health Topic'. www.cdc.gov. Retrieved 2016-03-25.
- ^Gallagher, Sean; Heberger, John R. (2013-02-01). 'Examining the Interaction of Force and Repetition on Musculoskeletal Disorder Risk A Systematic Literature Review'. Human Factors: The Journal of the Human Factors and Ergonomics Society. 55 (1): 108–124. doi:10.1177/0018720812449648. ISSN0018-7208. PMC4495348. PMID23516797.
- ^Goodridge, Donna; Lawson, Josh; Marciniuk, Darcy; Rennie, Donna (2011-09-20). 'A population-based profile of adult Canadians living with participation and activity limitations'. Canadian Medical Association Journal. 183 (13): E1017–E1024. doi:10.1503/cmaj.110153. ISSN0820-3946. PMC3176864. PMID21825051.
- ^McLean SM, May S, Klaber-Moffett J, Sharp DM, Gardiner E (July 2010). 'Risk factors for the onset of non-specific neck pain: a systematic review'. Journal of Epidemiology and Community Health. 64 (7): 565–72. doi:10.1136/jech.2009.090720. PMID20466711.
- ^Haukkal, Eija; Leino-Arjasl, Päivi; Ojajärvil, Anneli; Takalal, Esa-Pekka; Viikari-Juntural, Eira; Riihimäkil, Hilkka (2011). 'Mental stress and psychosocial factors at work in relation to multiple-site musculoskeletal pain: A longitudinal study of kitchen workers'. European Journal of Pain. 15 (4): 432–8. doi:10.1016/j.ejpain.2010.09.005. PMID20932789.
- ^Hauke, Angelika; Flintrop, Julia; Brun, Emmanuelle; Rugulies, Reiner (July 1, 2011). 'The impact of work-related psychosocial stressors on the onset of musculoskeletal disorders in specific body regions: A review and meta-analysis of 54 longitudinal studies'. Work & Stress. 25 (3): 243–256. doi:10.1080/02678373.2011.614069. ISSN0267-8373.
- ^ abcdef'Occupational Injuries/Illnesses and Fatal Injuries Profiles'. Bureau of Labor Statistics. United States Department of Labor. 2014. Retrieved 25 March 2016.
- ^American Nurses Association. (2001). Nursingworld organizational health & safety survey. Silver Spring, MD.
External links[edit]
| Classification |
|
|---|
- Musculoskeletal disorders Single Entry Point European Agency for Safety and Health at Work (OSHA)
- Good Practices to prevent Musculoskeletal disorders European Agency for Safety and Health at Work (OSHA)
- Musculoskeletal disorders homepageHealth and Safety Executive (HSE)
- Hazards and risks associated with manual handling of loads in the workplace European Agency for Safety and Health at Work (OSHA)
- National Institute for Occupational Safety and Health Musculoskeletal Health Program [1]
Abstract
Objective. To retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD).
Methods. Patients with severe ILD and >12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8).
Results. Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and >12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (all with disease duration <12 months and/or acute onset/exacerbation of ILD) had >30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post-Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%).
Conclusion. This study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention.
Rituximab is a treatment option in anti-synthetase syndrome-related interstital lung disease.
Rituximab was most effective in recent onset anti-synthetase syndrome with acute-onset interstitial lung disease.
Introduction
The anti-synthetase syndrome (ASS), first described by Marguerie and coworkers in 1990 [1], is characterized by the presence of anti-aminoacyl tRNA synthetase (aaRS) autoantibodies, PM/DM, interstitial lung disease (ILD), RP, arthritis, and mechanic’s hands. At present eight different anti-aaRS antibodies have been identified, the most common being anti-Jo1, directed against histidyl-tRNA synthetase and found in ∼20–30% of all myositis patients [2]. The clinical phenotype of the syndrome seems to depend on which one of the anti-aaRSs is present; the frequency of myositis varies somewhat between the different anti-aaRSs, whereas ILD appears to be present in the vast majority of patients with ASS, the highest proportion being seen in patients with non-anti-Jo1 aaRS antibodies [3–5]. Importantly, ILD in ASS is associated with morbidity and mortality [6, 7]. Hence, effective treatment for ILD is one of the major clinical challenges in ASS.
In case reports, many different immunomodulatory drugs, including AZA, CYC, cyclosporin, MMF and tacrolimus, have been evaluated in ASS patients, all with observed effects on the ILD component [8–12].
During the last decade, rituximab (Rtx), an anti-CD 20+ mAb, has been used in the treatment of a variety of rheumatic inflammatory conditions. Several small retrospective studies have shown at least partial benefit of Rtx in refractory PM/DM, ASS included [13–15]. However, the controlled randomized study of 195 Rtx-treated patients with refractory myositis did not show any statistical difference between the two treatment arms for primary and secondary endpoints [16]. But, interestingly, when further analysing data from this study, the authors found that patients with anti-aaRS antibody had predictably shorter time to improvement compared with patients without myositis-specific antibodies. In the same study, there was also a trend towards an association of improvement in patients with reduced lung function [17].
So far there have been few reports published on ASS-associated ILD treated with Rtx. Marie et al. [18] showed an increase in forced vital capacity (FVC)/diffusing capacity of the lungs for carbon monoxide (DLCO) and a decrease/stabilization in the extent of ILD for seven Rtx-treated ASS patients with refractory ILD, with a follow-up of at least 12 months. A significant increase in FVC at 12 weeks post-Rtx for two anti-Jo1-positive patients with DM was seen in the pilot study of Levine [19]. Nalotto et al. [20] described a significant increase in DLCO 6 months post Rtx in a patient with ASS and progressive ILD.
In a recent consensus report on outcome measures in CTD-associated ILD, FVC and the total extent of ILD on HRCT were defined as appropriate core domains for clinical trials [21]. Data on ILD extent in ASS are limited, but there are a number of case reports using other CT evaluation methods [22].
From our tertiary referral hospital, we reported a short-term beneficial effect of Rtx in 11 patients with ASS-associated ILD [23]. In the current study, we present long-term follow-up data on pulmonary function tests (PFTs) and the extent of ILD (as indicated by HRCT) in those patients, and in an additional 19 patients with ASS-associated ILD. In all these patients, the main indication for Rtx treatment was severe ILD, but two-thirds of the patients also had signs of myositis. Hence, data on muscle function pre- and post-Rtx treatment will also be presented.
Patients and methods
Study population
Patients from Oslo University Hospital (OUH) diagnosed between 1994 and 2013 with a positive serological test to aaRS antibodies, the presence of ILD defined by the American Thoracic Society (ATS) criteria [24], and/or probable or definite myositis according to Bohan and Peter criteria [25] were defined as ASS (n = 112). Of these patients, 34 were treated with Rtx, 30/34 with severe ILD as the treatment indication and 24/30 with a follow-up of >12 months. Severe ILD was defined by FVC <70% of predicted, and/or DLCO <60% of predicted, and/or patients who needed mechanical respiratory support. The patients were classified with acute or gradual onset of ILD, according to the definition by Tillie-Leblond et al. [26]. The study was approved by the regional committee of health and medical research ethics in South-East Norway.
Serum antibody assays
Serum anti-Jo-1 and anti-SSA were detected by automated ELISA (EliA, Phadia; Freiburg, Germany). Anti-Jo-1, anti-threonyl-(PL-7), anti-alanyl-(PL-12), anti-glycyl-(EJ) and anti-isoleucyl-(OJ) tRNA synthetase antibodies were detected by a commercial immunoblot assay (Euroline Myositis kit, Euroimmune Laboratory, Luebeck, Germany).
PFTs
PFT analyses included FVC, FEV1 and DLCO (uncorrected for alveolar volume), all three being expressed as a percentage of expected reference values [27]. According to an international consensus statement of the ATS on idiopathic pulmonary fibrosis, improvement in FVC of ≥10% and/or DLCO of ≥15% was defined as clinically significant [24].
HRCT images
Low-dose thin-section CT images were obtained in the supine position during breath-holding and deep inspiration taken a median 0 months (range 0–3) before Rtx and a median 5 months (range 3–12) after Rtx treatment. The images were reconstructed both from 1 to 1.25-mm thick sections at 10-mm intervals and from 2.5-mm contiguous images, then reviewed in random order by two chest radiologists (A.G. and T.M.A.). The observers, blinded to the patient’s clinical condition, evaluated the presence/extent of ILD. These findings included ground-glass opacity, interlobular septal thickening, airspace consolidation, and reticular pattern [28].
The percentage of lung parenchyma with an ILD component was evaluated independently for each thin-section image. Volumes were precisely measured by drawing freehand regions of interest on the screen [29]. Thus, observers were able to score the overall extent of ILD, and relate this to the total volume of lung parenchyma.
Myositis evaluation
Myositis parameters included plasma creatinine kinase (CK) values and the manual muscle test for eight muscles (MMT8) [30]. CK values were recorded 0–2 months pre-Rtx and 3–6 months post-Rtx. CK above the upper reference value of the OUH laboratory (>150 U/l) was defined as abnormal. MMT8 measurements were performed by a physiotherapist. Since three patients (#1, #21 and #28) were not able to perform MMT8 adequately, the test was measured as a percentage of the total possible score. In all but two patients (#4, #10), the test was performed 0–2 months pre-RTX and 3–7 months post-Rtx.
Serious adverse events and mortality
Deaths were registered throughout the observation period and not only in connection with the Rtx infusions. Serious adverse events (SAEs) were defined as events requiring hospitalization, registered 0–20 weeks after being given the Rtx infusion.
Statistical analysis
PFT, affected lung parenchyma in HRCT images, CK and MMT8 values pre- and post-Rtx treatment were compared using the Wilcoxon signed-rank test, with the significance level set at P < 0.05.
Results
Treatment indications and clinical characteristics
From 2006 to 2013, 34 of the 112 ASS patients followed at OUH received at least one infusion of Rtx. The treatment indications for Rtx were severe, progressive and/or therapy-resistant lung disease (30 cases), severe arthritis (2 cases), myositis (1 case) and lymphoma (1 case). In the 33 cases with ASS-related indications, plenary discussions at the Department of Rheumatology were undertaken before Rtx was initiated.
Of the 30 patients who received Rtx due to ILD, 6 had <12 months follow-up; leaving 24 patients (7 males, 17 females) eligible for the long-term follow-up analyses (Table 1). Short-term follow-up data for 9 of the 24 patients were published in 2009 [23]. The 24 patients with >12 months follow-up had median disease duration of 84 months (23–440), 19 were anti-Jo-1-positive, three anti-PL-7 and two anti-PL-12-positive (Table 1). Anti-SSA was present in 18/24 patients (75%). Acute onset/exacerbation of ILD was evident in 50% of the patients, and two patients were diagnosed with pulmonary hypertension (#11, #13). One of these patients (#13) later received a bilateral lung transplant. Myositis and arthritis were diagnosed in 79% and 13% of the patients, respectively. One patient presented with necrotizing digital ulcers (#20).
Patient characteristics and treatments
| ID/age/ sex | Anti- aaRS | Acute onset/ exacerb. of ILD | Total disease duration, months | Time from first Rtx, months | Rtx Cycles, n | Medication before first Rtx | Medication after first Rtx | Other clinical symptoms | SAE | Vital status | Cause of death |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1/60/M | Jo-1 | Yes | 23 | 22 | 2 | None | CYC, GC > 10 mg | Myositis | Sepsis | D | Endocarditis |
| 2/47/Fa | Jo-1 | Yes | 440 | 80 | 4 | AZA, CSA, CYC | AZA | Myositis | Purpura | A | |
| 4/69/Ma | Jo-1 | Yes | 104 | 92 | 1 | CYC, AZA, GC > 10 mg | AZA, GC < 10 mg | Myositis | A | ||
| 5/44/Kb | Jo-1 | Yes | 75 | 73 | 2 | None | CYC, HQC, MMF, GC | Myositis | A | ||
| 6/28/K | PL-12 | No | 197 | 118 | 4 | GC > 10 mg, CSA, HCQ, AZA | GC < 10 mg | A | |||
| 7/37/M | Jo-1 | No | 120 | 74 | 1 | CYC, CSA, TAC, INF, IVIG, GC > 10 mg | AZA, MMF, GC > 10 mg, IVIG | Myositis | Abscess | D | Pneumocystis/ psychiatric condition |
| 8/66/K | Jo-1 | No | 101 | 82 | 1 | CYC, GC > 10 mg | AZA MMF, GC < 10 mg | Myositis | A | ||
| 10/69/K | Jo-1 | No | 98 | 80 | 1 | CYC, CSA, GC > 10 mg | AZA, MMF, GC < 10 mg | Myositis | A | ||
| 11/58/K | Jo-1 | No | 44 | 12 | 1 | CYC, CSA, TAC, AZA, GC > 10 mg | AZA, MMF, GC > 10 mg | Myositis, PH | D | Heart-failure | |
| 12/56/Ka,b | Jo-1 | Yes | 36 | 32 | 1 | None | CYC, AZA, GC > 10 mg | Myositis | A | ||
| 13/57/M | Jo-1 | No | 105 | 61 | 2 | CYC, AZA, GC > 10 mg | CYC, AZA, MMF, CSA, GC < 10 mg, | Myositis, PH, Tx | D | Infection/rejection | |
| 15/41/K | PL-12 | No | 108 | 34 | 4 | MTX, AZA, SSZ, GC > 10 mg | MMF, CYC, GC 10 mg | Arthritis | A | ||
| 16/46/Ma | PL-7 | Yes | 65 | 57 | 2 | CYC, GC > 10 mg | CYC, MMF, GC < 10 mg, IVIG | Myositis | A | ||
| 17/46/K | Jo-1 | No | 96 | 56 | 6 | AZA, GC > 10 mg | CYC, CSA, MMF, GC < 10 mg | Myositis, Arthritis | Neutropenia, Sepsis | A | |
| 18/34/Ma,b | Jo-1 | Yes | 51 | 46 | 2 | None | CYC, AZA, MMF, GC > 10 mg | Myositis | A | ||
| 19/56/K | Jo-1 | No | 44 | 35 | 6 | CYC, HCQ, GC > 10 mg | AZA, GC < 10 mg | Myositis | A | ||
| 20/69/Ka,b | PL-7 | Yes | 48 | 46 | 1 | None | CYC, AZA, GC | Vascular ulcers | A | ||
| 21/71/K | Jo-1 | No | 102 | 57 | 3 | AZA, GC > 10 mg | CYC, MMF, GC | Arthritis | A | ||
| 23/55/M | PL-7 | No | 93 | 24 | 3 | GC > 10 mg, AZA, CYC, MMF | GC 10 mg | A | |||
| 24/61/K | Jo-1 | Yes | 26 | 23 | 2 | GC > 10 mg | CYC, AZA, GC > 10 mg | Myositis | A | ||
| 28/78/Ka,b | Jo-1 | Yes | 49 | 47 | 1 | None | CYC, GC > 10 mg, AZA | Myositis | |||
| 31/55/K | Jo-1 | No | 101 | 75 | 11 | AZA, CYC, GC > 10 mg, MMF | AZA, MMF, GC > 10 mg | Myositis | Pneumocystis | A | |
| 32/60/K | Jo-1 | Yes | 41 | 37 | 3 | None | CYC, AZA, MMF, IVIG, GC < 10 mg, TAC, | Myositis | A | ||
| 33/57/K | Jo-1 | Yes | 38 | 30 | 2 | None | CYC, GC > 10 mg, AZA MMF, IVIG, PP | Myositis | Pneumocystis Sepsis | A | |
| Disease duration <12 months | |||||||||||
| 3/66/M | Jo-1 | No | 52 | 8 | 1 | GC > 10 mg | GC < 10 mg | PH | D | Infection/ heart-failure | |
| 9/60/K | Jo-1 | Yes | 27 | 3 | 1 | GC > 10 mg | CYC, GC > 10 mg | Myositis | Pneumocystis | D | Infection |
| 25/41/K | Jo-1 | No | 102 | 6 | 1 | GC > 10 mg | HCQ | A | |||
| 26/39/Ka | Jo-1 | Yes | 11 | 7 | 1 | None | CYC, GC > 10 mg, AZA, MMF | Myositis | A | ||
| 30/44/Ma | Jo-1 | Yes | 18 | 11 | 1 | CYC, GC > 10 mg | TAC, GC | A | |||
| 34/72/M | Jo-1 | No | 69 | 11 | 2 | GC > 10 mg, AZA, MMF | GCC > 110 mg | Myositis | D | Infection/ pulmonary cancer | |
| ID/age/ sex | Anti- aaRS | Acute onset/ exacerb. of ILD | Total disease duration, months | Time from first Rtx, months | Rtx Cycles, n | Medication before first Rtx | Medication after first Rtx | Other clinical symptoms | SAE | Vital status | Cause of death |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1/60/M | Jo-1 | Yes | 23 | 22 | 2 | None | CYC, GC > 10 mg | Myositis | Sepsis | D | Endocarditis |
| 2/47/Fa | Jo-1 | Yes | 440 | 80 | 4 | AZA, CSA, CYC | AZA | Myositis | Purpura | A | |
| 4/69/Ma | Jo-1 | Yes | 104 | 92 | 1 | CYC, AZA, GC > 10 mg | AZA, GC < 10 mg | Myositis | A | ||
| 5/44/Kb | Jo-1 | Yes | 75 | 73 | 2 | None | CYC, HQC, MMF, GC | Myositis | A | ||
| 6/28/K | PL-12 | No | 197 | 118 | 4 | GC > 10 mg, CSA, HCQ, AZA | GC < 10 mg | A | |||
| 7/37/M | Jo-1 | No | 120 | 74 | 1 | CYC, CSA, TAC, INF, IVIG, GC > 10 mg | AZA, MMF, GC > 10 mg, IVIG | Myositis | Abscess | D | Pneumocystis/ psychiatric condition |
| 8/66/K | Jo-1 | No | 101 | 82 | 1 | CYC, GC > 10 mg | AZA MMF, GC < 10 mg | Myositis | A | ||
| 10/69/K | Jo-1 | No | 98 | 80 | 1 | CYC, CSA, GC > 10 mg | AZA, MMF, GC < 10 mg | Myositis | A | ||
| 11/58/K | Jo-1 | No | 44 | 12 | 1 | CYC, CSA, TAC, AZA, GC > 10 mg | AZA, MMF, GC > 10 mg | Myositis, PH | D | Heart-failure | |
| 12/56/Ka,b | Jo-1 | Yes | 36 | 32 | 1 | None | CYC, AZA, GC > 10 mg | Myositis | A | ||
| 13/57/M | Jo-1 | No | 105 | 61 | 2 | CYC, AZA, GC > 10 mg | CYC, AZA, MMF, CSA, GC < 10 mg, | Myositis, PH, Tx | D | Infection/rejection | |
| 15/41/K | PL-12 | No | 108 | 34 | 4 | MTX, AZA, SSZ, GC > 10 mg | MMF, CYC, GC 10 mg | Arthritis | A | ||
| 16/46/Ma | PL-7 | Yes | 65 | 57 | 2 | CYC, GC > 10 mg | CYC, MMF, GC < 10 mg, IVIG | Myositis | A | ||
| 17/46/K | Jo-1 | No | 96 | 56 | 6 | AZA, GC > 10 mg | CYC, CSA, MMF, GC < 10 mg | Myositis, Arthritis | Neutropenia, Sepsis | A | |
| 18/34/Ma,b | Jo-1 | Yes | 51 | 46 | 2 | None | CYC, AZA, MMF, GC > 10 mg | Myositis | A | ||
| 19/56/K | Jo-1 | No | 44 | 35 | 6 | CYC, HCQ, GC > 10 mg | AZA, GC < 10 mg | Myositis | A | ||
| 20/69/Ka,b | PL-7 | Yes | 48 | 46 | 1 | None | CYC, AZA, GC | Vascular ulcers | A | ||
| 21/71/K | Jo-1 | No | 102 | 57 | 3 | AZA, GC > 10 mg | CYC, MMF, GC | Arthritis | A | ||
| 23/55/M | PL-7 | No | 93 | 24 | 3 | GC > 10 mg, AZA, CYC, MMF | GC 10 mg | A | |||
| 24/61/K | Jo-1 | Yes | 26 | 23 | 2 | GC > 10 mg | CYC, AZA, GC > 10 mg | Myositis | A | ||
| 28/78/Ka,b | Jo-1 | Yes | 49 | 47 | 1 | None | CYC, GC > 10 mg, AZA | Myositis | |||
| 31/55/K | Jo-1 | No | 101 | 75 | 11 | AZA, CYC, GC > 10 mg, MMF | AZA, MMF, GC > 10 mg | Myositis | Pneumocystis | A | |
| 32/60/K | Jo-1 | Yes | 41 | 37 | 3 | None | CYC, AZA, MMF, IVIG, GC < 10 mg, TAC, | Myositis | A | ||
| 33/57/K | Jo-1 | Yes | 38 | 30 | 2 | None | CYC, GC > 10 mg, AZA MMF, IVIG, PP | Myositis | Pneumocystis Sepsis | A | |
| Disease duration <12 months | |||||||||||
| 3/66/M | Jo-1 | No | 52 | 8 | 1 | GC > 10 mg | GC < 10 mg | PH | D | Infection/ heart-failure | |
| 9/60/K | Jo-1 | Yes | 27 | 3 | 1 | GC > 10 mg | CYC, GC > 10 mg | Myositis | Pneumocystis | D | Infection |
| 25/41/K | Jo-1 | No | 102 | 6 | 1 | GC > 10 mg | HCQ | A | |||
| 26/39/Ka | Jo-1 | Yes | 11 | 7 | 1 | None | CYC, GC > 10 mg, AZA, MMF | Myositis | A | ||
| 30/44/Ma | Jo-1 | Yes | 18 | 11 | 1 | CYC, GC > 10 mg | TAC, GC | A | |||
| 34/72/M | Jo-1 | No | 69 | 11 | 2 | GC > 10 mg, AZA, MMF | GCC > 110 mg | Myositis | D | Infection/ pulmonary cancer | |
aPatients with >30% increase in FVC, FEV1 and DLCO post-Rtx. bPatients with >60% decrease in extent of ILD in HRCT images post-Rtx. GC: glucocorticoids; INF: infliximab; PH: pulmonary hypertension; PP: plasmapheresis; TAC: tacrolimus; Tx: transplantation; A: alive; D: dead.
Patient characteristics and treatments
| ID/age/ sex | Anti- aaRS | Acute onset/ exacerb. of ILD | Total disease duration, months | Time from first Rtx, months | Rtx Cycles, n | Medication before first Rtx | Medication after first Rtx | Other clinical symptoms | SAE | Vital status | Cause of death |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1/60/M | Jo-1 | Yes | 23 | 22 | 2 | None | CYC, GC > 10 mg | Myositis | Sepsis | D | Endocarditis |
| 2/47/Fa | Jo-1 | Yes | 440 | 80 | 4 | AZA, CSA, CYC | AZA | Myositis | Purpura | A | |
| 4/69/Ma | Jo-1 | Yes | 104 | 92 | 1 | CYC, AZA, GC > 10 mg | AZA, GC < 10 mg | Myositis | A | ||
| 5/44/Kb | Jo-1 | Yes | 75 | 73 | 2 | None | CYC, HQC, MMF, GC | Myositis | A | ||
| 6/28/K | PL-12 | No | 197 | 118 | 4 | GC > 10 mg, CSA, HCQ, AZA | GC < 10 mg | A | |||
| 7/37/M | Jo-1 | No | 120 | 74 | 1 | CYC, CSA, TAC, INF, IVIG, GC > 10 mg | AZA, MMF, GC > 10 mg, IVIG | Myositis | Abscess | D | Pneumocystis/ psychiatric condition |
| 8/66/K | Jo-1 | No | 101 | 82 | 1 | CYC, GC > 10 mg | AZA MMF, GC < 10 mg | Myositis | A | ||
| 10/69/K | Jo-1 | No | 98 | 80 | 1 | CYC, CSA, GC > 10 mg | AZA, MMF, GC < 10 mg | Myositis | A | ||
| 11/58/K | Jo-1 | No | 44 | 12 | 1 | CYC, CSA, TAC, AZA, GC > 10 mg | AZA, MMF, GC > 10 mg | Myositis, PH | D | Heart-failure | |
| 12/56/Ka,b | Jo-1 | Yes | 36 | 32 | 1 | None | CYC, AZA, GC > 10 mg | Myositis | A | ||
| 13/57/M | Jo-1 | No | 105 | 61 | 2 | CYC, AZA, GC > 10 mg | CYC, AZA, MMF, CSA, GC < 10 mg, | Myositis, PH, Tx | D | Infection/rejection | |
| 15/41/K | PL-12 | No | 108 | 34 | 4 | MTX, AZA, SSZ, GC > 10 mg | MMF, CYC, GC 10 mg | Arthritis | A | ||
| 16/46/Ma | PL-7 | Yes | 65 | 57 | 2 | CYC, GC > 10 mg | CYC, MMF, GC < 10 mg, IVIG | Myositis | A | ||
| 17/46/K | Jo-1 | No | 96 | 56 | 6 | AZA, GC > 10 mg | CYC, CSA, MMF, GC < 10 mg | Myositis, Arthritis | Neutropenia, Sepsis | A | |
| 18/34/Ma,b | Jo-1 | Yes | 51 | 46 | 2 | None | CYC, AZA, MMF, GC > 10 mg | Myositis | A | ||
| 19/56/K | Jo-1 | No | 44 | 35 | 6 | CYC, HCQ, GC > 10 mg | AZA, GC < 10 mg | Myositis | A | ||
| 20/69/Ka,b | PL-7 | Yes | 48 | 46 | 1 | None | CYC, AZA, GC | Vascular ulcers | A | ||
| 21/71/K | Jo-1 | No | 102 | 57 | 3 | AZA, GC > 10 mg | CYC, MMF, GC | Arthritis | A | ||
| 23/55/M | PL-7 | No | 93 | 24 | 3 | GC > 10 mg, AZA, CYC, MMF | GC 10 mg | A | |||
| 24/61/K | Jo-1 | Yes | 26 | 23 | 2 | GC > 10 mg | CYC, AZA, GC > 10 mg | Myositis | A | ||
| 28/78/Ka,b | Jo-1 | Yes | 49 | 47 | 1 | None | CYC, GC > 10 mg, AZA | Myositis | |||
| 31/55/K | Jo-1 | No | 101 | 75 | 11 | AZA, CYC, GC > 10 mg, MMF | AZA, MMF, GC > 10 mg | Myositis | Pneumocystis | A | |
| 32/60/K | Jo-1 | Yes | 41 | 37 | 3 | None | CYC, AZA, MMF, IVIG, GC < 10 mg, TAC, | Myositis | A | ||
| 33/57/K | Jo-1 | Yes | 38 | 30 | 2 | None | CYC, GC > 10 mg, AZA MMF, IVIG, PP | Myositis | Pneumocystis Sepsis | A | |
| Disease duration <12 months | |||||||||||
| 3/66/M | Jo-1 | No | 52 | 8 | 1 | GC > 10 mg | GC < 10 mg | PH | D | Infection/ heart-failure | |
| 9/60/K | Jo-1 | Yes | 27 | 3 | 1 | GC > 10 mg | CYC, GC > 10 mg | Myositis | Pneumocystis | D | Infection |
| 25/41/K | Jo-1 | No | 102 | 6 | 1 | GC > 10 mg | HCQ | A | |||
| 26/39/Ka | Jo-1 | Yes | 11 | 7 | 1 | None | CYC, GC > 10 mg, AZA, MMF | Myositis | A | ||
| 30/44/Ma | Jo-1 | Yes | 18 | 11 | 1 | CYC, GC > 10 mg | TAC, GC | A | |||
| 34/72/M | Jo-1 | No | 69 | 11 | 2 | GC > 10 mg, AZA, MMF | GCC > 110 mg | Myositis | D | Infection/ pulmonary cancer | |
| ID/age/ sex | Anti- aaRS | Acute onset/ exacerb. of ILD | Total disease duration, months | Time from first Rtx, months | Rtx Cycles, n | Medication before first Rtx | Medication after first Rtx | Other clinical symptoms | SAE | Vital status | Cause of death |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1/60/M | Jo-1 | Yes | 23 | 22 | 2 | None | CYC, GC > 10 mg | Myositis | Sepsis | D | Endocarditis |
| 2/47/Fa | Jo-1 | Yes | 440 | 80 | 4 | AZA, CSA, CYC | AZA | Myositis | Purpura | A | |
| 4/69/Ma | Jo-1 | Yes | 104 | 92 | 1 | CYC, AZA, GC > 10 mg | AZA, GC < 10 mg | Myositis | A | ||
| 5/44/Kb | Jo-1 | Yes | 75 | 73 | 2 | None | CYC, HQC, MMF, GC | Myositis | A | ||
| 6/28/K | PL-12 | No | 197 | 118 | 4 | GC > 10 mg, CSA, HCQ, AZA | GC < 10 mg | A | |||
| 7/37/M | Jo-1 | No | 120 | 74 | 1 | CYC, CSA, TAC, INF, IVIG, GC > 10 mg | AZA, MMF, GC > 10 mg, IVIG | Myositis | Abscess | D | Pneumocystis/ psychiatric condition |
| 8/66/K | Jo-1 | No | 101 | 82 | 1 | CYC, GC > 10 mg | AZA MMF, GC < 10 mg | Myositis | A | ||
| 10/69/K | Jo-1 | No | 98 | 80 | 1 | CYC, CSA, GC > 10 mg | AZA, MMF, GC < 10 mg | Myositis | A | ||
| 11/58/K | Jo-1 | No | 44 | 12 | 1 | CYC, CSA, TAC, AZA, GC > 10 mg | AZA, MMF, GC > 10 mg | Myositis, PH | D | Heart-failure | |
| 12/56/Ka,b | Jo-1 | Yes | 36 | 32 | 1 | None | CYC, AZA, GC > 10 mg | Myositis | A | ||
| 13/57/M | Jo-1 | No | 105 | 61 | 2 | CYC, AZA, GC > 10 mg | CYC, AZA, MMF, CSA, GC < 10 mg, | Myositis, PH, Tx | D | Infection/rejection | |
| 15/41/K | PL-12 | No | 108 | 34 | 4 | MTX, AZA, SSZ, GC > 10 mg | MMF, CYC, GC 10 mg | Arthritis | A | ||
| 16/46/Ma | PL-7 | Yes | 65 | 57 | 2 | CYC, GC > 10 mg | CYC, MMF, GC < 10 mg, IVIG | Myositis | A | ||
| 17/46/K | Jo-1 | No | 96 | 56 | 6 | AZA, GC > 10 mg | CYC, CSA, MMF, GC < 10 mg | Myositis, Arthritis | Neutropenia, Sepsis | A | |
| 18/34/Ma,b | Jo-1 | Yes | 51 | 46 | 2 | None | CYC, AZA, MMF, GC > 10 mg | Myositis | A | ||
| 19/56/K | Jo-1 | No | 44 | 35 | 6 | CYC, HCQ, GC > 10 mg | AZA, GC < 10 mg | Myositis | A | ||
| 20/69/Ka,b | PL-7 | Yes | 48 | 46 | 1 | None | CYC, AZA, GC | Vascular ulcers | A | ||
| 21/71/K | Jo-1 | No | 102 | 57 | 3 | AZA, GC > 10 mg | CYC, MMF, GC | Arthritis | A | ||
| 23/55/M | PL-7 | No | 93 | 24 | 3 | GC > 10 mg, AZA, CYC, MMF | GC 10 mg | A | |||
| 24/61/K | Jo-1 | Yes | 26 | 23 | 2 | GC > 10 mg | CYC, AZA, GC > 10 mg | Myositis | A | ||
| 28/78/Ka,b | Jo-1 | Yes | 49 | 47 | 1 | None | CYC, GC > 10 mg, AZA | Myositis | |||
| 31/55/K | Jo-1 | No | 101 | 75 | 11 | AZA, CYC, GC > 10 mg, MMF | AZA, MMF, GC > 10 mg | Myositis | Pneumocystis | A | |
| 32/60/K | Jo-1 | Yes | 41 | 37 | 3 | None | CYC, AZA, MMF, IVIG, GC < 10 mg, TAC, | Myositis | A | ||
| 33/57/K | Jo-1 | Yes | 38 | 30 | 2 | None | CYC, GC > 10 mg, AZA MMF, IVIG, PP | Myositis | Pneumocystis Sepsis | A | |
| Disease duration <12 months | |||||||||||
| 3/66/M | Jo-1 | No | 52 | 8 | 1 | GC > 10 mg | GC < 10 mg | PH | D | Infection/ heart-failure | |
| 9/60/K | Jo-1 | Yes | 27 | 3 | 1 | GC > 10 mg | CYC, GC > 10 mg | Myositis | Pneumocystis | D | Infection |
| 25/41/K | Jo-1 | No | 102 | 6 | 1 | GC > 10 mg | HCQ | A | |||
| 26/39/Ka | Jo-1 | Yes | 11 | 7 | 1 | None | CYC, GC > 10 mg, AZA, MMF | Myositis | A | ||
| 30/44/Ma | Jo-1 | Yes | 18 | 11 | 1 | CYC, GC > 10 mg | TAC, GC | A | |||
| 34/72/M | Jo-1 | No | 69 | 11 | 2 | GC > 10 mg, AZA, MMF | GCC > 110 mg | Myositis | D | Infection/ pulmonary cancer | |
aPatients with >30% increase in FVC, FEV1 and DLCO post-Rtx. bPatients with >60% decrease in extent of ILD in HRCT images post-Rtx. GC: glucocorticoids; INF: infliximab; PH: pulmonary hypertension; PP: plasmapheresis; TAC: tacrolimus; Tx: transplantation; A: alive; D: dead.
Rtx treatment
Time from disease onset to first Rtx infusion varied between 1 and 330 months (median 15 months). Median follow-up from the first Rtx infusion was 52 months (range 12–118) (Table 1). The first cycle of Rtx treatment was given as one infusion of 1000 mg on each of days 0 and 14, except for three patients (#1, #7 and #11). Patients #7 and #11 were treated according to standard lymphoma protocol (4 × 375 mg/m2), while patient #1 was treated with a reduced dose because of perceived infection risk. The mean number of Rtx cycles was 2.7 (range 1–11), but 8/24 patients were treated with only one cycle during the observation period (Table 1). Four patients (#15, #17, #23 and #31) were only treated with one infusion of 1000 mg of Rtx on the last cycle. None of the patients were treated with Rtx as monotherapy, but 6/24 patients did not receive any other immunosuppressive therapy prior to Rtx (Table 1).
PFTs
PFTs obtained prior to the first infusion of Rtx were available in 21/24 patients (Fig. 1). The median percentage of predicted FVC increased from 58% (range 15–60) at the first Rtx treatment to 72% (range 38–105) at the last follow-up visit—an increase of 24% (P < 0.018). The median percentage of predicted FEV1 increased by 22%, from 58% (range 35–107) to 71% (range 31–115) at follow-up (P < 0.037). The increase in the median percentage of predicted DLCO was 17%, from 41% (range 15–60) to 48% (range 15–84) at follow-up (P < 0.025) (Fig. 2). Hence, improvements in both FVC and DLCO achieved clinical significance as defined by the ATS. Seven of the 24 patients (#2, #4, #8, #12, #18, #20 and #28) responded with >30% increase in all three parameters (patients marked by superscript ‘a’ in Table 1). In this group, all but one patient were treated with Rtx within a year after the onset of symptoms, and 4 of 6 were naive to immune-modulating therapies prior to the first Rtx cycle (Table 1).
Pulmonary function tests
Median changes in pulmonary function measured as forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and unadjusted diffusing capacity of the lungs for carbon monoxide (DLCO), pre- and post-Rtx treatment for 24 ASS patients with a median follow-up time of 52 months. Details of pulmonary function tests on individual patients are available in Fig. 2.
Pulmonary function tests
Median changes in pulmonary function measured as forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and unadjusted diffusing capacity of the lungs for carbon monoxide (DLCO), pre- and post-Rtx treatment for 24 ASS patients with a median follow-up time of 52 months. Details of pulmonary function tests on individual patients are available in Fig. 2.
Longitudinal changes in pulmonary function and diffusion capacity in 24 anti-synthetase syndrome patients treated with rituximab
The panels show the development of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and unadjusted diffusing capacity of the lungs for carbon monoxide (DLCO) in a period ranging from 10 months prior to the first rituximab infusion to 60 months after this infusion. The stapled vertical lines indicate the timing of repeated rituximab treatments. Details on individual patients are provided in Table 1.
Longitudinal changes in pulmonary function and diffusion capacity in 24 anti-synthetase syndrome patients treated with rituximab
The panels show the development of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and unadjusted diffusing capacity of the lungs for carbon monoxide (DLCO) in a period ranging from 10 months prior to the first rituximab infusion to 60 months after this infusion. The stapled vertical lines indicate the timing of repeated rituximab treatments. Details on individual patients are provided in Table 1.
HRCT images
HRCT images taken pre- and post-Rtx treatment were available for 23/24 patients (except for #33). The median volume of total lung parenchyma with ILD changes was 50% (range 25–100) pre-Rtx. After Rtx treatment, the extent of ILD was decreased to a median 33% (0–93), (P < 0.001) (Fig. 3). In five patients, the ILD-component decreased >60% (#5, #12, #18, #20, #28: patients marked by a superscript ‘b’ in Table 1). One patient (#13) had an increase in the extent of ILD, from 55% pre-Rtx to 88% post-Rtx (Fig. 3). This patient later received a lung transplant.
Extent of interstitial lung disease
(A) Percentage changes in affected volume of lung parenchyma measured in high-resolution CT (HRCT) images as a percentage of total volume of lung parenchyma pre- and post-rituximab (Rtx) treatment for 23 ASS patients. The images were taken 0–3 months pre-Rtx and 3–12 months post-Rtx. (B) HRCT scan pre-Rtx (upper picture) and (C) post-Rtx (lower picture) for patient #18. A reticular pattern with innumerable interlacing streaks and distortion of the lung architecture is present in both lungs. The patient had 77% overall extent of interstitial lung disease pre-Rtx. Five months post-Rtx, only subtle interstitial thickening is visible posteriorly.
Extent of interstitial lung disease
(A) Percentage changes in affected volume of lung parenchyma measured in high-resolution CT (HRCT) images as a percentage of total volume of lung parenchyma pre- and post-rituximab (Rtx) treatment for 23 ASS patients. The images were taken 0–3 months pre-Rtx and 3–12 months post-Rtx. (B) HRCT scan pre-Rtx (upper picture) and (C) post-Rtx (lower picture) for patient #18. A reticular pattern with innumerable interlacing streaks and distortion of the lung architecture is present in both lungs. The patient had 77% overall extent of interstitial lung disease pre-Rtx. Five months post-Rtx, only subtle interstitial thickening is visible posteriorly.
Myositis evaluation
CK values above the upper reference level (150 U/ml) were noted in 16/24 patients 0–2 months prior to the first Rtx infusion, and 4/24 patients 3–6 months post-Rtx (Fig. 4). The median CK value pre-Rtx was 990 U/l (range 157–7140) and the corresponding post-Rtx value was 88 U/l (range 31–1956), (P < 0.002). MMT8 data were retrievable for 15/24 patients. MMT8 increased from a median 93% of the maximum score pre-Rtx to a median 98% post-Rtx (P < 0.05) (Fig. 4). Further analyses showed that 4of 15 patients with available MMT8 data had normal CK levels pre-Rtx but reduced muscle strength (#10, #15, #19 and #20). Conversely, there were also four patients who had CK >150 U/ml, but scored maximum on MMT8 (#4, #5, #8 and #18) (Fig. 4).
Muscle outcome
(A) Median changes in muscle activity measured as creatinine kinase levels in 16 ASS patients taken 0–2 months pre-rituximab (Rtx) and 3–6 months post-Rtx treatment. (B) Median changes in muscle strength measured by manual muscle test for eight muscles (MMT8) in 15 ASS patients pre- and post-Rtx treatment. The MMT8 results were obtained 0–3 months pre-Rtx and 3–30 months post-Rtx.
Muscle outcome
(A) Median changes in muscle activity measured as creatinine kinase levels in 16 ASS patients taken 0–2 months pre-rituximab (Rtx) and 3–6 months post-Rtx treatment. (B) Median changes in muscle strength measured by manual muscle test for eight muscles (MMT8) in 15 ASS patients pre- and post-Rtx treatment. The MMT8 results were obtained 0–3 months pre-Rtx and 3–30 months post-Rtx.
Anti-Jo-1 levels
Of the 19 patients, 17 had serum anti-Jo-1 detected by ELISA, and 2 patients had anti-Jo-1 detected by immunoblot assay (#21, #33). In 9 of 17 patients, titres of anti-Jo-1 taken 0–3 months prior to Rtx and 2–6 months after treatment were available. In all these nine patients, anti-Jo-1 levels decreased following treatment, with a median decrease for the whole group of 33% (P < 0.008) (Fig. 5).
Serum anti-Jo-1 titres obtained before rituximab treatment, and 2–6 months after the treatment in nine ASS patients
Titres of serum anti-Jo-1 antibodies before and after rituximab (Rtx) treatment. The graph shows anti-Jo-1 levels obtained 0–3 months before Rtx and 2–6 months after Rtx in nine anti-synthetase syndrome patients.
Serum anti-Jo-1 titres obtained before rituximab treatment, and 2–6 months after the treatment in nine ASS patients
Titres of serum anti-Jo-1 antibodies before and after rituximab (Rtx) treatment. The graph shows anti-Jo-1 levels obtained 0–3 months before Rtx and 2–6 months after Rtx in nine anti-synthetase syndrome patients.
Immunomodulatory therapies
In total, 18 of 24 patients had failed other immunosuppressive treatment prior to the first Rtx infusion (Table 1). In 7 of 24 patients, Prednisolone was tapered from >10 mg daily to <10 mg daily following Rtx (Table 1). All but two patients (#6 and #23) either continued or started immunomodulatory therapy after the first Rtx cycle. In patients starting new immunomodulatory drugs, treatment was initiated 0–3 months post-Rtx treatment. Of the 12 patients receiving Rtx due to acute onset/exacerbation of ILD, 10 received combined induction therapy with Rtx and i.v. CYC.
Mortality and SAEs
Altogether, there were 7 deaths among the 34 Rtx-treated ASS patients, six 6 of which were probably caused by infection, all but one occurring >6 months after the last Rtx infusion (#9; Pneumocystis jirovecii pneumonia, registered 2 months post-Rtx). All deaths and SAEs were noted in the 30 patients with severe lung disease. During the observation period, seven non-fatal SAEs were identified, six of them infections. The non-infectious SAE was a purpural rash developing in direct connection with the Rtx infusion. Three of the six infectous SAEs were caused by P. jirovecii (Table 1). All of the six infection-related SAEs occurred 1–20 weeks after the last infusion of Rtx.
Discussion
Severe lung disease is a major determinant of morbidity and mortality in ASS. Here, we performed retrospective analyses of 24 Rtx-treated ASS patients with ILD and a median follow-up time of 52 months. Significant improvements, both in PFT and ILD extent in HRCT images were noted, indicating that Rtx could have effects on the ILD component in this patient group.
Interestingly, the most pronounced effects on lung function were noted in patients with disease duration <12 months at the first Rtx cycle and/or acute onset/exacerbation of ILD. In this group, seven patients increased >30% in FVC, FEV1 and DLCO during the observation period. One additional patient (#5) also had a >30% increase in FVC and FEV1 post-Rtx, but corresponding DLCO data were not retrievable. Furthermore, among the six patients with follow-up of <12 months (Table 1, lower panel), two patients (#26 and #30) with <1 year disease duration increased >30% in FVC, FEV1 and DLCO following Rtx (data not shown). Taken together, these results suggest that Rtx treatment may be most beneficial in ASS patients with disease duration <12 months and/or acute onset/exacerbation of ILD.
The HRCT analyses showed that the extent of ILD decreased post-Rtx in the majority of the ASS patients. This is consistent with other earlier case series/reports [18, 23, 31, 32]. In the current study, the total extent of ILD was scored without pattern differentiation. Hence, no suggestion of specfic ILD patterns in ASS was made.
The primary indication for Rtx treatment in the 24 patients reported was severe ILD, but two-thirds of the patients also had signs of myositis, with elevated CK levels and/or reduced MMT8 scores. Although our muscle evaluation data have limitations (e.g. large variation in CK level, different interpreters of the MMT8 test) and there was only a moderate increase in MMT8 post-Rtx, the results support previous notions of Rtx effects on the muscle component of ASS [14, 16].
Since Rtx treatment is associated with infections, and ILD in itself carries increased infection risk, it was not surprising that most SAEs were related to infections. Notably, Rtx was probably not the only factor contributing to the increased risk of infections; as many as 75% of the patients were on other immunomodulatory drugs prior to the first Rtx cycle, and all but two patients received other maintenance therapy after the Rtx treatment. All six patients with infection-related SAEs were treated with i.v. CYC either prior to or directly after the first Rtx cycle. Thus, infection prevention with antibiotic therapy for ASS-associated ILD patients treated with Rtx and/or CYC can be considered.
In total, 21% (7/34) of the patients died during the observation period, most of the deaths being related to infections. In comparison, the mortality rate for the total OUH ASS cohort with a median disease duration of 98 months (range 2–378) was 32% (25 of 78). Hence, the mortality rate did not appear to be higher in the Rtx-treated group than in non-Rtx-treated ASS patients from the same geographical area. Taken together, our data seem to be consistent with other studies reporting increased overall mortality for ASS, with ILD as the major determinant of mortality [33, 34].
All patients with available anti-Jo-1 titres (n = 9) before and after treatment displayed significant titre reductions following treatment, indicating that Rtx has an effect on anti-Jo-1 homeostasis. Enumeration of CD19+ cells was not done routinely; hence we do not know if anti-Jo-1 titre fluctuations correlated with repopulation of CD19+ cells.
Our report has limitations. First, data collection was retrospective, and treatments were not given according to standardized protocols. Secondly, none of the patients were treated with Rtx as monotherapy. Combined induction therapy with CYC was used in patients with acute onset/exacerbation of ILD, and different kinds of maintentance therapy were started 0–3 months after the first Rtx cycle. Thus, our data do not allow for speculations about the efficacy of Rtx as a single treatment for induction or maintenance therapy in ASS-associated ILD. Interestingly, data from Marie et al. [18] indicated that Rtx alone had an effect on ASS patients with refractory ILD. In their study, five out of seven patients (compared with 11 of 24 patients in this study) were refractory to CYC as monotherapy. In the study of Ingegnoli et al. [22] 4 of 8 CYC-treated patients with ASS-associated ILD deteriorated, as evaluated by HRCT-image analyses. This indicates that Rtx could be a treatment option in ASS patients with CYC-refractory ILD. However, from this study, no conclusions can be made on treatment regimen, Rtx either alone or in combination with CYC in ASS patients with severe ILD. A prospective study with two treatment arms (Rtx alone vs Rtx/CYC) could hopefully give some answers and is warranted.
This study is, to our knowledge, the first to report experience with Rtx in a large case series of ASS-related severe ILD with a median follow-up of >4 years. The results indicate that Rtx treatment could be of value in these patients, especially in those with short disease duration and/or acute onset/exacerbation of ILD, but SAEs, especially infections, remain an issue.
Acknowledgements
We thank Eli Taraldsrud at the Institute of Immunology, Oslo University Hospital, Oslo, Norway, for interpretation of the serology data.
Funding: This work was supported by grants from the Norwegian Women’s Public Health Association and the Norwegian Rheumatology Patient Foundation.
Disclosure statement: The authors have declared no conflicts of interest.
References
