Health status, work limitations, and return-to-work trajectories in injured workers with musculoskeletal disorders

Background The purpose of this study was to describe the health status and work limitations in injured workers with musculoskeletal disorders at 1 month post-injury, stratified by return-to-work status, and to document their return-to-work trajectories 6 months post-injury.
Introduction
Work-related musculoskeletal (MSK) disorders are common health problems and a major contributor to disability and costs in working populations. In Canada, MSK disorders are responsible for 10% of the short-term disability costs and 39% of the estimated long-term disability costs [1]. The natural course of low back pain and other MSK disorders is characterized by recurrent disabling symptoms and can be described as chronic-episodic [2–6]. Similarly, the trajectory of return-to-work (RTW) following a period of work absence due to MSK disorders is a complex and dynamic process, frequently involving recurrences of work absence [7, 8]. Already a decade ago, it was shown that a first return to work after an injury is frequently followed by one or more recurrences of work absence, making a focus on first return to work a limited and potentially misguiding index of RTW outcomes, and one that does not address the important issue of sustainability of return to work [9, 10].
Recently, Pransky et al. [7] pointed out that “despite an abundance of RTW research, the concept of RTW is often poorly defined, and there is not substantial agreement about what constitutes a successful RTW outcome.” Many studies have been focused on (first) return to work as the primary outcome measure, e.g., return to work is used as an indicator for a reduction in disability—usually with the assumption that workers who return to work are completely recovered from the disabling effects of the injury [10]. However, several studies have demonstrated that workers who return to work are not fully recovered from their initial complaints or injury [10–15]. The traditional outcome measures of return to work and time lost from work do not capture important information about the burden of injury that can be shown by self-reported measures of disability and functional limitations. Hence, to obtain a complete picture of the complex RTW process, capturing the recurrences of work absence, the persistence of disability, and their consequences for work performance, it is important to use multiple outcome measures during follow-up. Although a few studies have addressed health outcomes, such as pain, functional status, and general health, in relation to RTW status [11, 12, 14], little is known about depressive symptoms, which have been suggested to increase the total numbers of days on benefit [16] and about limitations at work in injured workers. Furthermore, it is largely unclear how injured workers “transit” in their RTW status over time. So far, we do know that a substantial proportion of workers with cumulative trauma disorders of the upper extremity [15] and compensated back pain (Côté et al., submitted) experience multiple episodes of work absence.
The purpose of this study was to describe the health status, assessed by multiple outcome measures, and work limitations, in injured workers with MSK disorders 1 month post-injury stratified by RTW status, and to document their RTW trajectories over a period of 6 months post-injury.
Materials and methods
Study design
The present study was conducted within the sampling frame of a prospective study of Ontario workers with a back or upper extremity (UE) MSK disorder, who filed a Workplace Safety and Insurance Board (WSIB) lost-time injury claim. Data was collected from two sources: self-reports of participants and WSIB administrative data. The participants were interviewed by phone at baseline (1 month post-injury), and 6 months post-injury. Participants provided information on their RTW experience, workplace, healthcare provider, insurer, and physical and mental health. From the WSIB, administrative information on sociodemographics, workplaces, and claims (e.g., site of injury, claim status, time receiving wage replacement benefits) was obtained. This information was linked to the interview data, when the participants provided written consent for linkage. Ethical approval for the study was granted by the University of Toronto’s Ethics Review Board. Participants were given the option to withdraw from the study at any point and to decline data linkage of their questionnaire responses with their WSIB data. It was made explicit to the respondents that study participation would in no way affect their claim with the insurer.
Participant recruitment and final study sample
Study eligibility required participants to have a new, accepted or pending, back or UE MSK lost-time claim, be absent from work for at least 5 days within the first 14 calendar days post-injury, and be 15 years of age or older. We excluded claimants with a fracture, amputation, burn, hernia, head injury, concussion, or electrocution, those who were not able to understand or speak English, and those with a security problem, who were incarcerated or received institutional care. From January to July 2005, a computer program run on WSIB weekly files resulted in the identification of 14,555 potential participants. Eligibility assessment and recruitment were conducted in three stages: at the WSIB tracking level, at the WSIB recruiting level, and the university-based research unit level (see Fig. 1).
Fig. 1Recruitment procedure and flow of participants
A total of 632 participants completed the baseline interview 1 month post-injury. The overall response rate was 61% (632 out of 1,038 eligible and contacted potential participants). Verbal consent for the interview data was obtained from all participants. The mean time between the date of injury and the date of interview was 29.6 days (SD 6.2; median 29 days, range 15–46 days). Approximately 98% of the participants were interviewed within 6 weeks post-injury. For the linkage with WSIB data, written consent was obtained from 479 participants, for which WSIB wage replacement data was available for 431 participants. A consent-to-linkage analysis showed that consenters (n = 479) and non-consenters were similar in terms of sociodemographic, workplace, health status, and work absence variables. However, consenters were more likely to have a higher level of education, and male consenters were more likely to be older than male non-consenters (Franche et al., submitted).
Definition of the RTW status
At baseline, four mutually exclusive RTW status groups were constructed, based on the workers’ responses to the following yes/no questions: “Have you gone back to work at any point since your injury (includes part-time or modified work)?” and “Are you currently working at any job right now?” The four groups were: (1) sustained first return to work (RTW-S), (2) return to work with recurrence(s) of work absence and working at time of interview (RTW-R working), (3) return to work with recurrence(s) of work absence and not working at time of interview (RTW-R not working), and (4) no return to work (No RTW). In the analyses, we collapsed the two return to work with recurrence(s) groups into one group (RTW-R). RTW status was assessed at each follow-up.
Measurements: health outcomes and work limitations
Pain intensity
We used two items from the Von Korff Pain Scale [17, 18] to measure pain intensity. On a 10-point numerical rating scale (0 = “no pain” to 10 = “pain as bad as could be”), participants were asked to indicate their level of perceived pain from their workplace injury (1) at the present time and (2) on average in the past month.
Functional status
Functional disability associated with back pain was measured using the Roland–Morris Disability Questionnaire [19], a 24-item questionnaire assessing the presence of activity limitations. Responses to individual items (yes/no) are summed up and range from 0 (no disability) to 24 (severe disability). The score is averaged and—for a better comparison with scores of other instruments—transformed to a standardized score of 0–100 (by multiplying each averaged score by 100), with a higher score indicating greater disability. The Roland–Morris has been shown to have good psychometric properties [20–25]. In the baseline sample, the internal consistency (Cronbachs α) was 0.92.
The 11-item QuickDASH was used to assess physical function and symptoms in participants with MSK disorders of the upper limb [26]. The QuickDASH is a shortened version of the DASH Outcome Measure [27]. The items are scored from 1 to 5. Responses to the individual items are summed, averaged, and transformed to a standardized score of 0–100, with a higher score indicating greater disability. Initial testing has shown that the QuickDASH has good psychometric properties [26]. The internal consistency in the present study was 0.90.
When participants reported pain in both the back and UE, they completed both the Roland–Morris and the QuickDASH. For these participants, scores from each instrument were converted into a z-score and the highest z-score was used as the index of functional status. For participants completing only one measure of functional status, the z-score of that measure was used as the index of functional status. In addition, for those completing both measures, determination of the main pain site, i.e., back or UE, was based on the highest z-score on the Roland–Morris or the QuickDASH.
General health
The Short Form-12 (SF-12), a 12-item version of the SF-36, was used to measure physical (Physical Component Summary Scale Score; PCS12) and mental (Mental Component Summary Scale Score; MCS12) health-related quality of life [28, 29]. To calculate the PCS12 and MCS12, test items are scored and transformed in an algorithm to norm-based scores with a mean of 50 and a standard deviation of 10 [29]. PCS12 and MCS12 scores range from 0 to 100, a higher score indicating better health. The psychometric properties of the SF-12 are good: coefficients for test–retest reliability, measured over 2 weeks, are 0.89 (PCS12) and 0.76 (MCS12) [28]. Moreover, Luo et al. [30] reported good internal consistency, validity, and responsiveness in patients with low back pain. In the present study, the internal consistency was 0.89 (PCS12) and 0.86 (MCS12) at baseline.
Depressive symptoms
The 20-item Center for Epidemiologic Studies Depression (CES-D) [31] scale was used to measure depressive symptoms. The items report the frequency of occurrence of symptoms in the past week on a 4-point rating scale ranging from “rarely or none of the time” (<1 day) to “most of the time” (5–7 days). The score ranges from 0 to 60 with a higher score denoting more depressive symptoms. CES-D scores ≥16 are indicative of individuals at risk for clinical depression [31]. The internal consistency was 0.92, measured in the baseline sample.
Work limitations
We used the 16-item version of the Work Limitations Questionnaire (WLQ-16) to assess limitations at work due to injury or associated treatment [32–35]. The WLQ-16 covers four domains: output demands (4 items), mental demands (6 items), physical demands (4 items), and time management demands (2 items). Items are scored on a 5-point scale, ranging from “none of the time” to “all of the time.” The scores on the individual items are summed, averaged, and transformed to a standardized score of 0–100, with a higher score indicative of more limitations. The internal consistency Cronbachs α’s were 0.82 (output demands), 0.86 (mental demands), 0.78 (physical demands), and 0.76 (time management demands) at baseline.
Sociodemographics, days off work, and comorbidity
Participants provided information on age, gender, education, living status, number of children under the age of 18, and personal income. Information on occupational status was obtained from the WSIB database. One self-reported question assessed how many full days of work a participant had missed due to the injury. In addition, data on time receiving wage replacement benefits was obtained from the WSIB database. The Saskatchewan Comorbidity Scale was used to measure comorbidity (Jaroszynski et al., unpublished work). The 16/14-item (women/men) self-report scale assesses the presence and severity of health problems. Participants are instructed to indicate whether they currently have a particular health problem/disease and, if so how much it has affected their health in the last 6 months. The response options range from 1 = “not at all” to 4 = “severe.” In the present study, two additional items pertaining to gynecological problems and pregnancy status were added for women. Responses were combined and categorized as: no comorbidity, comorbidity with no/mild effect on health, and comorbidity with moderate/severe effect on health.
Statistical analyses
Univariate statistics (means, standard deviations, frequency counts) were used to describe participants, for the total cohort and by RTW status, in terms of their baseline sociodemographics, health outcomes, and work limitations. Differences in baseline characteristics between the three RTW status groups (RTW-S, RTW-R, and No RTW) were tested using a χ2 test or analysis of variance. Multiple comparisons, with RTW-S as reference group, were performed with a Tukey correction. Group differences in health outcomes and work limitations, adjusted for identified covariates were tested with GLM analyses, and multiple comparisons were performed with a Bonferroni correction. To describe the RTW trajectories, we used the self-reported RTW status at baseline and 6-month follow-up. All statistical analyses were performed with SPSS 13.0 [36].
Results
Baseline characteristics and selection bias analysis
A total of 632 participants, 350 (55%) men and 282 (45%) women, completed the baseline interview 1 month post-injury. Table 1 shows the sociodemographic factors for the total sample and by RTW status at baseline. The mean age of the total cohort was 42.2 years (SD 10.8) and approximately 69% lived with a partner. The mean duration of time receiving wage replacement benefits, based on WSIB data, was 19.1 days (SD 8.9; median 20 days). Sixty-six percent of the participants were primarily experiencing back pain and 34% UE pain.
Table 1Baseline (1 month post-injury) sociodemographic characteristics, days off work, pain site, and comorbidity for the total study sample (n = 632) and by return-to-work status groupaTotalRTW-SRTW-RNo RTWN = 632N = 293 (46.9%)N = 88 (14.1%)N = 244 (39.0%)GenderN(%)N(%)N(%)N(%)    Female282(44.6)123(42.0)48(54.5)110 (45.1)    Male350(55.4)170(58.0)40(45.5)134(54.9)Age categories    15–29 years93(14.7)45(15.4)9(10.2)35(14.4)    30–39 years137(21.7)58(19.8)29(33.0)48(19.8)    40–49 years228(36.1)109(37.2)31(35.2)87(35.8)    ≥50 years173(27.4)81(27.6)19(21.6)73(30.0)Living with/without partner    Living with partner433(68.5)221(75.4)54(61.4)156(63.9)    Not living with partner199(31.5)72(24.6)34(38.6)88(36.1)Children under age 18    No children 341(54.0)158(53.9)48(54.5)131(53.7)    1 child118(18.7)53(18.1)17(19.3)47(19.3)    2 children118(18.7)57(19.5)15(17.0)44(18.0)    ≥3 children 55(8.7)25(8.5)8(9.1)22(9.0)Education    Some high school112(17.7)46(15.7)16(18.2)49(20.1)    High school completed177(28.0)75(25.6)30(34.1)69(28.3)    Some university or college130(20.6)70(23.9)14(15.9)45(18.4)    University/college completed213(33.7)102(34.8)28(31.8)81(33.2)Occupational status (N = 479)b    White collar89(18.6)47 (20.9)13(17.6)29(16.4)    Pink collar156(32.6)71(31.6)26(35.1)58(32.8)    Blue collar-indoor99(20.7)54(24.0)15(20.3)30(16.9)    Blue collar-outdoor68(14.2)28(12.4)10(13.5)28(15.8)    Missing67(14.0)25(11.1)10(13.5)32(18.1)Personal income    <$20,00095(15.0)31(10.6)12(13.6)47(19.3)    $20,000–39,999240(38.0)111(37.9)32(36.4)96(39.3)    $40,000–59,999180(28.5)88(30.0)28(31.8)64(26.2)    >$60,00081(12.8)46(15.7)9(10.2)25(10.2)    Missing36(5.7)17(5.8)7(8.0)12(4.9)Number of working hours/week at the time of the injury; n (%)    ≤37.5179(28.3)84(28.7)24(27.3)69(28.3)    >37.5–40.0281(44.5)128(43.7)40(45.5)110(45.1)    >40.0172(27.2)81(27.6)24(27.3)65(26.6)Duration of receiving full wage replacement benefits within first 30 days post-injurycn = 205n = 67n = 156    Days mean (SD)19.1(8.9)14.2(7.1)18.7(8.4)25.9(6.5)    Days; median20.013.019.029.0Self-reported full days off work due to injury    Days mean (SD)14.5(7.1)10.5(5.1)14.1(6.9)19.7(6.1)    Days; median14.010.013.519Pain site; n (%)    Back418(66.1)214(73.0)64(72.7)134(54.9)    Upper extremities214(33.9)79(27.0)24(27.3)110(45.1)Comorbidity; n (%)    No513(81.2)238(81.2)72(81.8)197(80.7)    Yes, with no/mild effect on health33(5.2)16(5.5)5(5.7)12(4.9)    Yes, with moderate/severe effect on health86(13.6)39(13.3)11(12.5)35(14.4)a N = 625 classified with regard to RTW status, N = 7 were working at time of the baseline interview, but were not asked item regarding recurrencesb WSIB information available for participants who provided informed consent for linkage of WSIB data with questionnaire datac N = 431 for WSIB temporary total compensation within 30 days of accident; Missing data due to (1) no informed consent for linkage of WSIB data with questionnaire data (N = 153) or (2) absence of data when claim was not a lost-time accepted claim (N = 48)
To examine a possible selection bias, we compared the cohort participants (n = 632) to a group of algorithm-selected potential participants (n = 3,712) on characteristics extracted from the WSIB database, where the algorithm mimicked the inclusion criteria of our study.1 The time frame during which their injury occurred was the same as for our study sample. This analysis showed that participants were comparable to potential participants with regards to firm size, industrial sector, and income level (Table 2). However, participants were more likely to be older and female. Women aged 40–49 were more likely to participate than women in the other age categories, and older men were more likely to participate than younger men. With respect to claim status, we compared only participants with accepted claims and available wage replacement data (n = 559) with potential participants, since this data is not available for participants with pending, denied or abandoned claims. Participants were more likely to have a longer duration on wage replacement benefits at 1 and 6 months post-injury and a higher rate of wage replacement re-instatement at 6 months post-injury than potential participants, suggestive of more severe work disability in our cohort.
Table 2Comparison of baseline study participants with algorithm-selected potential study participantsVariableFull baseline cohort (n = 632)Algorithm-selected potential participants (n = 3,712)Gender, n (%)    Female282 (44.6)1,365 (36.8)    Male350 (55.4)2,347 (63.2)Age at baseline interview, mean (SD) (median)42.2 (10.8) (43)40.3 (11.3) (40.7)Gender × age at baseline interview, n (%)    Females: 15–29 years40 (6.3)262 (7.1)    Females: 30–39 years59 (9.3)348 (9.4)    Females: 40–49 years109 (17.2)428 (11.5)    Females: ≥50 years74 (11.7)327 (8.8)    Males: 15–29 years53 (8.4)524 (14.1)    Males: 30–39 years78 (12.3)630 (17.0)    Males: 40–49 years119 (18.8)714 (19.2)    Males: ≥50 years99 (15.7)479 (12.9)Firm size, n (%)    <20 employees58 (9.2)335 (9.0)    20–99 employees100 (15.8)680 (18.3)    100–999 employees190(30.1)1,166 (31.4)    ≥1,000 employees150 (23.7)769 (20.7)    Schedule 2134 (21.2)761 (20.5)Industrial sector, n (%)    Automotive, manufacturing, steel109 (17.2)875 (23.6)    Service127 (20.1)812 (21.9)    Education, municipal, Schedule 2a146 (23.1)817 (22.0)    Healthcare85 (13.4)425 (11.4)    Transportation55 (8.7)333 (9.0)    Chemical/processing, electrical, food31 (4.9)212 (5.7)    Construction14 (2.2)154 (4.1)    Agriculture, forest, pulp and paper, mining15 (2.4)83 (2.2)    Unknown50 (7.9)1 (0.0)Occupational status, n (%)b    White collar109 (18.7)624 (16.8)    Pink collar209 (35.9)1,112 (30.0)    Blue collar-indoor132 (22.7)1,026 (27.6)    Blue collar-outdoor86 (14.8)631 (17.0)    Missing45 (7.7)319 (8.6)Weekly earnings in tertiles, n (%)    ≤$447.68116 (18.4)819 (22.1)    $447.68–≤$880.00281 (44.5)1,890 (50.9)    ≥$880.00157 (24.8)978 (26.3)    Missing78 (12.3)25 (0.7)Duration of time receiving wage replacement benefits (30 days post-injury), mean (SD) (median)c20.6 (9.0) (25)15.9 (9.4) (13)Duration of time receiving wage replacement benefits (180 days post-injury), mean (SD) (median)d58.7 (57.2) (33)37.6 (50.2) (14)Occurrence of re-instatement of wage replacement benefits (30 days post-injury), n (%)c    No507 (90.7)3,481 (93.8)    Yes52 (9.3)231 (6.2)Occurrence of re-instatement of wage replacement benefits (180 days post-injury), n (%)d    No463 (82.5)3,286 (88.5)    Yes98 (17.5)426 (11.5)Claim status (30 days post-injury), n (%)    Lost-time-accepted431 (68.2)2,893 (77.9)    Lost-time-pending171 (27.1)765 (20.6)    Lost-time-denied19 (3.0)43 (1.2)    Lost-time-amalgamated5 (0.8)1 (0.0)    No lost-time-accepted6 (0.9)6 (0.2)a Schedule 2 firms do not operate under the collective liability insurance principle, and, as such, are individually responsible for the full cost of the injury/illness claims filed by their workers. Schedule 2 employers include federal, provincial and municipal governments, railways, airlines, shipping, and telephone companiesb Data on the full baseline cohort is restricted to participants with accepted claims (n = 582)c Data on the full baseline cohort is restricted to participants with accepted claims and available wage replacement data 30 days post-injury (n = 559)d Data on the full baseline cohort is restricted to participants with accepted claims and available wage replacement data 180 days post-injury (n = 561)Note: Italics–The main differences between the full baseline cohort and the algorithm-selected potential participants
Group differences in baseline characteristics
A total of 625 participants were categorized into one of the four RTW status groups. The remaining seven participants were working when interviewed at baseline, but not asked about recurrence(s) due to an error in a skip pattern of the questionnaire, which was subsequently corrected. At baseline (approximately 1 month post-injury), 47% of the participants reported a sustained first return to work, 5% a return to work with recurrence(s) of work absence and working at time of interview, almost 9% a return to work with recurrence(s) of work absence and not working at time of interview, and 39% no return to work.
With regards to gender, age, children under age 18, education, occupational status, and working hours per week at the time of the injury no statistically significant differences were observed across the three RTW groups. However, participants who had a sustained first return to work reported more often that they lived with a partner (χ2 = 11.0, p = .004) and reported a higher personal income (χ2 = 11.7, p = .069) than those with a recurrence or no return to work. These variables were used as covariates in subsequent analyses.
With respect to the mean duration of time receiving wage replacement benefits, based on WSIB data, significant differences were observed across all three RTW groups (F = 122.6, p = .000). Significant differences were also seen with self-reported full days off work due to the injury (F = 169.7, p = .0000). With respect to pain site, a statistically significant difference was found across the RTW groups: participants with a sustained first return to work and those who experienced a recurrence reported low back pain more often, and participants who did not return to work reported pain in the UE more often (χ2 = 21.6, p = <.0001). A total of 81% of the participants reported no comorbidity, whereas 5% reported no/mild effects on health, and 14% reported moderate/severe effects on health, with no statistically significant group differences.
Group differences in health outcomes and work limitations
Table 3 presents the adjusted (for age, gender, living status, and income level) estimated means for baseline health outcomes and work limitations by RTW status, with multiple comparison results. Participants with a sustained first return to work reported significantly less pain compared to those with a recurrence and no return to work. Moreover, they also reported significantly less pain in the past month compared to those with no return to work. In participants with back pain, those with a sustained first return to work reported significantly less functional disability compared to those with a recurrence and no return to work. In participants with UE pain, we observed that those with a sustained first return to work reported significantly less functional disability compared to those who did not return to work, but not compared to those who experienced a recurrence. With regards to physical and mental health as well as depressive symptoms, participants with a sustained first return to work reported significantly better health and fewer depressive symptoms than those with a recurrence and no return to work. It is interesting to note that high levels of depressive symptomatology, indicative of being at risk for clinical depression, were found in all participants, especially in those with a recurrence and those who did not return to work. For all outcomes, there were no significant differences between participants who experienced a recurrence and those who did not return to work. With regards to limitations at work, those with a sustained first return to work and those with a recurrence, reported limitations in all domains, but mainly for physical demands and time management demands. As expected, participants with a sustained first return to work reported significantly fewer limitations than those with a recurrence.
Table 3Estimated means (95% confidence intervals, CI) of baseline (1 month post-injury) health outcomes and limitations at work by return-to-work status group (N = 625), adjusted for age, gender, living status, and personal incomeRTW-SaRTW-RNo RTWN = 293 (46.9%)N = 88 (14.1%)N = 244 (39.0%)Estimated mean (95% CI)Estimated mean (95% CI)pEstimated mean (95% CI)pPerceived painRange 0–10    Pain at time of interview3.84 (3.54–4.13)5.19 (4.64–5.73).0005.94 (5.62–6.27).000    Pain in the past month8.45 (8.25–9.13)8.78 (8.40–9.16).4218.90 (8.68–9.13).014Roland Morris    Range 0–100; N = 41852.73 (49.29–56.17)68.14 (61.75–74.54).00075.66 (71.30–80.03).000Quick DASH    Range 0–100; N = 21447.58 (42.61–52.55)54.94 (46.01–63.87).46963.15 (58.98–67.33).000Physical SF-12    Range 0–10037.03 (35.98–38.09)32.75 (30.80–34.69) .00031.63 (30.47–32.78).000Mental SF-12    Range 0–10048.55 (47.18–49.91)44.40 (41.88–46.92).01445.58 (44.08–47.07).013Depressive symptoms    CES-D; Range 0–6013.16 (11.74–14.59)18.15 (15.53–20.78).00318.70 (17.14–20.26).000Work limitationsRange 0–100    Physical demands46.00 (42.79–49.22)62.81 (56.80–68.82) .000n.a.    Mental demands17.12 (14.70–19.55)29.41 (24.88–33.95).000n.a.    Output demands18.65 (15.95–21.35)35.59 (30.56–40.61).000n.a.    Time management41.83 (38.43–45.23)61.90 (55.61–68.20).000n.a.a The RTW-S group is the reference group for the multiple comparisons
Attrition analysis
Six months after injury, the 632 participants who had completed the baseline interview were approached again to complete the follow-up interview. Overall, 446 participants, 238 (53%) men and 208 (47%) women, completed the follow-up interview (retention rate of 70.6%). Reasons for non-response in the follow-up interview were “unable to contact” (n = 92), “avoided contact” (n = 49), and “refused to participate” (n = 45). An attrition analysis, comparing respondents (n = 446) of the 6-month interview with non-respondents (n = 186), revealed that non-respondents were more likely to be younger, to work longer hours at the time of injury, and to specify “back” as their primary pain site. Moreover, male non-respondents tended to be younger than male respondents, whereas in females differences in age were not statistically significant. Otherwise, non-respondents did not differ significantly with respect to other sociodemographic, workplace, health status, and work absence variables tested, including time receiving wage replacement benefits, re-instatement of wage replacement benefits 6 month post-injury, self-reported work absence duration 1 month post-injury, and claim status. Full details of the attrition bias analysis have been reported elsewhere (Franche et al., submitted).
RTW trajectories from baseline to 6 month follow-up
Figure 2 shows the RTW trajectories for 439 participants, based on self-reported RTW status at baseline and 6 month follow-up. The majority (73%) of workers with a sustained first return to work at baseline were still at work 6 months later. However, 27% had experienced at least one recurrence during that time period. All participants who experienced a recurrence remained, by definition, in this group. Of those participants who had not returned to work at baseline, 59% had a sustained first return to work 6 months later, 17% had made a RTW attempt with a recurrence, and 24% were still off work 6 months post-injury. Six months post-injury, the rate of recurrences of work absence in workers who had made at least one RTW attempt was 38% [n = 153 recurrences/(n = 439 minus n = 40 with no RTW attempt)].
Fig. 2Return-to-work trajectories based on self-reported return-to-work status at baseline (1 month post-injury) and 6-month follow-up (n = 439). aRTW-S, sustained first return to work; bRTW-R working, return to work with recurrence(s) of work absence and working at time of interview; cRTW-R not working, return to work with recurrence(s) of work absence and not working at time of interview; dNo RTW, no return to work
Discussion
The findings of this cohort study suggest the presence of a pattern in baseline health states and work limitations specific to RTW status, 1 month post-injury. Workers with a sustained first return to work reported less pain, less functional disability, better physical and mental health, fewer depressive symptoms, and fewer work limitations compared to those who experienced a recurrence of work absence or who never returned to work. The study adds to the literature by demonstrating that depressive symptoms and limitations at work are prevalent in workers 1 month post-injury, including in those with a sustained first return to work. A substantial rate of recurrences of work absence over 6 months was found (38%), even in workers who had initially made a sustained first return to work at baseline (27%). Moreover, of those workers who did not return to work at baseline, 17% attempted to return and experienced a recurrence within 6 months of the injury, and 24% were still off work at 6 months post-injury.
Our findings are consistent with previous research suggesting that a return to work does not translate into a complete recovery from a MSK disorder [11, 12, 14, 15]. For example, in a study among 205 workers with MSK injury, Evanoff et al. [14] found that 88% of the workers had returned to work (with 83% working at full duty) at 6 month follow-up, and of these 24% reported continuing disability due to the injury (including 20% of those working at full duty). In our study, participants with a sustained first return to work at 1 month post-injury had SF-12 physical and mental health subscales scores below the healthy population average of 50 [29], and high levels of work limitations, specifically for physical demands and time management demands. Thus, the results suggest that many workers, while back at work, still have health problems and experience difficulties in meeting their work demands. Furthermore, the importance of measuring multiple health outcomes, in particular depressive symptoms, was shown by the high levels of depressive symptoms, indicative of being at risk for clinical depression, in injured workers suffering from MSK disorders, particularly in those who experienced a recurrence and those who did not return to work. Our finding of high levels of depressive symptoms in injured workers is in line with earlier studies showing that depressive symptoms are prevalent in MSK-injured workers [37, 38] and highlights the need to address and examine the mental health of workers suffering a workplace injury. Moreover, 6 months post-injury we found a high rate of recurrences of work absence (38%) in workers who had made at least one RTW attempt, which is consistent with studies suggesting that there is considerable movement in and out of work after the first return to work [15 Côté et al., submitted]. In a study among 1,321 US workers who filed a workers compensation claim for back pain, Côté et al. (submitted) observed that 23% and 30% of the workers, 6 and 12 months post-onset of back pain, respectively, experienced multiple work absences.
When interpreting the results, the following methodological issues must be considered. Though reasonable for a study among claimants, the overall participation rate of 61% raises the question of selective participation, which may have biased the results. However, the cohort was shown to be representative of the most comparable claimant group with regards to basic demographic and workplace variables, but not with regards to duration of time receiving wage replacement benefits and rates of wage replacement re-instatement, suggesting the presence of more severe disability in the cohort. Hence, the generalizability of the results remains limited with respect to workers with less severe work disability. More importantly, the rates of self-reported recurrence of work absence may be inflated in our cohort.
A related issue concerns the loss-to-follow-up of 29%. The attrition analysis demonstrated that non-respondents and respondents were similar with regards to time receiving wage replacement benefits, the occurrence of re-instatement of wage replacement benefits, and self-reported work absence duration. Non-respondents were younger males, worked longer hours, and were more likely to specify “back” as their primary pain site compared to respondents.
Future research should further explore the relationship between recurrence(s) of work absence, health outcomes, and work limitations over an extended period of time. We found that workers who experienced a recurrence after a first return to work clearly report more health problems and work limitations than those with a sustained first return to work, and their health status is often comparable to workers who do not return to work. Our trajectory analyses were based on a 6 months time window and it was not yet possible to examine multiple recurrences and their effects on health outcomes and work limitations over a longer period of time. However, 12 month follow-up data will make such analyses possible in the future. Moreover, we have to examine important and meaningful changes in health outcomes and work limitations between baseline and follow-up across the possible RTW trajectories [39], and also study them in relation to a broad range of factors (e.g., RTW interventions, disability management strategies) that might have influenced the RTW process and the outcomes considered. Finally, future research should identify early prognostic factors of the trajectories, particularly focusing on the “problematic” trajectories (recurrences and persistent work absence), so that guidance for an optimal reintegration or for recurrence prevention can be provided.
To conclude, the results of this prospective study suggest that workers who had a sustained first return to work report a better health status and fewer work limitations than those who experienced a recurrence after a first return to work or who did not return to work. However, it is also demonstrated that a return to work is not equivalent to a complete recovery from MSK disorders. Workers who had a sustained first return to work still reported meaningful health limitations, as compared to the general population and significant work limitations. Given the considerable impact of disability on worker health and costs for the workers, employers, and society, the findings highlight the importance of considering multiple health outcomes, including depressive symptoms and work limitations, when studying the complex process of return to work and when developing RTW interventions and disability management strategies.

work limitations
musculoskeletal disorders
return to work
health outcomes
workers’ compensation


Dorsal dumb-bell melanotic schwannoma operated on by posterior and anterior approach: case report and a review of the literature

The schwannomas are benign tumors originating from Schwann cells which constitute the nerve sheath. The dorsal pigmented type of schwannomas is relatively rare (Goldstein in Am J Med Genet 86:62–65, 2004; Kurtkaya-Yapicier in Histol Histopathol 18(3):925–934, 2003). There are two distinct types of melanotic schwannoma: the sporadic melanotic schwannomas and the psammomatous melanotic schwannomas of Carney complex. We report a case of a patient harboring a right dorsal dumb-bell melanotic schwannoma and left adrenal mass. The patient underwent a surgical procedure for en bloc total removal of the mass by a posterior and anterior approach. Histopathological examination revealed the diagnosis of melanotic schwannoma. At present, we have no reliable marker of histopathological malignancy of melanotic schwannoma so the follow-up period ought to continue for a period of more than 5 years. As the total removal of the melanotic neurinomas is mandatory to prevent possible malignant transformation of the tumor recurrence or regrowth, we believe that the posterior and trans-thoracic approach are the most suitable one for the dorsal dumb-bell schwannoma.
Introduction
Dorsal dumb-bell melanotic schwannomas are very rare [13]. They are rather frequently associated to Carney’s complex [8–10]. They present problems on different aspects, such as pre-operative diagnosis, surgical approach and post-operative course. We describe the case of a 53-year-old man who presented with left adrenal hyperplasia and right paravertebral mass suggesting a dumb-bell schwannoma.
Case report
Presentation and examination
In January 2003, a 53-year-old salesman, heavy smoker with an elevate level of arterial hypertension, began to complain about pain in his right chest and upper limb. Chest X-ray and thoracic CT scan in the following February revealed a D9–D10 dumb-bell mass extending into the intrathoracic right space for about 2.5 cm. The patient was admitted to our clinic. A spinal dorsal MRI confirmed the presence of the voluminous D9–D10 right paravertebral mass (Figs. 1, 2). Abdomen MRI showed an almost 4 cm swelling of the left suprarenal gland, suggesting a pheochromocytoma (Fig. 3). The neurologic examination and brain MRI were normal. The renal arterial echodoppler, the dosing of vanilmandelic acid, alpha-fetoprotein, carcinoembryonic antigen, urinary catecholamine and cortisol were normal. The renin activity and the plasmatic level of aldosteron resulted normal in orthostasis and increased in recumbency. The medullar adrenal gland scintigrams (123 IIs MIBG-148 MBqs e.v.) resulted negative for pheochromocytoma. Therefore, we excluded a pheochromocytoma and the patient underwent a surgical procedure for total removal of the dorsal mass by posterior and anterior approach in collaboration with the thoracic surgeons.
Fig. 1MR images demonstrating a right dumb-bell intra-extradural mass at T9–T10 level extending into the intrathoracic right space for about 2.5 cm. Coronal and axial T1-weighted images with Gd-DTPA enhancementFig. 2Sagittal T2-weighted MRI showing T9–T10 right intervertebral foramen occupied by the tumorFig. 3Coronal abdominal spectral fat saturation inversion recovery (SPIR) MR images showing left suprarenal swelling
Operation
A D9–D10 laminectomy after radioscopic control was performed. A right dumb-bell intra-extradural mass of blackish aspect was seen. En bloc total removal of a markedly melanotic intradural lesion was achieved using operating microscope. Then the patient was placed in the left lateral decubitus and by trans-thoracic approach the paravertebral mass was radically removed en bloc, also freeing the right D9–D10 intervertebral foramen from the black and well-encapsulated neoformation. Accurate plastic of the paravertebral pleural wall was obtained. Histological examination revealed melanotic schwannoma with mitotic index not superior to one for ten fields on high magnification indicating low risk for malignancy.
Postoperative course
Post-operative course was uneventful, with marked improvement of the painful symptomatology and good healing of the surgical wounds. The patient was discharged from our ward after 10 days, with a recommendation for ichnographic controls of the left adrenal gland hyperplasia. During a 2-year follow-up period, no recurrence was evident on surveillance MRI.
Discussion
The schwannomas are benign tumors originating from Schwann cells which constitute the nerve sheath. The first case was described by Bjornboe [13, 15] in 1934 in a patient with neurofibromatosis type I. There are two distinct types of melanotic schwannoma: the sporadic and the psammomatous melanotic schwannomas of Carney complex [8, 14, 24, 27, 29, 36]. In 1985, Carney described a syndrome characterized by mixomas (heart, skin and breast), mucus-cutaneous spotty pigmentations and endocrine overactivity (due to thyroid dysfunction or hypophysial adenoma or Cushing syndrome secondary to adrenocortical pigmented primary nodular hyperplasia) [8, 9].
A year later, a Mendelian dominant heredity was defined responsible for the symptomatologic complex [43]. About 50% of patients with melanotic psammomatous schwannomas are affected by the syndrome of Carney and one-fifth of them are carriers of multiple lesions [21, 42]. Generally, melanotic schwannoma affects the spinal nerves, the central nervous system and the autonomous nerve system, but extra-nervous locations can also exist. The dorsal location represents 30.5% of the spinal melanotic schwannoma [41]. Until today we were able to find 47 spinal cases of extramedullary melanotic neurinoma in literature (Table 1) [1, 2, 3, 5, 6, 7, 11, 12, 13, 16, 18, 20, 21, 26, 28, 30, 31, 33, 34, 35, 38, 39, 44, 45]. The clinical presentation is not specific but similar to that of other extramedullary spinal tumors (radicular pain, dysesthesias, progressive sensorial-motor deficits). Preoperative diagnosis is based on magnetic resonance imaging (MRI): melanotic schwannomas appear hyperintense on T1-weighted sequences and hypointense on T2-weighted sequences compared to the nonmelanotic type of schwannomas that are hypo-isointense on T1 and hyperintense on T2 [1, 13, 17, 25, 37].
Table 1Review of 47 cases of spinal extramedullary melanotic schwannoma reported in literatureReferencesAgeGenderLevelAprile et al. [1]70FL3Bagchi et al. [2]40MT6–T7Belak et al. [3]44–DorsalBosman et al. [4]43ML4–L5Bouziani et al. [5]46MLumbarBuhl et al. [6]28ML5–S1Bunc et al. [7]––T12–L2Cornejo et al. [10]36ML3–L4Di Gregorio et al. [11]––SacralErlandson et al. [12]36ML5–S1Goasguen et al. [13]66FC2–C3Graziani et al. [15]40FT3Gregorios et al. [16]45FT2Iizuka et al. [18]58FT10Killeen et al. [19]26FS1Krichen et al. [20]27MC6–C7Kuchelmeister et al. [21]53FC5–C6Le Cam et al. [23]35FL4Leger et al. [24]36MC4Lowman et al. [26]17FT12–L1Lowman et al. [26]26FC6Ludvikova et al. [27]56FSpineLudvikova et al. [27]58MSpineMandybur et al. [28]59MT7Martin-Reay et al. [29]32MSacrumMcGavran et al. [30]12FT2McGavran et al. [30]49FC8Mennemeyer et al. [31]23FL1Mennemeyer et al. [31]25MT7Mennemeyer et al. [31]36MS1Parent et al. [33]63FS1Paris et al. [34]49FC8Parker et al. [35]18FDorsalPrieto-Rodriguez et al. [36]38MT5Schmitz et al. [38]42FCervicalTawk et al. [39]61MT7Vallat-Decouvelaere et al. [41]5 casesF and MC–T–L–SZhang et al. [44]5 casesF and MSpinal nerve rootZonenshayn et al. [45]27FL2 and L4–L5
The histological differential diagnosis with the other spinal pigmented tumors is with the meningeal melanocitoma, the pigmented neurofibroma, the paraganglioma, the ganglioneuroma, the fibrous form of meningioma and above all with the primitive melanoma or relative metastasis [13, 15]. Even if the association of the left adrenal swelling and arterial hypertension with the dumb-bell thoracic melanotic schwannoma can be correlated to the Carney complex, in our opinion our patient did not harbor such a syndrome. In fact only the adrenocortical pigmented primary nodular hyperplasia is a characteristic stigmata of Carney complex. Moreover, our patient did not show cutaneous signs of neurofibromatosis and his family history was negative for Carney complex stigmata. The total body CT scan showed the left adrenal mass and excluded any other typical lesion of the syndrome. The increased plasmatic level of renin and aldosteron in recumbency in our patient, that was on heavy medical therapy for high level of arterial blood pressure, may be correlated to left adrenal hyperplasia or solitary adrenal adenoma [40] and not to adrenocortical pigmented nodular hyperplasia, which is the cause of ACTH-independent adrenal Cushing’s syndrome [8] and normally do not trigger elevation of plasmatic aldosteron. Moreover, in our case the histological examination of the neurinoma did not show the most common, psammomatous aspect of Carney complex [8, 13]. In summary, we did not perform a left adrenal biopsy as we ruled out the Carney syndrome and malignancy of the adrenal mass by clinic and radiological investigations. Hypertension, adrenal mass and dumb-bell melanotic schwannoma do not imply Carney complex.
In our patient the hypertension was not correlated to the Carney complex, but to the hyperaldosteronism caused by left adrenal hyperplasia or solitary adrenal adenoma. Nevertheless, neurosurgeons ought to keep in mind the connection between the melanotic schwannoma and the Carney complex, since more than 50% of the cases described in literature have been related to such syndrome. A complete endocrinological evaluation and a total body CT should always be performed together with a genetic study in the suspicion of Carney complex. The risk of possible malignant transformation of the neurinoma should also be taken into consideration as cases of recurrences or metastases have been described even 13 years after surgery [4, 6, 19, 21, 23, 32, 41]. It is not possible to have any reliable histopathological indication of possible malignant transformation after the first surgical operation [42]. The follow-up ought to continue for a period of more than 5 years. We have both to check the primitive tumor regrowth or recurrence and the possible remote locations, particularly in the lungs.
From the surgical point of view the total removal of the melanotic neurinomas is mandatory to prevent possible malignant transformation of the tumor remnants. The therapeutic potential of radiotherapy is not proven [42]. The prognosis depends, therefore, almost entirely on the extent of surgical removal of the tumor [3, 44]. So we believe that the posterior and anterior approach is the most suitable one to remove the dorsal dumb-bell schwannoma completely, both in the thoracic cavity and in the intervertebral foramen, and to avoid possible liquoral leakage.

dorsal dumb-bell melanotic schwannoma
spinal tumor
carney syndrome
thoracic nerve sheath tumor


Determining the “Health Benefit Basket” of the Statutory Health Insurance scheme in Germany

The issue of defining health benefit catalogues has recently gained new importance in Germany as a result of the creation of the new Institute for Quality and Efficiency. The Institute was designed to support the Federal Joint Committee conducting effectiveness studies for benefit coverage decisions. The Committee and the contractual partners (sickness funds and providers) define the benefit catalogues for the Statutory Health Insurance in the framework of Social Code Book V, Germany’s most relevant health care scheme. Unlike other countries, the German federal government limits its regulatory role to defining procedures that determine the scope of Statutory Health Insurance services. The explicitness of the benefit catalogues varies greatly between different sectors. While benefits in outpatient care are rather explicitly defined, benefit definitions for inpatient care are vague. It is argued that the establishment of the new Institute and the development of the DRG system are initial steps towards a more effective and explicit benefit catalogue.
Organizational structure and actors involved in the definition of benefit catalogues
A fundamental aspect of the German health care system is the sharing of decision-making powers between the federal government, the individual states, and designated self-governmental institutions. Responsibilities are traditionally delegated to membership-based, self-regulated institutions of payers and providers that are involved in financing and delivering health care. In the largest scheme (which covers 88% of the population), the Statutory Health Insurance (SHI), sickness funds, their associations and associations of SHI-affiliated physicians and dentists are recognized as quasipublic corporations. These corporatist bodies constitute the self-regulated structures that operate the financing and delivery of benefits covered by the SHI scheme within the legal framework of the Social Code Book (SGB) V [1].
In joint committees of payers (associations of sickness funds) and providers (associations of physicians and/or dentists and/or the Hospital Federation) legitimized actors define benefits, prices, and standards (federal level) and negotiate horizontal contracts to control and sanction their members (regional level). The vertical implementation of decisions taken at senior levels is combined with strong horizontal decision making and contracting among the legitimized actors involved in the various care sectors [2].
Physicians treating SHI-insured patients are organized into 17 regional physicians’ associations. The Federal Association of SHI Physicians is responsible for cooperation on the federal level. SHI-accredited dentists are organized the same way as physicians through 17 dentists’ associations and the Federal Association of SHI Dentists. The German Hospital Federation is also involved in the decision-making process.
The payers’ side is made up of autonomous sickness funds organized on a regional and/or federal basis. They are obliged to raise contributions from their members and to determine the contribution rate necessary to cover expenditures. Their responsibilities include contracting, negotiating prices, quantity and quality assurance measures. Services covered by such contracts are usually accessible to all fund members without any prior approval by the fund, except for preventive spa treatments, rehabilitative services and short-term home nursing care. If there is any doubt, the sickness funds must obtain an expert opinion on the medical necessity for treatment from the Medical Review Board, which serves as a joint institution of the sickness funds.
The most important body in the benefit negotiations between sickness funds and physicians concerning the scope of benefits is the Federal Joint Committee. Based on the legislative framework the Committee issues directives relating to all sectors of care. The main body of the Committee consists of nine representatives of the federal associations of sickness funds, nine representatives from provider groups, two neutral members with one proposed by each side, and a neutral chairperson-accepted by both sides. In addition, nine nonvoting representatives of formally accredited patient organizations have the right to participate in consultations, and to propose issues to be assessed and decided upon. The directives of the Committee are legally binding for all actors in the SHI scheme. These directives primarily concern the coverage of benefits and assure that SHI services are adequate, appropriate, and efficient.
The actual criteria defining benefits vary widely between sectors and types of catalogues. The most important benefit catalogues in the German SHI scheme and its underlying criteria are displayed in Tables 1 and 2. This article concentrates on HC1 (services of curative care) of the International Classification for Health Accounts (ICHA) taxonomy [3].Table 1 Catalogues and criteria used for defining benefitsLegal statusDecision maker(Original) purposePositive/negative definition of benefitsDegree of explicitnessaIf itemized: goods, procedures only; linked to indicationsUpdatingCriteria used for defining benefitsNCECEBOtherSHI GBR LawParliamentEntitlementsP/N1/2–When necessary+–––––SHI FJC general directivesDirectiveFJCEntitlementsP2–When necessary+++(+)b––SHI FJC special directives: positiveDirectiveFJCEntitlementsP2/3Goods, procedures, indicationWhen necessary+++(+)b––SHI FJC appendices to directives: negativeDirectiveFJCEntitlementsN3Goods, procedures, indicationWhen necessary+++(+)b––SHI DRGContractCommittee on Hospital PaymentReimbursementP3ProceduresEvery year+++–––SHI EBMContractValuation Committee (Physicians)ReimbursementP3ProceduresWhen necessary+++–––SHI BEMAContractValuation Committee (Dentists)ReimbursementP3ProceduresWhen necessary+++–––SHI BEL-IIContractValuation Committee (Dentists)ReimbursementP3GoodsWhen necessary+++–––Statutory long-term care insurance: GBRLawParliamentEntitlementsP/N1–––+––––FJC Federal Joint Committee, SHI Statutory Health Insurance, GBR General Benefit Regulation, DRG diagnosis-related group,
EBM Uniform Value Scale, BEMA Uniform Value Scale–dentists, BEL-II Uniform Value Scale–dental technicians, N need, C costs, E effectiveness,
CE cost-effectiveness, B budgeta 1, “all necessary”; 2, areas of care; 3, itemsb Although explicitly mentioned, it is provided principally for medical devicesTable 2 Benefit-defining laws/ decrees and cataloguesStatutory Health Insurance (SHI) - general benefit regulationSHI - general directives of the Federal Joint CommiteeSHI - special directives of the Federal Joint Commitee (positive)SHI - appendices to directives of the Federal Joint Commitee (negative)SHI - DRGSHI - EBMSHI - BEMASHI - BEL-IIStatutory long term care insurance - general benefit regulationCatalogue: type of document, actors and contentsHC.1.xxx (X)xHC.1.2xxx (X)xHC.1.3.1xxx (XI)xHC.1.3.2xxx (I)x (XII)xxHC.1.3.3xxx (II)x (XI)xHC.1.3.9xxx (III)x (XI)HC.2.1/2.2xxHC.2.3xHC.3.1xxHC.3.2xxHC.3.3xx (IV)xHC.4.1xxxHC.4.2xxxxHC.4.3xx (V)HC.5.1.1xxHC.5.1.2xxx (VI)HC.5.2xxx (VII)HC.6.1xxx (VIII)HC.6.3xHC.6.4xxx (IX)xxHC.6.5xFJC Federal Joint Committee,
SHI Statutory Health Insurance, GBR General Benefit Regulation, DRG diagnosis-related group, EBM Uniform Value Scale,
BEMA Uniform Value Scale–dentists, BEL-II Uniform Value Scale–dental technicians,  I Directives on the Provision of Prosthetic Services II Directives on Psychotherapy
III Directives on Nonphysician Care
IV Directives on Home Nursing Care V Directives on Patient Transport VI Directives on OTC
VII Directives on Medical Aids VIII Directives on Maternity Care IX Directives on A. Early Detection of Cancer, B. Dental Prophylaxis & C. Medical Examinations for the Early Detection of Diseases X Appendix to Directive according to SGB V, Sect. 137c (to evaluate hospital procedures)
XI Appendix to Directive on Medical Procedures, XII Appendix to Directive on New Dental Procedures
In-patient curative care
If curative care (i.e., to detect, cure, prevent the worsening, or relieve the discomforts of accompanying diseases) cannot be achieved by ambulatory treatment (SGB V, Sect. 39), the insured party is entitled to inpatient treatment in accordance with SGB V, Sect. 27. This health care entitlement is linked to a copayment of €10 per calendar day to a maximum of 28 calendar days per year [SGB V, Sect. 39(4)1].
Hospital services are granted in accordance with the care ability of each hospital and with the level of care assigned to each hospital. In each individual case the provision of services needs to be suitable and adequate for the insured. This includes medical treatment, nursing care, the provision of pharmaceuticals, cures and therapeutic appliances, as well as board and accommodation [4].
Hospital care may be only provided in hospitals included in the hospital plan of the respective federal state, in university hospitals, or in hospitals that have concluded a service provision contract with the sickness funds (SGB V, Sect. 108). While the spectrum of services provided by the respective hospitals is indirectly determined by the hospital plan (which also determines governmental subsidies for investments), the reimbursement for the provided services is decided in negotiations between each hospital and the association of sickness funds.
The Federal Joint Committee presides over matters of exclusion of health care services, and/or the evaluation and examination of treatment methods; the Committee handles these matters in response to requests from the federal associations of sickness funds and the German Hospital Federation. The method under examination will be scrutinized as to its suitability to provide adequate, expedient, and economical care for the insured persons, with general state-of-the-art medical knowledge taken into consideration. Should the examination reveal that the method does not meet the aforementioned, it may no longer be provided at the expense of the SHI system. In such instances, the Federal Joint Committee issues a corresponding directive according to SGB V, Sect. 137c (1) (see Fig. 1). Health care services in the framework of clinical studies are not subject to the directive. This means that all health care services that are not excluded by a directive of the Federal Joint Committee may be provided at SHI’s expense.Fig. 1 DRG Case Fees Catalogue for inpatient care
The SHI Reform Act 2000 required the selection and implementation of a case fee system for reimbursement effective as of 1 January 2003. On 27 June 2000 the federal associations of sickness funds, the Association of Private Health Insurance, and the German Hospital Federation adopted the Australian system of diagnosis-related groups (DRGs) as the basis for developing a German DRG system. On 10 May 2001 they founded the Institute for the Payment System in Hospitals (InEK) which is intended to support the introduction and the further development of the DRG system. The InEK is controlled and supervised by the Committee on Hospital Payment, an institution consisting of representatives from the contracting partners (see Fig. 1). The matters addressed by the DRG Institute consist of defining the DRG case groups, the maintenance of the DRG system, and its severity classification system, the development of a coding directive and proposals for adapting German modifications of the International Classification of Diseases ICD-10 and the Operating Procedures System (OPS) into the DRG system. The Institute is also responsible for the calculation of DRG cost weights and individual adjustments within the DRG system.
As the basis for the new pricing system a uniform case fee catalogue with fixed payments for services and benefits, valid throughout Germany, was developed. The catalogue lists all procedures (services) performed in hospitals in accordance with respective clinical diagnoses. At the same time the DRG system constitutes the catalogue of services and benefits covered by the SHI scheme for inpatient care. The inclusion of new health care services in the DRG system is reflected at the beginning of each year when a new version of the OPS and the ICD-10 is made available and is linked to a DRG [5].
The Case Fees Catalogue of 2005 consists of 876 DRGs, of which 33 are not remunerable with a case fee, and an additional list of 71 negotiated extra remunerations. The German DRG system is subdivided into 23 major diagnosis categories (MDCs) which refer in principle to a body system or cause of a disease. The MDC category also defines the first of the four digits of a DRG. The second and third digits of a DRG indicate the respective partition. The partition differentiates between surgical procedures (01–39), other procedures (40–59), and medical (conservative) procedures (60–99) carried out during a hospital stay, thus linking a DRG to benefits provided in a hospital. The fourth digit further subdivides a DRG according to a patient’s clinical complexity level, which is comprised of such factors as complexity of secondary diagnoses, cause of discharge and patient gender [6].
For inpatient services not covered by the DRG system (e.g., new methods of treatment), agreements are made with the hospitals concerned. The local contractual partners inform the contract partners at the federal level of such agreements, who may then decide to initiate an evaluation process in order to exclude these new services from the benefit package [SGB V, Sect. 137c; V, Sect. 6 (2), Hospital Payment Act]. In principle however, as noted above, all health care services that are not explicitly excluded by a directive of the Federal Joint Committee can be provided at the expense of the SHI.
Outpatient care
The provision of medical and dental care must be regulated and secured by agreements between the respective regional physicians’ association/regional dentists’ association and the regional associations of the sickness funds (SGB V, Sect. 72). Whereas, in accordance with SGB V, Sect. 137c, medical care in hospitals shall be, “adequate, expedient and cost-effective”, for ambulatory care, in accordance with Sect. 135, the criteria to be applied are “diagnostic and therapeutic expedience, medical necessity and cost-effectiveness.” Thus the inclusion and/or exclusion of health care services from the benefit catalogues differ in the two sectors. In the outpatient sector a service provided must be confirmed to fulfill the criteria “expedience, necessity and cost-effectiveness” in order to be included into the catalogue of services and benefits. In contrast to that, health care services in the inpatient sector is excluded from the benefit catalogue of the sickness funds only if the criteria are proven to be unfulfilled. For this reason it is possible that the health care services provided in the inpatient sector are not included in the benefit catalogue of the outpatient sector [7].
Basic medical and diagnostic care
Insured persons are entitled to preventive care, detection, and treatment of diseases [SGB V, Sect. 28 (1)]. This entitlement also embraces complementary services by nonphysicians and practitioners, provided that they are prescribed by a physician. The legislative authority, however, does not define in detail the entitlements of the insured persons, but regulates the procedures with which the institutions of self-governance and the contractual partners determine the scope of SHI services [8].
In accordance with SGB V, Sect. 92 (1), the Federal Joint Committee issues directives in respect of adequate, expedient and cost-effective medical care for the insured persons. The directives consist of a general part that explains their aim, their users and mentions the corresponding paragraph in the SGB V. After the initial section the directives become more detailed. For example, the Directive on Medical Procedures that regulates the in- and exclusion of benefits in the outpatient sector initially defines the term of a new service and the conditions an evaluation is depended upon. Thereafter it is stated that the regional physicians’ associations, the Federal Association of SHI Physicians and the federal associations of sickness funds have the right to propose services for their inclusion. Then the criteria for the inclusion of services, the classification of evidence and the decision-making process are described in detail. The services included or excluded through the evaluation process are listed in the annexes [9].
While the Federal Joint Committee decides on the in- and exclusion of services into the benefit package, the Valuation Committee, which consists of seven representatives of the Federal Association of SHI Physicians and representatives of the federal associations of sickness funds, defines the actual benefit catalogue for the insured, the Uniform Value Scale (EBM). The EBM defines, as an integral component of the Federal Framework Contract–Physicians (BMV-Ä), the scope of medical care to be provided under the SHI throughout Germany. If the Valuation Committee fails to reach a consensus, at least two of its members or the Federal Ministry for Health and Social Security may demand that the extended Valuation Committee in accordance with SGB V, Sect. 87 (4), be brought in to resolve a split decision. Resolutions are to be submitted to the Ministry of Health, which, in the event of unresolved objection, may define alternative executions.
The BMV-Ä is concluded between the Federal Association of SHI Physicians and the federal associations of sickness funds (SGB V, Sect. 82). In addition to the scope of health care provided under the SHI, the BMV-Ä regulates participation in ambulatory care, the pertinent aspects of quality assurance, and entitlement to benefits. Thus the EBM and the directives of the Federal Joint Committee are both integral parts of this contract. In Sect. 2 of the BMV-Ä, the description of a service in the EBM is stipulated as a condition for the provision of the respective service. As a result, the EBM constitutes the catalogue of services and benefits covered by the SHI (see Fig. 2).Fig. 2 Uniform Value Scale for physicians for outpatient care
The broad structure and the contents of the EBM are stipulated in SGB V, Sect. 87 [10]: (a) The EBM displays the health care services covered by the SHI scheme and their monetary value in relation to one another in the form of a points system. (b) A basic remuneration for general practitioners is defined. (c) Health care services are grouped into packages of similar services. (d) Differentiation is made between the health care services to be provided exclusively by general practitioners and those to be provided exclusively by specialists. (e) The respective health care services are assigned exclusively to the groups of specialists that are allowed to provide them.
The EBM catalogue is structured into six main chapters and various sections. Chapter I describes general regulations regarding the provision and reimbursement of health care services. Chapters II–IV contain health care services related to different physician groups and/or special criteria. Chapter V lists the general health care services provided by most physicians reimbursed with case fees. Chapter VI contains appendices (e.g., a list of services which are already contained in other services and are therefore not reimbursed additionally) [11].
As an appendix to the BMV-Ä there is an agreement that applies to care provided by general practitioners under SGB V, Sect. 73. It defines the provision of medical treatments and the early detection of diseases. The definition of individual services to be provided is included in the EBM. In addition to these central agreements, which are uniform for all sickness funds, there are numerous “small” contracts determining the scope of the health care services covered by the German SHI scheme.
Outpatient dental care
While benefits for ambulatory physician services are legally defined in generic terms only, legislation regulating dental care is much more detailed in the SGB V. One reason for this is that the respective committee of the joint institutions until 2003 failed to provide more explicit definitions [12]. The basic entitlements of the insured to dental care are defined in SGB V, Sect. 28 (2): The insured are entitled to prevention, early detection, and treatment of diseases of the teeth, the mouth, and the jaw. Consequently only prophylactic treatment, basic dental care, and dental prosthetic services are covered by the sickness funds [13].
Similar to the definition of benefits for basic medical care, the directives of the Federal Joint Committee broadly define when patients are entitled to a benefit. However, they do not define specific items that must be included. Therefore the Dental Valuation Committee, which consists of representatives of the federal associations of the sickness funds and the Federal Association of SHI Dentists defines the Uniform Value Scale for Dentists (BEMA; see Fig. 3). The BEMA lists services that are reimbursed by the sickness funds, thereby explicitly defining the SHI benefit catalogue. The services of dental technicians producing the material needed for orthodontic or prosthetic services are listed in a similar framework, the Uniform Value Scale for Dental Technicians (BEL-II) which is negotiated by the same Committee.Fig. 3 Uniform Value Scales for dentists and dental technicians
Orthodontic treatments, except those for the treatment of abnormalities, are to begin during childhood and are excluded for insured parties over the age of 18 years (SGB V, Sect. 29). To prevent overprovision of services dentists must prepare a cost schedule that is reviewed by the sickness funds. Prosthetic services are only partially covered by the sickness funds and are therefore defined more explicitly. The insured receive a so-called “subsidy” as a percentage of a “standard” treatment, defined by the Federal Joint Committee in a directive according to SGB V, Sect. 56. The directive currently in force defines a standard treatment for 52 findings. For each standard treatment all reimbursable services of the dentists and the dental technicians are listed separately according to the BEMA and the BEL-II [14].
Sickness funds usually cover 50% of the standard treatment costs. This proportion can increase to 70% or 80% if a patient can prove yearly preventive dental checkups over the past 5 or 10 years, and the patient’s efforts for dental hygiene are observable. Higher payment levels, up to full coverage of the costs of the standard treatment, are provided only for persons of very low income. Patients are free to choose nonstandard treatments [SGB V, Sect. 55 (5)] or include additional services [SGB V, Sect. 55 (4)]; however, the amount of sickness funds’ payments remains unchanged.
Outpatient care performed by nonphysicians
The term “cures” subsumes health care services in Germany that are provided by nonmedical practitioners, which include professional, recognized therapists, such as physiotherapists and occupational therapists [15]. The entitlement of the insured to cures is found in SGB V, Sect. 32. It is limited by copayments for insured parties over the age of 18 years under SGB V, Sect. 61 (3).
A further limitation on entitlements is imposed under SGB V, Sect. 34 (4), “Excluded Pharmaceuticals, Cures and Medical Aids.” The Ministry of Health is entitled to exclude cures from the catalogue of services and benefits covered by the SHI through decrees, with the approval of the Federal Council (upper chamber of the federal Parliament). However, a corresponding legal decree does not exist at present.
The scope of services covered by the SHI scheme is explicitly described and regulated by the Directive on Non-physician Care issued by the Federal Joint Committee under SGB V, Sect. 92 [16]. The prescription of more cost-effective measures with equal efficacy, for example, drugs and other therapeutic appliances that achieve the same therapeutic objective, is to be given precedence. The benefits are listed in the directive in connection with an indication. New benefits and/or an extension of the indications for a given benefit may only be prescribed after the Federal Joint Committee has recognized their therapeutic value and included them into its directive (SGB V, Sect. 138).
The federal associations of sickness funds and representatives of non-physicians compile a Catalogue of Non-physician Care. The catalogue facilitates the implementation of the directive on Non-physician Care issued by the Federal Joint Committee (see Fig. 4; SGB V, Sect. 125), which regulates: (a) the content, scope and frequency of cures, (b) further training measures and quality assurance (c) the content and scope of collaboration between non-physicians and the prescribing SHI physician, (d) measures to meet the aim of cost-effectiveness, and (e) specifications for remuneration structures.Fig. 4 Catalogue of Non-physician Care
Conclusions
Despite the existence of various catalogues and directives for the SHI scheme, the benefit package is not defined in detail because the obligation of the catalogues and their explicitness varies largely. Inpatient services not listed in the DRG catalogue can still be covered by the SHI scheme as long as they are not explicitly excluded by the Directive according to SGB V, Sect. 237c. However in the ambulatory sector only those procedures listed in the SHI EBM or in the SHI BEMA are covered as benefits in the outpatient sector.
With the exception of the Catalogue of Non-physician Care the benefits described in the DRG, EBM, BEMA, and BEL-II are the aggregate results of decisions taken at various levels, and they are not linked to specific indications. The reason for this is that they were originally defined for reimbursement and were not meant to define the SHI benefit basket in full detail. For example, as DRGs aggregate multiple procedures and diagnoses, benefits (medical procedures) provided under one DRG will vary from case to case. Additionally, the patient clinical complexity level of a DRG is determined by diagnoses including comorbidities, gender and cause of discharge and not on the basis of the actual services provided. Therefore the scope of a DRG is very broad. Conversely, the development of a DRG catalogue can also be seen as a starting point towards a more explicitly defined benefit catalogue, and subsequently lead to benefit catalogues where all approved interventions are listed and grouped around the relevant diagnoses [2].
In recent years strong efforts have been made by the German government to move towards a more explicitly defined benefit basket. The creation of the Federal Joint Committee out of four smaller committees for the different sectors of care can be considered an improvement. The number of issued directives since the inception of the committee supports the assumption that it is more productive than its predecessors. This development suggests that the German health care system is moving towards a more explicitly defined benefit catalogue [17].
Until now the use of cost-effectiveness studies as part of the decision criteria for the inclusion of new benefits is widely lacking. The criteria of cost-effectiveness was only taken into consideration for benefit decisions on medical devices. However, it is likely that it will be considered for other benefits in the future as well. The creation of a supporting institute to the Federal Joint Committee, the Institute for Quality and Efficiency, in 2004, which increasingly commissions effectiveness studies, was one major step in that direction [2]. Although this will increase the information base for decisions [18, 19], the future impact of the cost-effectiveness criteria on the decision-making process and therefore on the structure of the health basket still remains unclear.

germany
health benefit plans
health services
health priorities
national health programs


The Future of Biologic Agents in the Treatment of Sjögren’s Syndrome

The gain in knowledge regarding the cellular mechanisms of T and B lymphocyte activity in the pathogenesis of Sjögren’s syndrome (SS) and the current availability of various biological agents (anti-TNF-α, IFN- α, anti-CD20, and anti-CD22) have resulted in new strategies for therapeutic intervention. In SS, various phase I and II studies have been performed to evaluate these new strategies. Currently, B cell-directed therapies seem to be more promising than T cell-related therapies. However, large, randomized, placebo-controlled clinical trials are needed to confirm the promising results of these early studies. When performing these trials, special attention has to be paid to prevent the occasional occurrence of the severe side effects.
Introduction
Sjögren’s syndrome (SS) is a chronic lymphoproliferative autoimmune disease with disturbances of T lymphocytes, B lymphocytes, and exocrine glandular cells [1]. SS can be primary (pSS) or secondary SS (sSS), the latter being associated with another autoimmune disease [e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE)].
Lymphocytic infiltrates are a characteristic histopathological finding in SS. These infiltrates consist of T and B cells. The expression of different cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-α (IFN-α), during the formation and proliferation of these infiltrates has been investigated. There is an overexpression of TNF-α, which is secreted by CD4+ T lymphocytes, mononuclear cells, and epithelial cells [2]. The intraglandular synthesis of TNF-α causes destruction of acini by up-regulation of Fas at the surface of the glandular epithelial cells, stimulation of secretion of type 2 and 9 matrix metalloproteases by epithelial cells, and overexpression of different chemokines [3–5]. IFN-α is produced by activated plasmacytoid dendritic cells in primary SS (pSS), and numerous IFN-α-producing cells have been detected in labial salivary glands [6]. IFN-α promotes the autoimmune process by increasing autoantibody production and through the formation of endogenous IFN-á inducers. IFNs have potent immunomodulating properties and are thought to trigger a systemic biological response [7].
Besides the presence of proinflammatory cytokines, described in the previous paragraph, recent studies have shown an important role for B cells in the pathogenesis of SS. Presence of autoantibodies and hypergammaglobulinemia are both considered to reflect B cell hyperactivity. Systemic complications of SS are associated with this B cell hyperactivity [8]. Moreover, about 5% of SS patients develop malignant B cell lymphoma [9]. B cell activating factor (BAFF), also known as B lymphocyte stimulator (BLyS), is an important factor in local and systemic autoimmunity [1]. Dysregulated BAFF expression is implicated in disease progression and perpetuation of humoral autoimmunity. Overproduction of BAFF in transgenic mice has been shown to result in B cell proliferation and antibody production resulting in inflammation and destruction of the salivary glands, as well as kidney failure similar to observations seen in SLE [10]. In humans, circulating BAFF levels are increased in patients with pSS and correlate with disease activity [11].
Recent insights in the cellular mechanisms of T and B lymphocyte activity in the pathogenesis of SS and the current availability of various biological agents have resulted in new strategies for therapeutic intervention. The use of these biological agents in the treatment of SS will be discussed in this review.
Biological Agents
Currently, biological agents have been introduced in various systemic autoimmune diseases, as rheumatoid arthritis and SLE. Biological agents most frequently applied in autoimmune diseases are monoclonal antibodies, soluble receptors, and molecular imitators [12]. These biological agents enhance or replace conventional immunosuppressive therapy. In contrast to rheumatoid arthritis and SLE, no biological agent has been approved yet for the treatment of SS, but several phase II and III studies have been or are currently conducted. The biological agents used in SS trials are IFN-α and agents targeting TNF-α and B cells (anti-CD20, anti-CD22). Although no trials have been performed yet with BAFF antagonists, this might be a promising therapy [13] and will be discussed in this review, as well.
Anti-TNF-α Monoclonal Antibodies
There are three main biological agents targeting TNF-α: the chimeric monoclonal IgG1 antibody infliximab, the receptor fusion protein etanercept, and the fully humanized monoclonal antibody adalimumab.
In an open-label study, short-term treatment with infliximab was reported to be very effective in active pSS over a 3-month period [14]. Sixteen patients received three infusions (3 mg/kg) at weeks 0, 2, and 6, which led to significant improvement in all clinical and functional parameters, including global assessments, erythrocyte sedimentation rate, whole salivary flow rate, tear secretion (Schirmer test), tender joint count, fatigue score, and sensation of dry eyes and dry mouth. Three patients, all with short disease duration (<3 years), were considered to be in complete remission up till 1 year. In 10 out of the 16 patients, SS symptoms, particularly mouth dryness, relapsed after a median of 9 weeks. In a follow-up study, a maintenance regimen of one infusion every 12 weeks was evaluated in these 10 patients. Retreatment induced an improvement of signs related to SS that was comparable with the effects from the three loading infusions [15]. To confirm these promising results from an uncontrolled study, the Trial of Remicade In Primary Sjögren’s Syndrome study was designed. In this multicenter, double-blinded, placebo-controlled, randomized clinical trial, 103 patients with active pSS were included and treated with infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6. Follow-up was 22 weeks. Primary endpoint was an improvement of >30% of two of three VAS scores measuring joint pain, fatigue, and dry eyes. There were several secondary endpoints of which one was the basal salivary flow rate. In contrast to the previously mentioned uncontrolled studies, no evidence of efficacy of infliximab treatment on all clinical and functional parameters could be demonstrated in this randomized controlled clinical trial [2].
A trial on 15 pSS patients (mean disease duration 3.6 years) with 25-mg etanercept, subcutaneously twice a week for 12 weeks, did not reveal a reduction in sicca symptoms and signs, neither did the repeated treatment for up to 26 weeks. Only in the subset of four patients with severe fatigue a decrease in fatigue was observed [16]. Another trial evaluating subcutaneous administration of etanercept vs placebo for 12 weeks (28 patients) also showed no clinical efficacy [17]. No trials of adalimumab treatment in pSS have been reported in the literature yet.
In conclusion, TNF-targeting treatment could not be proven to be of benefit in reducing the complaints of pSS patients.
IFN-α
IFNs are proteins with antiviral activity and potent immunomodulating properties. SS patients have an activated type I IFN system [6]. Such a role for IFN-α appears to contradict the reports described below, that low doses of IFN-α administered via the oromucosal route increase the unstimulated salivary output. However, it is hypothesized that oral IFN-α treatment may act by increasing saliva secretion by up-regulation of aquaporin 5 transcription without significantly influencing the underlying autoimmune process [6, 7].
In a phase II study, treatment of pSS patients with IFN-α administered via the oromucosal route (by dissolving lozenges) was demonstrated to be effective (improvement of salivary output, decreased complaints of xerostomia) and safe [18]. Based on these promising results, a randomized, parallel group, double-blinded, placebo-controlled clinical trial (497 pSS patients) was designed. Patients were randomized into two groups and received a 24-week daily treatment with either 450 IU IFN-α (150 IU three times per day) or placebo in a ratio 3:2, administered by the oromucosal route. This randomized, controlled clinical trial failed to demonstrate a significant effect on the primary endpoints (VAS score for oral dryness and stimulated whole salivary flow) in the IFN-α group relative to the placebo group. There was a significant increase in unstimulated whole saliva in the patients treated with IFN-α, which correlated positively and significantly with improvement in seven of eight symptoms associated with oral and ocular dryness. No adverse events were observed [7].
In conclusion, no clinical evidence for the efficacy of IFN-á treatment in pSS patients has been shown yet; however, an improvement of unstimulated whole saliva was observed. Further research is needed to objectify the effect of IFN-á on salivary gland tissue.
Anti-CD20 Monoclonal Antibodies
Anti-CD20 (rituximab) is a chimeric humanized monoclonal antibody specific for the B cell surface molecule CD20, which is expressed on the surface of normal and malignant pre-B and mature B lymphocytes. CD20 mediates B cell proliferation and differentiation. This antibody has been demonstrated to prevent B cells from proliferating and to induce lysis of B cells by complement-dependent and antibody-dependent cytotoxicity mechanisms as well as by direct induction of apoptosis [19].
Rituximab is currently used for the treatment of low-grade B cell lymphomas [20]. In controlled studies, it was shown to be safe and effective in the treatment of rheumatoid arthritis [21–23]. Moreover, open-label studies in SLE patients are promising [24].
In an open-label phase II study, 15 patients with pSS were treated with 4 infusions of rituximab (375 mg/m2 once weekly) and followed up for a 3-month period. Eight of the 15 patients were early pSS patients (mean disease duration 28 months, all had residual salivary gland function at baseline), and 7 patients had a concomitant mucosa-associated lymphoid tissue (MALT) lymphoma (mean disease duration 79 months).
In the early pSS patients, rituximab treatment resulted in significant improvement of subjective symptoms and an increase in salivary gland function. All patients showed a rapid depletion of peripheral B cells within a few weeks, accompanied by a decrease in IgM-RF levels [8]. Repeated parotid gland biopsies in five of the early patients after treatment showed redifferentation of the lymphoepithelial duct lesions into normal striated ducts, possibly indicating regeneration of salivary gland tissue (unpublished data).
Five of the eight pSS patients without a MALT lymphoma received a second course of rituximab (after 9–11 months) due to recurrence of symptoms. Retreatment resulted in the same significant improvement of the salivary flow rate and subjective symptoms compared to the results of the first treatment, together with a decrease in B cells and IgM-RF levels.
Six of the seven MALT/pSS patients were initially effectively treated with rituximab. The remaining MALT/pSS patient had progressive MALT disease and severe extraglandular SS disease within 3 months after the start of rituximab treatment. Cyclophosphamide was added, which led to stable disease of both MALT and SS. One of the six patients initially responding had a recurrence of MALT lymphoma after 9 months and was successfully retreated with rituximab. The other patients are still in remission (unpublished data).
In another open-label study, 16 pSS patients received only two weekly rituximab infusions (375 mg/m2), with a follow-up of 36 weeks. Again, treatment resulted in rapid complete depletion of peripheral B cells. At week 12, a significant improvement of VAS scores for fatigue and dryness was recorded, and at week 36, a significant improvement for VAS scores for global disease, fatigue, dry mouth, dry eyes, and dry vagina, but also in the number of tender joint and tender joint counts was seen [25]. Both in the study of Pijpe et al. [8] and the study of Devauchelle-Pensec et al. [25], patients with a short disease duration showed more improvements than patients with longer disease duration.
Two trials retrospectively evaluated the effect of rituximab (four infusions of 375 mg/m2) in 18 pSS patients (mean disease duration 10 years) with systemic features. Self-reported dryness improved in six patients (VAS scores not known for three patients, no improvement in the other nine patients). Both studies reported good efficacy of the treatment on systemic features [26, 27].
In conclusion, in phase II trials, it has been shown that rituximab seems to be effective for at least 6–9 months in pSS patients with active disease, improving both subjective and objective complaints. Retreatment with rituximab resulted in a similar good clinical response. In pSS patients with longer disease duration, without residual salivary gland function, rituximab treatment seems to be effective for systemic features. To confirm these promising results, randomized placebo-controlled clinical trials are needed.
Anti-CD22 Monoclonal Antibodies
Epratuzumab is a fully humanized monoclonal antibody specific for the B cell surface molecule CD22. CD22 is expressed on the surface of normal mature and malignant B lymphocytes. CD22 appears to be involved in the regulation of B cell activation through B cell receptor signaling and cell adhesion [28]. In an open-label phase I/II study, safety and efficacy of epratuzumab were investigated in 16 pSS patients. Follow-up was 6 months. These pSS patients received four doses of 360 mg/m2 epratuzumab intravenously. Mean disease duration before therapy was 2.9 years, and none of the patients had received prior B cell-targeted therapy. Most improvements occurred in the Schirmer test, unstimulated whole salivary flow and the VAS score for fatigue. The new developed disease activity score consisted of the four domains: dryness of the eyes, dryness of the mouth, fatigue, and laboratory parameters. Based on this score, 53% achieved at least 20% improvement in at least two domains at 6 weeks. Corresponding rates for 10, 18, and 32 weeks are 53, 47, and 67%. Remarkably, the number of responders was higher 6 months after the treatment administration than earlier. Peripheral B cells decreased with a median decrease of 54 and 39% at 6 and 18 weeks, respectively.
In conclusion, epratuzumab seems to be an effective treatment. Randomized, placebo-controlled clinical trials are needed before epratuzumab can be advised for general treatment in pSS patients [29].
Anti-BAFF
BAFF is a B cell-activating factor that acts as a positive regulator of B cell function and expansion. BAFF levels were found elevated in serum and saliva in SS patients, but no correlation could be shown between serum and saliva levels [30]. However, circulating levels of BAFF in pSS patients were shown to be a marker for disease activity [11].
To the best of our knowledge, no trials have been performed with anti-BAFF treatment in SS yet, but such an approach might be considered for future trials. Currently, two human BAFF antagonists have been developed, a human antibody (anti-BLyS) that binds to soluble BAFF and a fusion protein of one of the BAFF receptors [31, 32]. Especially, SS patients with elevated BAFF levels, hypergammaglobulinemia, elevated levels of autoantibodies, and associated B cell lymphoma might be candidates for anti-BAFF treatment [33].
Safety and Tolerability of Biological Agents
The most important side effects of treatment with biological agents are direct mild infusion reactions. Several patients developed a serum sickness-like disease a few days after the second infusion that might be related to the formation of antibodies against the biological agent [human anti-chimeric antibodies (HACAs) or human anti-human antibodies]. A few patients developed infections during treatment with a biological agent; however, some patients concomitantly used other immunosuppressive therapies. Therefore, the direct relation between the biological agent and the infection is unsure. All adverse events reported in the trials described in this review are reported in Table 1. According to this table, the most frequent side effects of treatment with biological agents are mild infusion reactions. The most severe side effect of the various treatments used in SS patients was the development of a serum sickness-like disease. This adverse effect of treatment occurred in 16% (8 of 49) of the patients treated with rituximab. HACA formation was observed in patients developing a serum sickness-like disease and occurred only in patients receiving low-dose corticosteroids and no other immunosuppressive drugs. It is assumed that higher doses of corticosteroids during treatment might prevent the occurrence of serum sickness.
Table 1Adverse events after treatment with biological agents in SS Agent/doseNumber of patients in trial (number treated with the agent)Premedication/concomitant immunosuppressive therapyInfusion reactionInfectionsSerum sicknessHACA/HAHA formationOtherAnti-TNF-α monoclonal antibodiesSteinfeld [14]Infliximab intravenous, 3 mg/kg16 (16)n.r./no1 (6%)2 (13%) (respiratory tract)–n.r.–Steinfeld [15]Infliximab intravenous, 3 mg/kg10 (10)n.r./no4 (40%)2 (20%) (enteritis, tonsillitis)–n.r.–Marriette [2]Infliximab intravenous, 5 mg/kg103 (54)n.r./continuation of hydroxychloroquine and corticosteroids (≤15 mg/day)2 (4%)2 (4%) (1 cutaneous, 1 respiratory tract)–n.r.2 (breast cancer, auto-immune hepatitis)aZandbelt [16]Etanercept subcutaneously, 25 mg15 (15)n.r./pilocarpine at a constant dose–1 (7%) (parotitis)–n.r.–Sankar [17]Etanercept subcutaneously, 25 mg28 (14)n.r./allowed to use long-term medication1 (7%)1 (7%) (skin lesion)b–n.r.–IFN-αShip [18]IFN-α oromucosal, 150 IU, 450 IU109 (87)n.r./non.a.––n.r.–cCummins [7]IFN-α oromucosal, 450 IU497 (300)n.r./non.a.–––23 (7.7%)d (34% gastrointestinal, 25% musculoskeletal)Anti-CD20Pijpe [8]Rituximab intravenous, 375 mg/m215 (15)25 mg prednisolon intravenously/patients with severe extraglandular manifestations (n = 3) received immunosuppressive therapy2 (13%)1 (7%) (zoster)4 (27%)e4 (27%)–Devauchelle-Pensec [25]Rituximab intravenous, 375 mg/m216 (16)n.r./no––1 (6%)n.r.–Gottenberg [26]Rituximab intravenous, 375 mg/m26 (6)n.r./hydroxychloroquine (n = 1), methylprednisolone (n = 3)1 (17%)–1 (17%)n.r.–Seror [27]Rituximab intravenous, 375 mg/m212 (12)n.r./cyclophosphamide (n = 1), hydroxychloroquine (n = 1), leflunomide (n = 1)1 (8%)–2 (17%)n.r.–Anti-CD22Steinfeld [29]Epratuzumab intravenous, 360 mg/m216 (16)0.5–1 g acetominophen, 25–50 mg antihistamine./no2 (13%)2 (13%) (sinusitis, dental abscess)–3 (19%)6 (38%) (TIA, osteoporotic fracture, diarrhea, dyspepsia, palpitations, paresthesia)n.a. Not applicable, n.r. not reported, HACA human anti-chimeric antibodies, HAHA human anti-human antibodiesaOne patient in the placebo group developed benign lymph node enlargementbOne patient in the placebo group developed a prolonged upper respiratory tract infectioncIn this study, there were mild adverse events; however, there were no significant differences between the groups. Adverse events were not specified.dEight patients (4.1%) in the placebo group developed adverse eventseOne of these 4 patients developed serum sickness after retreatment [8]
Future Perspectives
Biological agents are promising therapies for SS. Randomized studies failed to show a clinical effect of anti-TNF-α and IFN-α in the treatment of SS. Notwithstanding the unfortunate results of anti-TNF-α and IFN-α, B cell depletion (both anti-CD20 and anti-CD22) seems very promising. Again, this promising effect, as was previously also assumed for anti-TNF-α and IFN-α, must be confirmed in larger randomized controlled clinical trials.
HACAs have been reported to occur at a higher rate in patients with an autoimmune disease. It seems that monoclonal antibodies are more immunogenic in active autoimmune disease, independent of the type of disease. Additional use of immunosuppressive therapy in these patients might be mandatory to prevent serious side effects. These unwanted side effects might also be prevented by the use of fully humanized antibodies. The currently available humanized antibodies are promising, but need further study. Moreover, there is still a need for improved assessment parameters to monitor treatment effects, both subjectively and objectively. For studies on intervention of SS, evaluation of the parotid gland might be of use because function, composition of saliva, and histology can be evaluated on the same gland at different time points. Activity scores are currently under development by Bowman and Vitali [34, 35]. Finally, as soon as effective intervention treatments have been established, the cost-effectiveness of these currently very expensive antibodies needs to be analyzed to select those patients that might benefit the most from this kind of treatment.

biological agent
treatment
sjögren’s syndrome
therapy
autoimmune disease
monoclonal antibody