Key words
musculoskeletal diseases - physical medicine - molecular physical medicine - osteoporosis
- cytokines
Schlüsselwörter
muskuloskelettale Erkrankungen - physikalische Medizin - molekulare physikalische
Medizin - Osteoporose - Zytokine
Physical Medicine in the Context of Rheumatic Diseases
Physical Medicine in the Context of Rheumatic Diseases
Methods of physical medicine have played an invaluable role in the therapeutic concept
of rheumatic diseases far into the second half of the past century – when drug-based
treatments were limited and toxic. Since then, the significance of physical medicine
has unfortunately been outshined by the rapid therapeutic success of new Disease Modifying
Antirheumatic Drugs (DMARDs) and the biologics (so-called “anti-cytokine therapeutics”)
in the past 20 years. Nevertheless, physical medicine plays a still central role in
the multimodal therapy of rheumatic diseases, and is a key component of therapeutic
guidelines [1]
[2]
[3].
According to current data from the German Collaborative Arthritis Centers for the
treatment of rheumatoid arthritis (RA), 35.9% of the patients were in remission while
19.2% had low, 37.1% moderate and 7.8% high levels of disease activity based on the
Disease Activity Score 28 (DAS28) [4]. The remission rate increased by 8–10% only among patients with longer disease durations
in the years 2007–2014 while the rate remained unchanged in disease durations of shorter
than 2 years. Between 51.5–70% light to severe function impairments (Funktionsfragebogen
Hannover– FFbH<75) could also be measured in patients with ankylosing spondylitis
in the years 2007–2014 despite up to late pharmacological treatments [5]. Based on this shortcoming, an early intensification of therapy including physical
therapy modules is fully justified to further reduce the disease activity, and the
overall burden of disease of the affected patients.
Consequences of Disease for Patients with Inflammatory Rheumatic Diseases
Consequences of Disease for Patients with Inflammatory Rheumatic Diseases
The International Classification of Functioning, Disability, and Health (ICF) of the
World Health Organization provide the basis for systematic disease management for
chronic diseases [6]. The ICF bases the classification on an integrative biopsychosocial approach. It
also incorporates, on one hand, function capability and impairment with the components
body functions and structures, activity and participation as well as on the other
hand, context factors with the components environment and personalized factors. Pain
and accompanying musculoskeletal dysfunction frequently cause impairments in the ICF
component daily activities as well as participation in social life [7].
Thus, distinct daily disablements (impairment of function capacity based on the function
score FFbH at 70% or less) are present in 4 out of 10 patients with rheumatoid arthritis
and ankylosing spondylitis whereby nearly half of the patients experience severe functional
impairments (≤ 50% in FFbH) [8]. The function capacity that can be therapeutically modified or compensated by physical
therapy is of key significance for participation in professional life: approximately
50% of patients with inflammatory rheumatic diseases with severe function impairment
from RA or AS receive a disability pension in contrast to only every fifth to tenth
patient with mild function impairment (>70% FFbH) [8].
Current Challenges of Physical Medicine
Current Challenges of Physical Medicine
At present, physical medicine is faced with 2 major challenges: on one hand, it is
no longer necessary to rely solely on tradition and experience but rather to accept
the challenge of modern evidence-based medicine and consequently provide the respective
scientific knowledge and evidence of efficiency. On the other hand, in an era of increasing
budget of simultaneously rising costs of medicine, there is hardly any financial manoeuvring
space so attention must also be paid to economic restrictions.
Molecular physical medicine can definitively contribute to the solution of both of
these tasks. Based on research of the molecular and cellular biological effects of
physical therapy on the human body, the pathophysiological processes identified by
modern immunological basic research and by the comparison of medications, molecular
physical medicine can successfully prove its efficiency as well as deliver the required
scientific evidence [9]
[10].
As the effects of differentially indicative physical therapy treatments, in particular,
on specific mechanisms of the inflammatory occurrences and on immunocompetent cells
are widely unknown, the intervention of physiotherapeutics into this central regulatory
system in rheumatic diseases is exciting and likewise fascinating and presents a large
research field for today as well as the future.
To illustrate the actual interesting and very promising results of this new discipline
of molecular physical medicine for rheumatic symptoms several examples are outlined
below.
Efficiency and Molecular Effects by Thermotherapy
Efficiency and Molecular Effects by Thermotherapy
At the end of the 1970s, initial molecular findings in terms of a pro-inflammatory
effect of prostaglandin stimulation have been associated with cryotherapy [11]. In a pilot study of whole body cryotherapy, a significant decrease in pro-inflammatory
cytokines as well as improvements in activity and function parameters in inflammatory
rheumatic diseases could be objectified [12]. A reduction of prostaglandin E2 and leukotriene B4 due to local heat application
was described [13]. Additional studies could prove that it is possible to influence the cytokine level
with both local thermotherapy and whole body hyperthermia ([Table 1], [14]).
Table 1 Heat application and changes in the cytokine level [overview in 14].
-
Interleukin-1 synthesis is downregulated by light thermal stress.
-
TNF-alpha induced dissolution of WEHI 175 cells is antagonized by hyperthermia.
-
Interleukin-1 activity is increased in skin heated from the lymphatic system.
-
Interleukin-1 production is augmented through whole body hyperthermia in a murine
model (40°C, 60 min).
-
Rises in interleukin-6 levels are achieved with hot paraffin packs.
-
Interleukin-1 is reduced by serial hot mud packs.
-
Immunoglobulin production of mononuclear blood cells is stimulated by mild hyperthermia
in humans.
-
TNF-alpha increases during a spa treatment in an acratotherm in osteoarthritis patients.
|
By now, it could be proven that an intensive local and systemic hyperthermia (target
core temperature >41°C) inherits an immunosuppressive effect whereas a mild, moderate
systemic hyperthermia (target core temperature 38–40°C) induces immunomodulating and
immunostimulating effects [15].
When studying the molecular effects of a mild systemic hyperthermia in rheumatic diseases
in humans, it is of great interest in the era of medicinal biological therapy, directed,
against pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α, whether and how these
cytokines are altered and whether therapy at a cellular and molecular level has an
immunostimulating or anti-inflammatory effect.
Whole Body Hyperthermia by means of Hyperthermal Bath, Water-filtered Infrared A Radiation,
Radon Therapy and Healing Mud Baths
Whole Body Hyperthermia by means of Hyperthermal Bath, Water-filtered Infrared A Radiation,
Radon Therapy and Healing Mud Baths
The mild systemic hyperthermia in the form of a hyperthermal bath has already been
successfully applied as a so-called passive mild whole body hyperthermia in ankylosing
spondylitis (AS) since the end of the 1960s. The systemic application of this therapy
treatment has the advantage that deeper structures such as, e. g. the vertebral column,
can also be reached. When observing empirically the physical medicine, the passive
mild whole body hyperthermia principle appeared to act by muscle detonisation, increase
of blood circulation (hyperperfusion) and analgesic effect. When viewing this from
the perspective of molecular physical medicine, the focus is, however, on underlying
potential cellular and molecular mechanisms.
In an explorative study [16], 12 male AS patients with sole NSAR medication and 12 healthy males of comparable
age underwent a series of passive mild whole body hyperthermia in hyperthermal baths
(a total of 9 applications, target core body temperature 38.5°C). Albeit the analysis
of the peripheral T- and B-lymphocytes – as a correlate to a possible immunostimulation
and the systemic cortisol level as a correlate to a possible hyperthermia induced
stress reaction did not yield significant differences either before or at different
points during and after the serial passive mild whole body hyperthermia. In contrast,
the result of the analysis of the systemic cytokine level was surprising [17]: the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in the AS patients exhibited
significantly reduced serum levels at all measuring times up to 24 h after the last
hyperthermal bath in comparison to the healthy control group. Depending on the cytokine,
the reduction here was between 40–50% of the initial level prior to the serial passive
mild whole body hyperthermia.
In the meantime, improvements at the clinical level (e. g. parameters of activity,
function and, subsequently the functional health) as well as at the molecular level
(pro- and anti-inflammatory cytokines) could be objectified in inflammatory rheumatic
and degenerative diseases in a series of studies on whole body hyperthermia using
a variety of means (water-filtered Infrared A radiation [18]
[19], radon therapy [20], and healing mud baths [21]) in serial application (summary in [Table 2]). At the molecular level, an anti-inflammatory modulation of the cytokine profile
was common in all these studies.
Table 2 Summary of hyperthermia studies with molecular results.
|
Authors
|
Lange U et al. 2014 [18]
|
Lange U et al. 2017 [19]
|
Dischereit G et al. 2014 [20]
|
Dischereit G et al. 2017 [21]
|
Lange U et al. 2016 [24]
|
|
Disease(s)
|
Psoriatic Arthritis (PSA)
|
Ankylosing Spondylitis (AS)
|
Ankylosing Spondylitis(AS), Osteoarthritis (OA)
|
Osteoarthritis (OA of the hip and/or knee)
|
Rheumatoid Arthritis (RA), Osteoarthritis (OA)
|
|
Physical interventions
|
Serial water-filtered infrared A radiation (wIRAR), target body core temperature 38.5–39°C
|
Serial water-filtered infrared A radiation (wIRAR), target body core temperature 38.5–39°C
|
Serial radon hyperthermia in a therapeutic adit (sRH, 12 applications in 3 weeks)
|
Serial mud baths (sMB)
|
Serial radon hyperthermia in a therapeutic adit (sRH, 12 applications in 3 weeks)
|
|
Patients
|
n=15 PSA patients with multimodal physical therapy (MPT) –control group (KG)
n=20 PSA patients with MPT and 6 times wIRAR application in 8 days – intervention
group (IG)
|
n=15 AS patients with MPT – control group (KG)
n=20 AS patients with MPT and 6 times wIRAR application in 8 days – intervention group
(IG)
|
n=24 AS patients
n=24 OA patients
|
n=22 patients with OA and MPT n=18 patients with OA and MPT and sMB (9 applications in 3 weeks)
|
n=25 RA patients
n=24 OA patients
|
|
Observation period
|
Up to 6 months after the last wIRAR application
|
Up to 3 months after the last wIRAR application
|
Up to 3 months after last radon hyperthermia application
|
Clinical parameters up to 3 months after last mud bath
|
Lasting up to 3 months after last sRH application
|
|
Study design
|
Randomized, prospective
|
Randomized, prospective
|
Prospective
|
Randomized, prospective
|
Prospective
|
|
Clinical results
|
IG: significant improvement lasting up to 6 months of pain [VAS] (p<0.04)
HAQ (p<0.01)
DAS28 (p<0.01)
PASI without significant changes
KG: no significant changes of pain, and DAS28. Significant improvement of the HAQ after
3 months vs. baseline (p<0.02)
|
IG: significant improvement lasting up to 3 months of pain [VAS] (p<0.014) BASDAI (p<0.039)
BASFI (p<0.048)
KG: no significant changes of VAS, BASDAI, BASFI
|
AS: significant pain reduction after sRH, lasting up to 3 months (p<0.005, respectively).
Significant improvement of the BASDAI lasting up to 3 months (p<0.003), and the BAS-G
after 3 months (p<0.005)
OA: significant pain reduction after 3 months vs. baseline (p<0.005)
|
OA plus sMB presented right after the last mud bath a significant improvement of the
HAQ (p<0.01) and FFbH (p<0.01), and also a significant reduction of pain lasting up
to 3 months (p<0.01) and significant improvement of the WOMAC lasting up to 3 months
(p<0.037)
|
|
|
Molecular effects
|
IG: stable cytokine profile of TNF-α, IL-1ß, and IL-6
KG: right after wIRAR significant decrease of TNF-α (p<0.01), and after 3 months significant
increase (p<0.008)
|
IG: significant decrease after 3 months vs. baseline of IL-1ß (p<0.02)
TNF-α (p<0.012) KG: no significant changes
|
AS: significant reduction of the RANKL/OPG-ratio (p<0.005)
OA: significant reduction of TNF-α (p<0.0005)
|
Patients with OA and sMB showed a significant reduction of IL-1ß (p<0.001) and a significant increase
of IL-10 (p<0.001)
|
RA: significant reduction of the RANKL/OPG-ratio (p < 0.01), ACPA (p < 0.001), and TNF-
α (p < 0.001) OA: significant reduction of TNF-α (p <0.001)
|
Taken together, the results of these hyperthermia studies illustrate that a mild whole
body hyperthermia clinically induces a notable amelioration of rheumatic symptoms,
reflected by the molecular level. However, different intensities and modalities of
a hyperthermia obviously excert a different effect on various molecular inflammation
mediators as well.
Influence of the Molecular Mechanisms of Bone Metabolism by means of Whole Body Hyperthermia
and Physiotherapy
Influence of the Molecular Mechanisms of Bone Metabolism by means of Whole Body Hyperthermia
and Physiotherapy
In addition to the effects on the proinflammatory cytokines of the immune system,
a whole body hyperthermia also influences additional molecular mechanisms. This includes
the central molecular mechanism of bone metabolism of the RANK/RANKL/OPG system. The
soluble mediator receptor activator of nuclear factor-κB ligand (RANKL) which is primarily secreted from mesenchymal cells and osteoblasts mediates
an activation of the osteoclasts or differentiation of the osteoclast progenitors
via binding to the membrane-bound receptor RANK, which is expressed on osteoclasts
and their progenitor cells and thereby transmits the stimulation of the bone resorption.
The activating effect of RANKL is counterbalanced by osteoprotegerin (OPG), in which
OPG as soluble receptor without a signaling effect (so-called decoy receptor) competitively binds and thereby inactivates RANKL. It could be shown that an increase
of the RANKL/OPG ratio in the serum induces a measurable imbalance in the RANK/RANKL/OPG
system which is crucial in both primary as well as secondary osteoporosis.
Inflammation-induced secondary osteoporosis is separated in an increased production
and release of RANKL via activated inflammatory and immune cells. In this process,
RANKL represents a central osteoimmunological link in inflammatory rheumatic diseases
which has been confirmed by animal models of RA and spondyloarthritides on the basis
of an increase in the RANKL/OPG ratio in osteodestructive phases.
In the meantime, studies on AS [20]
[22]
[23] and osteoarthritis [23] using serial radon therapy – whole body hyperthermia (radon adit in Bad Gastein-Böckstein,
Austria) using could shown that molecular mechanisms of inflammation induced osteoporosis
are downregulated, along with molecular mechanisms of the underlying inflammation.
Among other parameters, the patients with AS displayed a significant decrease in the
RANKL/OPG ratio by shifting the molecular mechanisms of the bone metabolism to an
osteoanabolic state.
Similar results could also be achieved in patients with rheumatoid arthritis (RA)
[24]. Here, a significant reduction of the anti-CCP antibody level was also achieved.
Based on the fact that the anti-CCP antibodies correlate with bone destruction in
RA and anti-CCP antibodies directly induce the osteoclastogenesis and bone resorption
via adaptive immune system and bone resorption, an additional osteoprotective mechanism
at the molecular level can therefore be postulated.
When summarizing the effects on different patient cohorts, it can be hypothesized
that a serial radon and whole body hyperthermia therapy reduces the systemic RANKL
secretion of, amongst others, the T-cells. Consistent with this, the significant decrease
in the TNF-α serum level can also be interpreted as a reduced expression via T-cells
and other immune cells.
Moreover, in a randomized study applying a once weekly standardized training program
with an intervention group with consistent axial bone density values, not only a significant
functional improvement and reduction in pain but also a significant increase in bone
density on the right femoral neck in osteoporosis could be prospectively achieved
over 2 years. A significant reduction of the bone resorption marker crosslaps and
a significant increase of the bone formation marker osteocalcin could also been seen
as a molecular correlate of this osteoanabolic results [25].
In another short study [26] of 20 patients with spondyloarthritis and an indication for a cost-intensive TNF-blockade
therapy, a strong economic effect was successfully rendered for the first time through
regular physiotherapy over 4 months and a follow-up of 6 months. In this study, the
patients received etanercept at half of the standard dose combined with intensive
physiotherapy (3×45 min sessions per week). By this, a 40% improvement could be seen
in 50% of the patients after 4 months of treatment according to the criteria of the
Assessment of SpondyloArthritis Group (ASAS 40 response). The efficiency of etanercept
in a full dose resulted in an ASAS 40 response of 42% only after 6 months. From socioeconomic
aspects, considering the German market prices, a total cost saving of ca. 76000 €
could be achieved with the combination therapy – in comparison to the full biologic
therapy – in this study. The results indicate also that adequate physiotherapy has
a substantial positive influence on the cytokine-transmitted disease mechanisms.
Conclusions for the Practice
Conclusions for the Practice
-
Methods of molecular medicine facilitate the analysis of central messenger molecules
of inflammatory processes – which, among other factors, are critical for the interaction
between cells of the immune systems and bone cells.
-
Physiotherapeutical measures cause significant effects on inflammatory processes and
bone metabolism, which correlate to clinical parameters.
-
The available results provide explanations for the physiotherapeutical modes of action
at the molecular level. As a result, this moves physical medicine from an empirical,
deductive discipline to an evidence-based discipline.
-
The previous studies of molecular physical medicine emphasize the necessity of physical
treatment measures in a multi-mode treatment plan for rheumatic diseases.
-
Molecular physical medicine is economic and potentially cost saving reducing the costs
of expensive pharmacological therapy.
