German evidence-based guidelines for the treatment of Psoriasis vulgaris (short version)

Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1–S126, 2006; or http://www.psoriasis-leitlinie.de).
Introduction
The Deutsche Dermatologische Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the treatment of plaque psoriasis. The full version of the Guidelines has been published in the Journal der Deutschen Dermatologischen Gesellschaft (JDDG 2006 Suppl 2) and is available at http://www.psoriasis-leitlinie.de [149]. This article summarizes the key points of the Guidelines.
Background
Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries is 1.5–2% [2]. Studies on the impairment of life quality have shown that, depending on the severity of the disease, a significant burden may exist in the form of a disability or psychosocial stigmatization [3]. Patient surveys have shown that the mental and physical impairment associated with psoriasis is comparable to that of other significant chronic conditions, such as type 2 diabetes or chronic respiratory diseases [4].
Patient surveys have shown that only 25% of psoriasis patients are highly satisfied with the outcome of their treatment, another 50% indicate moderate satisfaction, and approximately 20% report low treatment satisfaction [5]. In addition, there is a high non-compliance rate in the intake of medication of up to 40% [1].
Experience has shown that treatment selection for patients with psoriasis vulgaris is more commonly based on traditional concepts than on evidence-based data on the efficacy of various therapeutic options. In addition, it appears that systemic therapies are occasionally not applied in situations where they are needed due to the increased effort involved in monitoring the patients for unwanted side effects and possible interactions with other drugs.
Goal of the Guidelines
The overall objective of the Guidelines is to provide dermatologists in clinics and private practice with an accepted and evidence-based decision-making tool for the selection and implementation of a suitable and efficacious treatment for patients with psoriasis vulgaris. The focus of the Guidelines is on the induction therapy of mild, moderate, and severe plaque-type psoriasis in adults.Physicians’ personal experiences and traditional therapeutic concepts should be supplemented and, if necessary, replaced by an evidence-based assessment of the efficacy of individual therapies in psoriasis vulgaris.The guidelines provide in-depth explanations of the available systemic and topical treatments for psoriasis, including the different photo- and photochemical therapies, and provide detailed descriptions of the administration and safety aspects.By providing background information on the profile of the available drugs, including efficacy, safety, and aspects of practicality and costs, the Guidelines should facilitate the process of selecting an appropriate treatment for each individual patient. This should help increase compliance and optimize the benefit/risk ratio of psoriasis therapies.
Methods
A detailed description of the methodology employed in developing the Guidelines can be found in the Method Report on the Guidelines (http://www.psoriasis-leitlinie.de).
Basis of data
A systematic search of the literature was carried out in May 2005 with the objective of assessing the effectiveness of individual therapeutic options. This search yielded 6,224 publications of which 142 studies fulfilled the inclusion criteria for the Guidelines (see Box 1) and were therefore included in the assessment of the effectiveness of the relevant treatment. Various other aspects were evaluated on the basis of information presented in available literature, without a systematic analysis, and the years of personal experience of the experts.
Evidence assessment
The efficacy and effectiveness of each intervention was evaluated using evidence-based criteria.
The methodological quality of each individual study was assessed using the following grades of evidence (GE):A1Meta-analysis that includes at least one randomized study with grade A2 evidence. In addition, the results of the different studies included in the meta-analysis must be consistent with one another.A2A high-quality (e.g. sample-size calculation, flow chart, intention-to-treat (ITT) analysis, sufficient size) randomized, double-blind comparative clinical study.BRandomized clinical study of lesser quality or other comparative study (non-randomized, cohort, or case-control study).CNon-comparative study.DExpert opinion.Individual interventions (i.e., as monotherapy) were rated according to the following levels of evidence (LE):Intervention is supported by studies with grade A1 evidence or studies with grade A2 evidence whose results are predominantly consistent with one another.Intervention is supported by studies with grade A2 evidence or studies with grade B evidence whose results are predominantly consistent with one another.Intervention is supported by studies with grade B evidence or studies with grade C evidence whose results are predominantly consistent with one another.Little or no systematic empirical evidence
Therapeutic recommendation
A distinct rating of the therapeutic options or a strict clinical algorithm cannot be defined for the treatment of psoriasis vulgaris. The criteria for selecting a particular therapy are complex. The decision for a specific treatment should be based on the profile of the available drugs and the characteristics of a given patient. The decision for or against a therapy remains a case-by-case decision. These Guidelines provide a reasonable form of assistance in deciding on a suitable therapy and are an instrument for optimizing the required therapeutic process.
The recommendations formulated in the text are supported graphically in selected key recommendations by the following indications of the strength of the therapeutic recommendation:↑↑Measure is highly recommended↑Measure is recommended→Neutral↓Measure is not recommended↓↓Measure is highly inadvisableThe strength of the recommendation reflects both a treatment’s efficacy and the level of evidence supporting it as well as aspects of safety, practicality, and the cost/benefit ratio. A consensus on the strength of the recommendation was reached during the Consensus Conference.
Results
Therapeutic options are named and discussed in alphabetical order.
Therapeutic strategies
Fig. 1
Overview of the therapeutic options evaluated for chronic plaque psoriasis (the therapeutic options are listed alphabetically and do not represent a ranking)
Evaluation of topical and systemic therapies in tabular form
These tables are intended to provide a rough orientation for evaluating the therapeutic options. Cumulative calculations of the individual aspects for the overall evaluation of the therapeutic options are not possible and cannot be drawn upon for the final analysis of a therapeutic option. The product assessment for each individual patient may deviate greatly. A direct comparison between systemic and topical therapies is not possible because of the different severity of the psoriasis lesions of patients treated with topical or systemic treatments. The evaluations reported here were made on the basis of data extracted from the literature and expert opinions.
For further details refer to the Methods Report at www.psoriasis-leitlinie.de
Topical monotherapy
Phototherapy and systemic monotherapy
(a) Efficacy The evaluation of the efficacy column reflects the percentage of patients who achieved a reduction in the baseline Psoriasis Area and Severity Index (PASI) of ≥75%.
ScaleSystemic therapyTopical therapy++++Approx. 90%Approx. 60%+++Approx. 70%Approx. 45%++Approx. 50%Approx. 30%+Approx. 30%Approx. 15%+/−Approx. 10%Approx. 5%–Not definedNot defined
The evidence level applies only to the estimate of efficacy.
(b) Safety/tolerance in induction therapy or maintenance therapy This refers to the risk of occurrence of severe adverse drug reactions or the probability of adverse drug reactions that would result in the discontinuation of therapy.
(c) Practicality (Patient) This evaluation analyzes the effort involved in handling and administrating the treatment regimen by the patient.
(d) Practicality (Physician) This aspect considers the amount of work (documentation, explanation, monitoring), personnel and equipment needs, time for physician/patient interaction, remuneration of therapeutic measures, invoicing difficulties/risk of recourse claims from the health insurance companies.
(e) Cost/benefit Consideration of the costs of an induction therapy or a maintenance therapy.
The evaluations of safety/tolerance in induction therapy or maintenance therapy as well as practicality for the physician or patient and the cost/benefit were performed using a scale ranging from poor (–) to good (++++). The gradation between these two extremes was made based on expert opinion and unsystematic literature search. A level of evidence was not given for these evaluations since no systematic literature review was performed.
Evaluation of topical therapies
Calcineurin inhibitors
Table 1
Tabular summary
Calcineurin inhibitors
First approved in Germany
 Pimecrolimus (Elidel®)
2002 (Atopic dermatitis, not approved for psoriasis vulgaris)
 Tacrolimus (Protopic®)
2002 (Atopic dermatitis, not approved for psoriasis vulgaris)
Recommended initial dosage
Pimecrolimus cream: 1× to 2× dailyTacrolimus: 1× to 2× daily (application on the face: Begin with 0.03% salve; increase later dosage to 0.1% salve)
Recommended maintenance dosage
Individual therapeutic adjustment
Expected beginning of clinical effect
After approximately 2 weeks
Response rate
No data available
Important contraindications
Pregnancy and nursing (due to lack of experience) skin infections, immune suppression
Important adverse drug reactions (ADRs)
Burning sensation on skin, skin infections
Important drug interactions
None known
Other
Cave: Do not combine with phototherapy! Photoprotection!
Corticosteroids
Table 2
Tabular summary
Corticosteroids
First approved in Germany
1956 (Psoriasis vulgaris)
Recommended control parameters
None
Recommended initial dosage
One to two times daily
Recommended maintenance dosage
Gradual reduction following onset of effect
Expected beginning of clinical effect
After 1–2 weeks
Response rate
Betamethasone dipropionate, two times daily: marked improvement or clearance of the skin lesions in 46–56% patients after 4 weeks (LE 1)
Important contraindications
Skin infections, rosacea, perioral dermatitis
Important ADRs
Skin infections, perioral dermatitis, skin atrophy, hypertrichosis, striae
Important drug interactions
None
Other
–
Coal tar
Table 3
Tabular summary
Coal tar
First approved in Germany
Listed active ingredient since 2000 (DAC on page 170), historical application, various tar-containing externals are licensed as drugs, application of tar as anti-psoriatic following publication by Goeckermann in 1925
Recommended control parameters
After long-term application/application on large areas: if needed clinical controls for potential development of skin carcinoma
Recommended initial dosage
5–20% salve preparations or gels for local therapy, 1× daily
Recommended maintenance dosage
No long-term application (max. 4 weeks, DAC 2000)
Expected beginning of clinical effect
After 4–8 weeks, efficacy improves in combination with UV application
Response rate
There is insufficient data available on the response rate as a monotherapy (LE 4)
Important contraindications
Pregnancy and nursing
Important ADRs
Color, odor, carcinogenic risk, phototoxicity—which is part of the desired effect
Important drug interactions
Not known with topical use
Other
DAC 2000 (on page 170), Hazardous Goods Directive Appendix 4 No. 13
Dithranol
Table 4
Tabular summary
Dithranol
First approved in Germany
Psoralon
1983 (Psoriasis vulgaris)
Psoradexan
1994 (Psoriasis vulgaris)
Micanol
1997 (Psoriasis vulgaris)
Recommended control parameters
Intensity of irritation
Recommended initial dosage
Begin with 0.5% preparation for long-term therapy or 1% for short-contact therapy, then increase if tolerated
Recommended maintenance dosage
Not recommended for maintenance therapy
Expected beginning of clinical effect
After 2–3 weeks
Response rate
Marked improvement or clearance of skin lesions in 30–50% of the patients (LE 2)
Important contraindications
Acute, erythrodermic forms of psoriasis vulgaris; pustular psoriasis
Important ADRs
Burning and reddening of the skin in >10%
Important drug interactions
–
Other
–
Tazarotene
Table 5
Tabular summary
Tazarotene
First approved in Germany
1997 (psoriasis vulgaris)
Recommended control parameters
Check development of skin irritations
Recommended initial dosage
Begin with one treatment daily of tazarotene gel 0.05% in the evening for approximately 1–2 weeks
Recommended maintenance dosage
If necessary continue for 1–2 weeks with tazarotene gel 0.1%
Expected beginning of clinical effect
After 1–2 weeks
Response rate
After 12 weeks therapy with 0.1% tazarotene gel improved findings of at least 50% in approximately 50% of the patients (LE 2)
Important contraindications
Pregnancy, nursing
Important ADRs
Pruritus, burning sensation of skin, erythema, irritation
Important drug interactions
Avoid concomitant use of preparations with irritating and drying properties
Other
–
Vitamin D3 and analogues
Table 6
Tabular summary
Vitamin D3 and analogues
First approved in Germany
 Calcipotriol
1992 (Psoriasis vulgaris)
 Tacalcitol
1994 (Psoriasis vulgaris)
 Calcitriol
1999 (Psoriasis vulgaris)
 Calcipotriol/Betamethasone
2002 (Psoriasis vulgaris)
Recommended control parameters
Monitor for skin irritations
Recommended initial dosage
Calcipotriol: 1× to 2× daily to affected locations, up to a maximum of 30% of the body surface
Tacalcitol: 1× daily to affected locations, up to a maximum of 20% of the body surface
Calcitriol: 2× daily to affected locations, up to a maximum of 35% of the body surface
Recommended maintenance dosage
Calcipotriol: 1× to 2× daily, up to 100 g/week for up to 1 year
Tacalcitol: 1× daily for 8 weeks, for up to 18 months, on a maximum of 15% of the body surface with up to 3.5 g daily
Calcitriol: insufficient experience with the application for more than 6 weeks
Expected beginning of clinical effect
After 1–2 weeks
Response rate
Between 30 and 50% of the patients demonstrated a marked improvement or clearance of the lesions after 4–6 weeks (LE 1)
Important contraindications
Diseases with abnormal calcium metabolism, severe liver and renal diseases
Important ADRs
Skin irritation (reddening, itching, burning)
Important drug interactions
Drugs which elevate the calcium levels, (e.g. thiazide diuretics), no concomitant application of topical salicylic acid preparations (inactivation)
Other
Exposure to UV light results in inactivation of the vitamin D3-analogues
Phototherapy
Table 7
Tabular summary
Phototherapy
First approved in Germany
Clinical experience, depending on the modality for >50 years
Recommended control parameters
Regular skin inspection (UV erythema)
Recommended initial dosage
Individual dose depends on skin type; options:
• UVB: 70% of minimum erythema dose (MED)
• Oral PUVA (photochemotherapy): 75% of the minimum phototoxic dose (MPD)
• Bath/cream PUVA: 20–30% of MPD
Recommended maintenance dosage
Increase according to degree of UV erythema
Expected beginning of clinical effect
After 1–2 weeks
Response rate
In >75% of the patients PASI, 75 after 4–6 weeks (LE 2)
Important contraindications
Photo-dermatoses/photosensitive diseases, skin malignancies, immunosuppressionOnly PUVA: pregnancy and nursing
Important ADRs
Erythema, itching, blistering, malignanciesOnly oral PUVA: nausea
Important drug interactions
Drugs causing phototoxicity or photoallergy
Other
Combination with topical preparations acts synergistically, PUVA may not be combined with cyclosporine
Evaluation of systemic therapies
Efalizumab
Table 8
Tabular summary
Efalizumab
First approved in Germany
September 2004 (psoriasis vulgaris)
Recommended control parameters
Prior to therapy exclusion of significant infections, complete blood count, liver values
Recommended initial dosage
0.7 mg/kg body weight (BW) per week
Recommended maintenance dosage
1 mg/kg BW per week
Expected beginning of clinical effect
After 4–8 weeks
Response rate
PASI 75 for approximately 30% of the patients after 12 weeks (LE 1)
Important contraindications (limited selection)
Chronic or acute infections, pregnancy, malignant diseases, immune deficiencies, no vaccinations before or during treatment
Important ADRs (limited selection)
Flu-like injection reactions, leukocytosis and lymphocytosis, rebound, exacerbation and arthralgia, thrombocytopenia
Important drug interactions
Not known
Other
Stop therapy due to the risk of exacerbation and rebound if a PASI reduction of 50% is not achieved after 12 weeks
Table 9
Laboratory controls during treatment with efalizumab
aHb (hemoglobin), HCT (hematocrit), erythrocytes, leukocytes, differential blood count, platelets
bALT alanine aminotransferase, AST aspartate aminotransferase
Etanercept
Table 10
Tabular summary
Etanercept
First approved in Germany
2002 (Psoriasis arthritis )/2004 (psoriasis vulgaris)
Recommended control parameters
Prior to therapy exclusion of tuberculosis, complete blood count, liver and renal values, urinanalysis
Recommended initial dosage
Twice 25 mg per week or 2× 50 mg/week
Recommended maintenance dosage
Twice 25 mg per week
Expected beginning of clinical effect
After 4–8 weeks, at the latest after 12 weeks
Response rate
PASI 75 in 34% (2 × 25 mg) or 49% (2 × 50 mg) of the patients at the end of the induction phase (12 weeks) (LE 1)
Important contraindications (limited selection)
Infections, pregnancy, nursing, heart failure NYHA III–IV
Important ADRs (limited selection)
Local reactions, infections
Important drug interactions (limited selection)
Anakinra (IL-1 receptor antagonist)
Other
–
Table 11
Laboratory controls during treatment with etanercept
Infliximab
Table 12
Tabular summary
Infliximab
First approved in Germany
2004 (Psoriasis arthritis)/2005 (psoriasis vulgaris)
Recommended control parameters
Prior to therapy exclusion of tuberculosis, during therapy: leukocyte and platelet counts, liver value controls, signs of clinical infection
Recommended initial dosage
5 mg/kg BW at week 0, 2, 6
Recommended maintenance dosage
5 mg/kg BW in dosage intervals of 8 weeks
Expected beginning of clinical effect
After 1–2 weeks
Response rate
PASI 75 in ≥80% of the patients with moderate to severe psoriasis vulgaris (LE 1)
Important contraindications (limited selection)
Acute or chronic infections, tuberculosis, cardiac failure NYHA III–IV, pregnancy and nursing
Important ADRs (limited selection)
Infusion reactions, severe infections, progression of heart failure NYHA III–IV, very rare liver failure, autoimmune phenomena
Important drug interactions (limited selection)
Anakinra (IL-1 receptor antagonist)
Other
–
Table 13
Laboratory controls during treatment with infliximab
aHb, HCT, erythrocytes, leukocytes, differential blood count, platelets
Cyclosporine
Table 14
Tabular summary
Cyclosporine
First approved in Germany
1983 (Transplantation medicine)
1993 (Psoriasis vulgaris)
Recommended control parameters
Interview/examination:
• Status of skin and mucous membranes
• Signs of infection
• Neurological, gastrointestinal symptoms
• Blood pressure
Laboratory controls: see Table 14
Recommended initial dosage
2.5–3 (max. 5) mg/kg BW
Recommended maintenance dosage
Interval therapy (between 8 and 16 weeks) with dosage reduction at the end of the induction therapy (e.g., 0.5 mg/kg BW every 14 days) or
Continuous long-term therapy with dosage reduction (e.g. by 50 mg every 4 weeks after week 12) and a dosage increase by 50 mg with relapse
Maximum total duration of therapy: 2 years
Expected beginning of clinical effect
After approximately 4 weeks
Response rate
Dose-dependent: after 8–16 weeks with 3 mg/kg BW; PASI 90 in approximately 30–50% of patient and PASI 75 in approximately 50–70% of patients (LE 1)
Important contraindications (limited selection)
Absolute:
Reduced renal function, insufficiently controlled arterial hypertension, uncontrolled infections, relevant malignancies (current or previous, in particular hematologic diseases and cutaneous malignancies with the exception of basal cell carcinoma)
Relative:
Relevant hepatic dysfunction, pregnancy and nursing, concomitant use of substance which interacts with cyclosporine, concomitant UV-therapy or prior PUVA-pre-therapy with cumulative dosage >1000 J/cm², concomitant application of other immunosuppressives, retinoids or long-term prior-therapy with methotrexate (MTX)
Important ADRs (limited selection)
Renal failure, increase of blood pressure, liver failure, nausea, anorexia, vomiting, diarrhea, hypertrichosis, gingival hyperplasia, tremor, weariness, parasthesia, hyperlipidemia
Important drug interactions (limited selection)
Increase of the cyclosporine level (CYP3A inhibition) through:
Allopurinol, calcium antagonists, amiodarone, antibiotics (macrolides, clarithromycin, josamycin, ponsinomycin, pristinamycin, doxycycline, gentamicin, tobramycin, ticarcillin, quinolones), ketoconazole, oral contraceptives, methylprednisolone (high dosages), ranitidine, cimetidine, grapefruit juice
Decrease of the cyclosporine level (CYP3A induction) through: Carbamazepine, phenytoin, barbiturates, metamizole, St. John’s wort
Possible reinforcement of nephrotoxic adverse drug reactions through: Aminoglycosides, amphotericin B, ciprofloxacin, acyclovir, non-steroidal antiphlogistics
Specific interactions:
Potassium-saving substances: increased risk of hyperpotassemia
Reduced clearance of: Digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (e.g. lovastatin), diclofenac
Other
Increased risk of lympho-proliferative diseases in transplant patients. Increased risk of squamous cell carcinoma in psoriasis patients following excessive phototherapy.
Only moderately effective in and not approved for psoriatic arthritis
Also used successfully in the therapy of chronic-inflammatory diseases in children
Table 15
Laboratory controls during treatment with cyclosporine
aErythrocytes, leukocytes, platelets
bALT, AST, AP (alkaline phosphatase), γGT (gamma glutamyl transpeptidase), bilirubin
cSodium, potassium
dRecommended twice (fasting) and week-2 and 0
eOnly with indication (e.g. muscle cramps)
Fumaric acid esters
Table 16
Tabular summary
Fumaric acid esters
First approved in Germany
1995 (Psoriasis vulgaris)
Recommended control parameters
Serum creatinine, transaminases/γGT, complete blood count including differential blood count, urinanalysis
Recommended initial dosage
According to recommended dosage regimen see Table 17
Recommended maintenance dosage
Individually adapted dosage
Expected beginning of clinical effect
After approximately 6 weeks
Response rate
PASI 75 in 50–70% of the patients at the end of the induction phase after 16 weeks (LE 2)
Important contraindications (limited selection)
Chronic diseases of the gastrointestinal tract and/or the kidneys and chronic diseases, which are accompanied by an impairment of the leukocyte count or functions, malignant diseases, pregnancy and nursing
Important ADRs (limited selection)
Gastrointestinal complaints, flush, lymphopenia, eosinophilia
Important drug interactions
None known
Other
–
Table 17
Dosage regimen for Fumaderm therapy
Fumaderm initial
Fumaderm
Week 1
1-0-0
Week 2
1-0-1
Week 3
1-1-1
Week 4
1-0-0
Week 5
1-0-1
Week 6
1-1-1
Week 7
2-1-1
Week 8
2-1-2
Week 9
2-2-2
Table 18
Laboratory controls during treatment with fumaric acid esters
aLeukocytes, platelets, erythrocytes, differential blood count
Methotrexate
Table 19
Tabular summary
Methotrexate
First approved in Germany
 Lantarel®
1991 (Psoriasis vulgaris)
 Metex® 7.5/10 mg
1992 (Psoriasis vulgaris)
 Metex® 2.5 mg
2004 (Psoriasis vulgaris)
Recommended control parameters
Complete blood count (Hb, HCT, differential blood count, platelets), renal function (serum creatinine, urea, urine sediment), liver values (serum transaminases), III-procollagen amino terminal propeptides
Recommended initial dosage
5–15 mg per week
Recommended maintenance dosage
5–22.5 mg per week depending on effect
Expected beginning of clinical effect
After 4–8 weeks
Response rate
PASI 75 in approximately 60% of the patients at the end of the induction phase of 16 weeks (LE 3)
Important contraindications (limited selection)
Absolute contraindications:
Desire to have children (for both men and women), pregnancy and nursing, inadequate contraception, drug consumption, alcoholism, known sensitivity to active ingredient methotrexate (e.g. pulmonary toxicity), bone marrow dysfunction, severe liver disease, severe infections, immunodeficiency, active peptic ulcers, hematologic changes (leucopenia, thrombocytopenia, anemia), renal failure
Relative contraindications:
Kidney disorders, liver disorders, history of arsenic consumption , chronic congestive cardio-myopathy, adiposity, old age, diabetes mellitus, history of hepatitis, lack of patient compliance, ulcerative colitis, diarrhea, NSAID use, gastritis
Important ADRs (limited selection)
Liver fibrosis/cirrhosis, pneumonia/alveolitis, bone marrow depression, renal damage, alopecia (reversible), nausea, weariness, vomiting, elevated transaminases, infection, gastrointestinal ulcerations, nephrotoxicity
Important drug interactions (limited selection)
Cyclosporine, salicylates, sulfonamides, probenecide, penicillin, colchicin, NSAIDs (naproxene, ibuprofene, etc.), ethanol, co-trimoxazole, pyrimethamine, chloramphenicol, sulfonamides, prostaglandin synthesis inhibitors, cytostatics, probenecide, barbiturates, phenytoin, retinoids, sulfonamides, sulfonylurea, tetracyclines, co-trimoxazol, chloramphenicol, dipyridamole, retinoids, ethanol, leflunomide
Other
Consistent avoidance of alcohol, X-ray of the lungs prior to beginning therapy
Table 20
Laboratory controls during treatment with MTX [137]
aHb, HCT, erythrocytes, leukocytes, differential blood count, platelets
bALT, AST, AP, γGT, albumin, bilirubin, lactate dehydrogenase (LDH)
cLiver biopsy instead of a liver sonography in risk groups
Retinoids
Table 21
Tabular summary
Acitretin
First approved in Germany
1992 (Psoriasis vulgaris)
Recommended control parameters
Erythrocyte sedimentation rate (ESR), complete blood count, liver values, renal values, blood lipid values, pregnancy test, x-ray control of the bones in case of long-term therapy
Recommended initial dosage
0.3–0.5 mg/kg BW per day for approximately 4 weeks, then 0.5–0.8 mg/kg BW
Recommended maintenance dosage
Individual dosaging dependent on the results and tolerance
Expected beginning of clinical effect
After 4–8 weeks
Response rate
Widely variable and dose-dependent, no definite statement possible, partial remission (PASI 75) in 25–75% of the patients (30–40 mg per day) (LE 3) in studies
Important contraindications (limited selection)
Renal and liver damage, desire to have children in female patients of child-bearing age, pregnancy, nursing, alcohol abuse, manifest diabetes mellitus, wearing of contact lenses, history of pancreatitis, hyperlipidemia requiring drug treatment
Important ADRs (limited selection)
Hypervitaminosis A (e.g., cheilitis, xerosis, nose-bleeding, alopecia, increased skin fragility)
Important drug interactions (limited selection)
Phenytoin, tetracyclines, methotrexate, alcohol, mini-pill
Other
Contraception up to 2 years after discontinuation in female patients of child-bearing age
aDouble contraception is recommended (e.g., condom + pill; IUD/Nuva-Ring + pill; cave: no low-dosed progesterone preparations/mini-pills) during and up to 2 years after the end of therapy; effectiveness is reduced by acitretin
Table 22
Laboratory controls during treatment with Acitretin
aHb, HCT, leukocytes, platelets
bPreferably assayed twice (week-2 and 0); HDL, high-density lipidoprotein
Other therapies
Climate/balneotherapy
Table 23
Tabular summary
Climate/balneotherapy
First approved in Germany
Clinical experience with balneotherapy has existed for more than 200 years
Recommended control parameters
Regular skin inspection
Recommended initial dosage
Therapy regimens vary depending on the institution/location
Recommended maintenance dosage
Therapy regimens vary depending on the institution/location
Expected beginning of clinical effect
Varies greatly
Response rate
Varies greatly (LE 4)
Important contraindications
Dependent on modality selected
Important ADRs
Dependent on modality selected
Important drug interactions
Not applicable
Other
Balneotherapy and climate therapy are frequently combined
Psychosocial therapy
Notes on the use of the Guidelines
The presentation of the therapies deliberately focused on those aspects deemed particularly relevant by a panel of experts. Aspects which are not of specific importance for a certain intervention, but which are part of the physician’s general obligations to the patient, such as the investigation of intolerance and allergies toward certain drugs or the exclusion of contraindications, are not individually listed, but it is nevertheless taken for granted that these are part of the physician’s duty to provide care.
It is recommended that each and every user carefully reads and follows the product information and compare it with the recommendations in the Guidelines on dosaging, contraindications, and drug interactions for completeness and currentness. Every dose or application is administered at the user’s own risk. The authors and the publishers kindly request that users inform them of any inaccuracies that they might notice. The users are requested to keep themselves constantly informed of any new findings subsequent to the publication of the Guidelines.

evidence-based guidelines
treatment
psoriasis vulgaris


Testicular cancer: a longitudinal pilot study on stress response symptoms and quality of life in couples before and after chemotherapy

Goals of work The current study was designed to longitudinally examine stress response symptoms (SRS) and quality of life (QoL) in couples confronted with disseminated testicular cancer. The objectives were to examine couples’ patterns of adjustment over time and possible differences in adjustment between the patient and his partner.
Introduction
Testicular cancer is a rare disease, although it is the most common tumor in men aged 20–35 years. About 500 new cases are diagnosed each year in The Netherlands [1]. Testicular cancer is distinguished into seminomas and nonseminomas, and each type accounts for about half of the total. Half of the men with nonseminoma are diagnosed with disseminated disease that is treated with chemotherapy [2]. Since the introduction of cisplatin-based chemotherapy in the late 1970s, up to 80% of the patients with disseminated disease can be cured [3–5].
Chemotherapy for testicular cancer has several acute physical side effects like nausea, fatigue, and neuropathy [6]. On a psychological level, patients receiving chemotherapy have been found to report anxiety, depression, and distress [7–10]. The partners of testicular cancer patients receiving chemotherapy may encounter adverse sequelae as well. Partners have to struggle with the fear of potentially losing their significant other. Partners are the primary source of information for family members and friends while their husbands are admitted to the hospital. In addition to this social task, partners often take on the caregiver role between chemotherapy cycles. Caregiving for cancer patients was found to negatively impact a caregiver’s physical and mental health [11–13].
The impact of testicular cancer on younger couples might differ from the impact on couples who face cancer at an older age. The young couples confronted with testicular cancer might not have been together for a substantial period of time. This can make the relationship more vulnerable to the stressors induced by major life events. Earlier studies have shown that relationships of shorter duration are more sensitive to disruption after a testicular cancer diagnosis [14, 15], although another study did not find such a connection [16]. Also, couples are confronted with possible treatment-related infertility and sexual difficulties at a time in life where partners are often focused on starting a family. Couples may face several individual and dyadic stressors after the diagnosis of testicular cancer, leading to the experience of distress and lowered quality of life (QoL). This is particularly true when chemotherapy is part of the treatment protocol, as it is a more demanding treatment modality than surgery alone in the case of testicular cancer.
Several prospective studies focused on dyadic adjustment and functioning from cancer diagnosis in a variety of sites, up to 1 1/2 years later [17–20]. Although both patients and partners were reported to suffer from distress, levels of distress did not necessarily correspond within couples. Different patterns of distress and adjustment were found to be associated with gender and health status. Some studies reported that female partners were most vulnerable because they reported higher levels of distress than female and male patients and male partners [20–22].
One pilot study examined the course of distress and QoL in testicular cancer patients before, during, and after chemotherapy (complete data on ten patients). Patients reported highest levels of distress shortly before the start of chemotherapy. Distress and anxiety decreased over time [23]. Another recent prospective study on a large group of testicular cancer patients receiving chemotherapy focused on global QoL during the first 2 years after diagnosis. A considerable impairment in global QoL was found after 3 months. However, after 2 years 36% of patients reported improved functioning compared to baseline [24]. At the University Medical Center Groningen (UMCG) in The Netherlands, a tertiairy referral center for patients with testicular cancer, and at the University of Texas M. D. Anderson Cancer Center, USA considerable institutional research was done into epidemiology, short- and long-term medical, and sexual outcomes of testicular cancer [25–28]. These cross-sectional and retrospective studies were done on QoL of testicular survivors [29], their partners [30], and marital and sexual satisfaction [16, 31–33]. We chose to expand these findings by performing a prospective study, and the findings of Trask and Fossa by including partners in our prospective study. Patterns of stress response symptoms (SRS) and QoL of patients and partners were examined at three time points during the first year. SRS can occur after a range of traumatic events, including cancer. They involve intrusive thoughts and avoidance of thoughts and situations that remind them of the event, and are often studied in cancer patients [34]. Goals of the present study were: (1) to explore differences and relationships between patients and partners’ SRS and QoL and to relate those to relationship aspects (duration and presence of children); (2) to examine change over time in SRS and QoL in patients and partners; (3) to relate earlier levels of SRS and QoL in patients and partners to later levels; and (4) to examine differences in QoL of patients and partners with that of a reference group of men and women.
Materials and methods
Procedure and participants
All patients diagnosed with a disseminated nonseminomatous testicular tumor who consecutively visited the UMCG in The Netherlands for treatment between April 2001 and March 2004 and who were married or cohabiting were approached for this study. Only patients who received chemotherapy and had a steady relationship (n=30) could be included in this study. Other inclusion criteria were age over 18 years at study entry, sufficient command of the Dutch language, no previous treatment for cancer, and absence of a psychiatric history. The study was introduced to the patients and their partners after orchiectomy (removal of the affected testicle) was performed. Couples received a questionnaire at the following three time points: after orchiectomy but before the start of chemotherapy (T1), immediately after completion of chemotherapy, which is approximately 3 months after T1 (T2), and 1 year after T1 (T3). The patients received four cycles of cisplatin, etoposide, and bleomycin with a 3-week interval between each cycle. Couples received a letter with information about the objectives of the study, an informed consent form, the questionnaires, and a prepaid return envelope. Thirty of the 70 patients diagnosed during the above-mentioned time period appeared to meet all of the inclusion criteria. They and their partners were approached to participate in the study. Of the eligible 30 couples, 21 participated (70%). Two couples did not complete all three measurement times, therefore, only 19 couples provided complete data. The study was approved by the Medical Ethics Committee of the UMCG.
Measurements
Sociodemographics: Data on the following sociodemographic variables were collected at T1: age, educational level, employment status, presence of children, and duration of the relationship. Highest educational level completed was measured on a seven-point scale: primary school [1], and lower vocational [2], lower secondary [3], middle secondary [4], high secondary [5], higher vocational degrees [6], and advanced university [7]. Employment status could be indicated as employed for wages, housekeeping, student, unemployed, unable to work, or retired.
SRS were measured with the Impact of Event Scale (IES) [35, 36]. This scale (15 items) makes an inventory of the extent to which a subject is currently occupied with an event by measuring intrusion (intrusively experienced ideas, images, feelings, or bad dreams about the event; 7 items) and avoidance of unpleasant feelings or memories of the event (8 items), resulting in a total score of SRS. Patients and partners rated the frequency of SRS with respect to his cancer during the preceding 7 days. Examples of items include: “Any reminder brings back feelings about it” (intrusion) and “I try to banish it from my memory.” The IES is a valid instrument for measuring cancer-related SRS [37, 38]. With this questionnaire, information was obtained about the degree to which confrontation with testicular cancer was influencing the current daily life of the respondent. Higher scores indicate more SRS. The Dutch version of the IES indicates a total score of more than 26 as severe SRS, for which psychological help is recommended. Reliability of this scale was good for patients (Cronbach’s alpha for the different measurement times ranged from 0.82 to 0.89) and for partners (Cronbach’s alpha for the different measurement times ranged from 0.78 to 0.93).
QoL was measured with three subscales of the RAND-36 [39]: physical functioning (ten items), social functioning (two items) and mental health (five items). To avoid statistical problems due to multiple comparisons, we chose these three subscales as a representation of overall QoL. The RAND-36 measures generic QoL. After recoding and transformation, scores on the subscales could range from 0 to 100. Higher scores indicate a better QoL. Reliability of these scales was good to very good for patients (Cronbach’s alpha for the different measurement times ranged from 0.67 to 0.90) and for partners (Cronbach’s alpha for the different measurement times ranged from 0.75 to 0.92). The Dutch manual for the RAND-36 provides reference scores. These comprised the mean scores of a group of 691 nonselected men and 372 nonselected women from a random representative sample of persons aged 18 years and older from the population register of a municipality in the north of The Netherlands (number of inhabitants=108,000). The mean age of the persons in the total random sample was 44.1 years (range 18–89 years) [39].
Statistical analyses
The database consisted of matched pairs of patients and partners, making analyses on pair level possible. Paired t tests and chi-square test were performed to examine differences in sociodemographics between patients and partners. Wilcoxon signed rank test (because of small sample size) and correlations were computed to examine differences and relationships in SRS and QoL between patients and partners. Independent t tests were performed for having children (yes or no) with SRS and QoL. Pearson’s product moment correlations were calculated to examine the relationship between duration of the relationship and patients and partners’ SRS and QoL. Repeated measures analysis of variance (ANOVA) was used to examine change over time in functioning. Pearson’s product moment correlations were calculated to examine relationships between the functioning of patient and that of the partner and between measurement times. Strong correlation coefficients (>0.50) indicate consistency between measurement times and stable responses between earlier and later levels of functioning. Independent t tests were performed to compare QoL of patients and partners with those of a reference group of men and women.
Results
Sociodemographic and treatment-related variables
Sociodemographic and treatment related variables are reported in Table 1. Patients were older than partners (t=−3.1, p<0.01). The mean time couples had been together was 5.7 years. Eighteen patients were employed for wages and 1 was a student, whereas 11 partners were employed for wages, 4 were home-keepers and the remaining 4 partners were students (chi-square=19.0, p=0.04). Of the 21 couples, 5 had children and 14 did not. After chemotherapy was completed (at T2), all patients were restaged. Patients without biochemical or radiological abnormalities were considered to have reached complete remission (n=8). In case of proven residual disease, a resection of residual retroperitoneal tumor mass (RRRTM) was performed. Eleven patients underwent this surgery and were considered to be in complete remission afterward. None of the 19 patients experienced a relapse during follow-up (up to T3).
Table 1Descriptives of sociodemographic and treatment-related variables PatientPartnerMeanSDMeanSDAge (years)b31.66.628.97.6 Range19.9–43.519.8–44.7Duration relationship (years)5.76.3 Range1–22Education level3.61.44.01.6N%N%Employment statusb Employed for wages18951158 Student15421 Housewife421Children Yes526 No1474RRRTM + Yes1158 No842RRRTM Resection of residual retroperitoneal tumor massap<0.01bp<0.05
Patients’ and partners’ SRS and QoL
At T1, SRS of patients were moderately strongly and negatively related to those of partners (r=−0.48, p<0.05). At T2, social functioning of patients was moderately strongly and positively related to that of partners (r=0.53, p<0.05). At the three measurement times all other correlations between patients’ SRS and QoL and those of partners were low to moderate, ranging from r=0.04 to 0.34, and not statistically significant. At T1, in two couples, both patient and partner experienced SRS above the cut-off point. At T2 and T3 there were no couples in which both patient and partner experienced SRS above the cut-off point. Wilcoxon tests showed only one significant difference between patients and partners’ functioning. At T2, patients reported a lower level of physical functioning than did partners (Z=−2.6, p<0.01).
Independent t tests did not show a significant relationship between having children and SRS for patients at all measurement times, and for partners at T1 and T2. At T3 partners with children reported higher levels of SRS than partners who did not have children (t=2.6, p=0.018). The presence of children was unrelated to patients’ and partners’ QoL at all measurement times. The duration of the relationship was not significantly related to the patients’ or partner’s SRS or QoL at all measurement times and relationships were absent to very weak.
The course of SRS and QoL over time in patients and partners
Repeated measures ANOVA showed that the SRS of patients fluctuated according to a quadratic trend: The highest level was reported at T1 and after a decrease at T2, the level was increased again somewhat at T3. Earlier levels of SRS in patients were highly positively related to later levels (Table 2). At T1, five of the patients (26%) reported stress response levels above the cut-off point; at T2, two patients (11%); and at T3, three patients (16%). Two patients reported clinically elevated levels of stress response levels at all measurement times. For partners the level of SRS declined, via a linear trend. Partners’ reports of stress response levels were moderately strongly related between T1 and T2, strongly between T2 and T3, and the relationship between T1 and T3 was weak (Table 2). At T1, ten of the partners (53%) reported stress response levels above the cut-off point, at T2, six (32%), and at T3, two (10.5%). One partner reported clinically elevated levels of stress response levels at all measurement times.
Table 2SRS and QoL of patients and partners T1T2T3Reference groupRepeated measures ANOVAT1–T2T2–T3T1–T3Mean (SD)Mean (SD)Mean (SD)Mean (SD)FprprprpStress response symptomsPatient18.1 (13.0)10.2 (10.7)12.3 (9.9)7.90.0120.650.0020.710.0010.700.001Partner25.8 (9.3)15.2 (12.6)12.1 (12.4)17.70.0010.41ns0.640.0030.16nsPhysical functioningPatient93.4 (10.8)70.5 (23.4)92.6 (13.3)84.5 (22.3)a,b,c21.40.0010.28ns0.38ns0.20nsPartner90.2 (19.0)90.8 (19.0)89.7 (19.9)80.7 (23.6)b,d0.19ns0.790.0010.800.0010.970.001Social functioningPatient77.6 (19.7)71.1 (22.8)90.8 (13.1)88.4 (19.6)d,e9.00.0080.610.0090.19ns0.17nsPartner72.1 (20.2)77.6 (20.7)f84.5 (16.5)86.1 (20.9)a12.90.0020.600.0070.37ns0.680.001Mental healthPatient68.2 (22.3)77.5 (11.9)81.9 (13.4)79.4 (17.3)d6.70.0190.550.0170.33ns0.23nsPartner69.1 (13.6)71.2 (15.6)74.3 (15.1)75.5 (18.9)2.6ns0.720.0010.640.0040.520.023ap<0.01 (independent t test T1 and reference group)bp<0.05 (independent t test T2 and reference group)cp<0.05 (independent t test T3 and reference group)dp<0.05 (independent t test T1 and reference group)ep<0.01 (independent t test T2 and reference group)fp<0.01 (Wilcoxon test patients and spouses)
Lower physical functioning was reported by patients at T2 compared to T1, but physical functioning returned to baseline level at T3. Earlier levels of physical functioning in patients were not significantly related to later levels, and correlations were low. A decline in social functioning of patients was also found at T2 compared to T1, but higher social functioning than at baseline was found at T3. Social functioning of patients at T1 was positively and strongly related to functioning at T2, but the relationships between T2–T3 and T1–T3 were low to moderate. Mental health of patients improved over time. Mental health at T1 was positively and strongly related to levels at T2, and weakly to levels at T3. The relationship between mental health at T2 and T3 was moderately strong.
For partners, no significant time effects were found for physical functioning and mental health. Earlier levels of physical functioning and mental health of partners were highly and positively related to later levels. Social functioning of partners improved over the year and was highly positively related between T1 and T2 and between T1 and T3. The relationship between T2 and T3 was moderately strong. (Table 2).
QoL of patients and partners compared to that of a reference group of men and women
At T1, patients (t=−3.4, p<0.01) and partners (t=−2.1, p<0.05) reported better physical functioning than the reference groups. Patients (t=2.3, p<0.05) and partners (t=2.9, p<0.01) reported worse social functioning than the reference groups at T1, and patients (t=2.2, p<0.05) reported worse mental health at T1. At T2, patients reported worse physical functioning than the reference group of men (t=2.6, p<0.02) but partners reported better physical functioning than the reference group of women (t=−2.2, p<0.05). Patients also reported worse social functioning than the reference men at T2 (t=3.3, p<0.01). No differences were found between the patients’ and partners’ mental health and the norm groups at T2. Only one significant difference was found at T3: Patients reported better physical functioning than men in the reference group (t=−2.6, p<0.02) (Table 2).
Discussion
The present study was the first to prospectively and longitudinally examine psychosocial functioning in both testicular cancer patients and their partners. We focused on SRS and QoL (physical functioning, social functioning, and mental health) after orchiectomy but before the start of chemotherapy, immediately after completion of chemotherapy, and 9 months later (1 year follow-up).
SRS in couples were most salient before the start of chemotherapy. Twenty-six percent of patients reported clinically elevated SRS at this time, a number comparable to the 30% of patients with clinically elevated distress found in a recent study on testicular cancer patients [23]. A review of stress response syndromes in adult cancer populations showed that the incidence of clinically elevated SRS ranged from 3 to 4% in patients recently diagnosed with early stage cancer [34]. The majority of these studies used the same questionnaire for measuring SRS as we did. The same review identified younger age, greater proximity to diagnosis, more advanced disease, and greater treatment intensity as risk factors for a higher level of SRS. The much higher percentage found in our study at the first measurement time may be explained by the prevalence of these four risk factors in our patient group.
Not only did patients appear distressed, but also almost twice as many of the partners compared to patients reported clinically elevated levels of SRS. Female sex was found to correlate with greater stress response symptomatology in cancer populations [34]. Of course, these spouses are not patients themselves, but they obviously face cancer-related fears and worries as well. Our results affirm earlier findings that female spouses of cancer patients are vulnerable to distress, and often report higher levels of distress compared to their male counterparts [20, 21, 40–42]. It was also found that partners who had children experienced more SRS a year after diagnosis compared to partners without children. This higher level of distress might also be a result of caregiving tasks that are often the domain of female partners.
SRS in couples decreased after completion of chemotherapy. One year after diagnosis, stress response levels in patients rose slightly, but they continued to decrease in partners. These patterns suggest that the period before chemotherapy commences is most stressful, and that recovery seems to occur within a year. At the time of the first measurement the responses of the couples seem to be colored by the fact that they had recently learned the diagnosis, and the outcome of treatment remained uncertain. Concerns of couples about side effects of chemotherapy such as nausea, the possibility of immunodeficiency, and hair loss may contribute to distress. Partners also have caregiving tasks that can exacerbate their distress [22]. All couples in this study received positive news about the results of treatment, and 1 year after diagnosis none of the patients had experienced a relapse of disease. Couples seemed to have recovered from this major life event over the year, possibly as a consequence of the success of treatment reducing insecurity about outcome.
An interesting finding was that before commencement of chemotherapy, the level of SRS of patient and partner was inversely related. When one spouse was reporting more SRS, the other reported less. This might be a psychological mechanism through which spouses want to protect one another from their own distress, a finding reported before in studies on couples facing cancer [40]. Another possible interpretation might be that patients who expressed very low levels of distress were using denial, avoidance, or other repressive psychological mechanisms while their partners carried the psychological burden of stress. A patient who expresses high distress may also allow his spouse to assume a stronger supportive role, and thus reduce her expression of stress.
In line with the medical trajectory, physical functioning of patients was worst after completion of chemotherapy. As a consequence of chemotherapy, many patients still experience adverse side effects, including fatigue and a sense of physical exhaustion. It is surprising to note that physical functioning of patients was better than that of the reference group before start of chemotherapy and 1 year later. The first measurement occurred shortly after removal of the affected testicle, and patients may have experienced physical relief after the initiation of treatment. It may also be that age contributed to the difference found between the patient group and the reference group. Younger age is associated with better physical functioning [39], and the mean age of the patients in this study was somewhat more than 10 years lower than that of the reference group. There may have been other differences from the reference group as well, such as physical activity and SES. Partners’ physical functioning did not change over the year but they also experienced better physical functioning than the reference group before and after chemotherapy. In an earlier cross-sectional study we found that partners of men who survived testicular cancer between 1–20 years reported better physical functioning than a reference group of women, even years after diagnosis [30]. Partners of testicular cancer patients may have changed the evaluation of their own health in a positive way after witnessing the diagnosis and treatment of a life-threatening illness.
In patients, social functioning was worst immediately after completion of chemotherapy, and in spouses before start of chemotherapy. Before start of chemotherapy, both partners reported worse social functioning compared to the reference groups. Before chemotherapy starts, couples are probably overwhelmed by the implications of a cancer diagnosis and focus more on the treatment to come rather than on being socially active as usual. As a consequence of chemotherapy, patients may still suffer from negative side effects like fatigue and impaired physical functioning, which in turn may affect their social functioning. Social functioning in patients and partners was positively related after completion of chemotherapy, meaning that when one partner experienced better social functioning the other also did. Couples had comparable social functioning to that of the reference groups 1 year after diagnosis; they seem to have returned to their usual social activities. This finding is in line with studies on testicular cancer survivors that show little or no change in social contacts and work activities [6, 43].
Mental health of patients improved over the year. It was poorer than that of men in the reference group but only before start of chemotherapy. Mental health of partners was comparable throughout the year and to that of a reference group of women, despite the high level of SRS they reported before start of chemotherapy. SRS apparently are a different expression of mental functioning and may be encapsulated or separated out.
It appeared that functioning in couples facing testicular cancer was not similar in patients and partners. Testicular cancer patients showed u-shaped trajectories of SRS, physical functioning, and social functioning. This pattern seemingly followed the medical trajectory they had undergone and was found before in a large group of testicular cancer patients [24]. Mental health of patients improved over the year. Spouses reported a decline in SRS and an improvement in social functioning, but no change in physical functioning or mental health over the year. Differences between patients and partners were also noticeable in stability of functioning. In patients, earlier levels of SRS were strongly predictive of later levels while less individual stability was found with regard to physical and social functioning and to mental health. Partners reported less individual stability in SRS over time, although individual stability was found between T2 and T3. However, partners were individually highly consistent in their reports of physical functioning and somewhat less strong in mental health and social functioning. In addition, correlations between the functioning of patients and partners were moderate to very low. We also found that at the second and third measurement time, there were no couples in which both the patient and the partner reported clinically elevated levels of SRS. This finding confirms the lack of correspondence in functioning between patient and partner.
These findings support recent studies that found different adjustment patterns for patients and partners, and a lack of correspondence in functioning [19, 20]. Research is needed to examine if these different reaction patterns to a cancer diagnosis affect the marital relationship.
This study has some limitations. First, the possibility of including couples was limited because testicular cancer has a low incidence, and because of the young age of patients at diagnosis, part of this group will not yet have established a steady relationship. Second, no information was available on the functioning of couples who declined to participate. They may have been those who were functioning best or worst, thus biasing the results in either direction. Third, because of the limited sample size, variables that measure more in depth relationship aspects like marital satisfaction were not included in this study. In a previous retrospective study on testicular cancer, factors identified as important for couple adjustment like good communication, spousal support, and marital satisfaction all appeared to facilitate better functioning [32]. These moderating factors in adjustment of both patient and spouse deserve to be studied prospectively in the future.
In summary, this study was the first longitudinal prospective exploration of functioning in couples facing testicular cancer during the first year after the diagnosis. Patients confronted with disseminated testicular cancer and their partners reacted differently to this stressor. Clinically elevated stress response levels were present in one third of patients and half of the partners before start of chemotherapy. Patients reported worst mental health before start of chemotherapy, and worst physical and social functioning immediately after completion of chemotherapy. Partners reported an improvement in social functioning, and no change in physical functioning and mental health over the year. QoL of patients and partners was comparable to that of the reference groups a year after start of chemotherapy, patients even reported better physical functioning at that time. These findings support earlier retrospective studies in testicular cancer survivors and their spouses that also reported few long-term effects in psychosocial functioning in the group overall, but that identified a small group that remains distressed [16, 31, 32]. Little correspondence was found in the functioning of the partners. Findings should be regarded as preliminary, as the study sample was limited in size. However, clinicians can be reassured that the effect of disseminated testicular cancer on the QoL of patients and their partners seems to be temporary, although a minority does seem to need clinical attention for SRS.

testicular cancer
stress response symptoms
quality of life
chemotherapy
partners


Effects of biophysical stimulation in patients undergoing arthroscopic reconstruction of anterior cruciate ligament: prospective, randomized and double blind study

Pre-clinical studies have shown that treatment by pulsed electromagnetic fields (PEMFs) can limit the catabolic effects of pro-inflammatory cytokines on articular cartilage and favour the anabolic activity of the chondrocytes. Anterior cruciate ligament (ACL) reconstruction is usually performed by arthroscopic procedure that, even if minimally invasive, may elicit an inflammatory joint reaction detrimental to articular cartilage. In this study the effect of I-ONE PEMFs treatment in patients undergoing ACL reconstruction was investigated. The study end-points were (1) evaluation of patients’ functional recovery by International Knee Documentation Committee (IKDC) Form; (2) use of non-steroidal anti-inflammatory drugs (NSAIDs), necessary to control joint pain and inflammation. The study design was prospective, randomized and double blind. Sixty-nine patients were included in the study at baseline. Follow-up visits were scheduled at 30, 60 and 180 days, followed by 2-year follow-up interview. Patients were evaluated by IKDC Form and were asked to report on the use of NSAIDs. Patients were randomized to active or placebo treatments; active device generated a magnetic field of 1.5 mT at 75 Hz. Patients were instructed to use the stimulator (I-ONE) for 4 h per day for 60 days. All patients underwent ACL reconstruction with use of quadruple hamstrings semitendinosus and gracilis technique. At baseline there were no differences in the IKDC scores between the two groups. At follow-up visits the SF-36 Health Survey score showed a statistically significant faster recovery in the group of patients treated with I-ONE stimulator (P < 0.05). NSAIDs use was less frequent among active patients than controls (P < 0.05). Joint swelling resolution and return to normal range of motion occurred faster in the active treated group (P < 0.05) too. The 2-year follow-up did not shown statistically significant difference between the two groups. Furthermore for longitudinal analysis the generalized linear mixed effects model was applied to calculate the group × time interaction coefficient; this interaction showed a significant difference (P < 0.0001) between the active and placebo groups for all investigated variables: SF-36 Health Survey, IKDC Subjective Knee Evaluation and VAS. Twenty-nine patients (15 in the active group; 14 in the placebo group) underwent both ACL reconstruction and meniscectomy; when they were analysed separately the differences in SF-36 Health Survey scores between the two groups were larger then what observed in the whole study group (P < 0.05). The results of this study show that patient’s functional recovery occurs earlier in the active group. No side effects were observed and the treatment was well tolerated. The use of I-ONE should always be considered after ACL reconstruction, particularly in professional athletes, to shorten the recovery time, to limit joint inflammatory reaction and its catabolic effects on articular cartilage and ultimately for joint preservation.
Introduction
Articular cartilage performs mechanical functions absorbing the different loads applied to a joint in the course of daily activity [19]. Homeostasis and mechanical competence of cartilage are regulated by the activity of the chondrocytes that maintain the function and the integrity of the extracellular matrix, proteoglycans and collagen.
In consideration of the scant repairability of the cartilage, even modest damages resulting from trauma or inflammation may be the starting point for cartilage degeneration leading over time to extensive lesions that deepen into the thickness of the cartilage itself, ultimately exposing the subchondral bone tissue [3, 17].
Joint injury may involve synovial tissue, cartilage and subchondral bone leading to joint inflammation, swelling and pain. Surgical interventions must certainly be included among the triggers of inflammatory reaction in a joint [12]. The development of arthroscopic procedures has undoubtedly limited joint damage associated to surgery for reconstruction of ligaments; nevertheless, it does not avoid the inflammatory response. Thus, while arthroscopic procedures make surgery less invasive, the inflammatory response at the joint remains and the release of pro-inflammatory cytokines in the synovial fluid is associated with an increase in the aggrecanase activities that lead to a degradation of the cartilage matrix, and also inhibit proteoglycan synthesis [11, 15, 18]. To prevent cartilage damage, current pharmacological therapies aim to control the catabolic effects of the pro-inflammatory cytokines and enhance anabolic activity, proteoglycan synthesis and proliferation of chondrocytes. Drugs that combine the above effects are called chondroprotectors; in this category should be included drugs with A2A adenosine receptor agonist activity, able to stimulate the physiological pathways that control inflammation and promote chondrocyte anabolic activities. Nevertheless, these drugs are in early stages of clinical testing [5].
Pre-clinical studies have shown that pulsed electromagnetic fields (PEMFs) in vitro favour the proliferation of chondrocytes [6, 16], stimulate proteoglycan synthesis [7] and demonstrate an A2A adenosine receptor agonist activity [20, 21]. Electromagnetic fields in vivo prevent degeneration of articular cartilage and down-regulate the synthesis and release of pro-inflammatory cytokines in the synovial fluid [2, 4, 8, 9]. These findings suggest that electromagnetic fields may be used to control joint inflammation and to stimulate cartilage anabolic activities, finally resulting in chondroprotection.
A clinical study performed in patients undergoing arthroscopic treatment for cartilage lesions showed that biophysical treatment with PEMFs was well tolerated by the patients and led to a decrease in the use of non-steroidal anti-inflammatory drugs (NSAIDs) and to an early functional recovery; the positive effect of the treatment was maintained at a 3-year follow-up [22].
Arthroscopic reconstruction is the treatment of choice following anterior cruciate ligament (ACL) rupture; although minimally invasive, the procedure is associated with joint reaction involving the synovia and it is expected to lead to an increase of pro-inflammatory cytokines in the synovial fluid with catabolic effect on articular cartilage. In this study, we evaluated whether the treatment with PEMFs could be used to control joint inflammatory response in patients undergoing ACL reconstruction. The end points of the study were: (1) patients’ functional recovery evaluated by International Knee Documentation Committee (IKDC) form; (2) use of NSAIDs, necessary to control joint pain and inflammation.
Materials and methods
Patients and study design
In 2004–2005, 84 patients undergoing ACL reconstruction were evaluated for inclusion in the study at five clinical centres. Of these, 69 gave their informed consent to participate in the study. The prospective randomized and double-blind study was approved by the local ethical committees. Inclusion criteria were the following: age between 18 and 45 years, ACL complete lesion following acute trauma or consequence of ligament chronic degeneration. All lesions were documented by MRI and confirmed during the intervention. The following were the exclusion criteria: osteonecrosis of the femoral condyle, rheumatoid arthritis, autoimmune disease, systemic disease and patients requiring meniscus repair.
The patients were assigned to the active or placebo group according to the following randomization criteria: age (18–30 or 31–45), sex, smoking status, origin of ACL rupture (traumatic or degenerative). For randomization of patients, a computer-generated schedule was prepared by a biostatistician. In this process, a random number seed was entered into the computer to generate a list that assigned equal numbers of active and placebo stimulators. The minimum number of patients per group required was calculated by power analysis taking into account the results of a previous study [22].
Of the 69 patients included, two never started the therapy, two dropped out within 2 weeks of therapy, and five did not return at follow-up visits; a total of 60 patients were therefore available for subsequent analysis. The ACL rupture occurred during sports activity in 49 patients (24 active and 25 placebo), daily activity in eight patients (four active and four placebo) and traffic accident in three patients (three active). At the time of ACL reconstruction 29 patients underwent also meniscectomy: 15 in the active group and 14 in the placebo.
Clinical evaluation
The patients were evaluated by IKDC Form before the intervention and at 30, 60 and 180 days afterwards. The different parts of the questionnaire, IKDC Current Health Assessment Form (SF-36 Health Survey), IKDC Subjective Knee Evaluation Form and IKDC Knee Examination Form were analysed separately. As regards the scores of the questionnaires, for each subject we considered the changes at follow-up visits with respect to the values recorded at baseline, before surgery.
Pain intensity was evaluated by visual analogue scale (VAS) of 10-cm length: 0 cm no pain, 10 cm maximum pain. The patients were allowed to use NSAIDs to control knee pain when present and had to report doing so.
A 2-year follow-up telephone interview was conducted and the patients were asked: (a) if they had undergone further surgery at the knee, (b) if they had pain at the knee, (c) if they had functional limitation in daily activity, (d) if they returned to previous sport activity level.
Surgical technique
ACL arthroscopic repair was performed by quadruple hamstrings semitendinosus and gracilis technique. Tendons were harvested with the tendons stripper through a 2–3 cm vertical incision on the antero-medial tibial area. Diameter of the quadruple hamstrings semitendinosus and gracilis tendons was measured, while the tibial tunnel and same size femoral tunnel (30 mm length) were prepared. The graft was pulled up through the tibial tunnel with the knee at 90° of flexion and suspended on the external femoral cortex (Endobutton, Smith and Nephew, London, UK). Distally, the graft was fixed with an interference absorbable screw at the tibia at 10° of flexion.
Rehabilitation
All the patients underwent standard rehabilitation using passive knee flexion daily. Exercises started within the third post-operative day with isometric quadriceps contractions and then progressed to active closed-chain exercises by 4–6 weeks postoperatively. During the first 20 days patients were instructed to use two crutches and then progressive weight bearing until the end of the second month.
Biophysical stimulation
The patients were treated with active or placebo devices. The active stimulators (I-ONE; IGEA, Carpi, Italy) generated a magnetic field of peak intensity of 1.5 mT at a frequency of 75 Hz; no heat or vibration was felt by the patient during treatment (Fig. 1).
Fig. 1Left I-ONE PEMFs generator. Right wave form of magnetic field, 1.5 mT peak value (top); electric field induced in a standard coil probe made of 50 turns (0.5 cm ∅) of copper wire (0.2 mm ∅), peak value 3 mV/cm (bottom)
The patients were instructed to use the stimulator for 4 h per day, not necessarily consecutively, for 60 days. Treatment started within 7 days from the surgery. Each device contained a clock to monitor the hours of use.
Statistical analysis
The results were analysed with SPSS 13.0 (Statistical Packages for Social Sciences Inc, Chicago, IL, USA). Comparison among the continuous variables in the two groups was performed with Student’s heteroschedastic t test; comparison of continuous variables within each group during follow-up was performed with Student’s paired t test.
Binomial and categorical variables were compared by contingency tables applying the chi-square test for 2 × 2 tables and the Cochran Mantel Haenszel test for larger size tables.
Generalized linear mixed effects model was applied to the SF-36 Health Survey, IKDC Subjective Knee Evaluation and VAS data to test if a different trend between the two groups was present during follow-up by correcting for the following covariates: sex, age, weight, height, hours of treatment, smoking status, use of NSAIDs. In this analysis, a mathematical model is built which takes into account the trend over time of individual patients belonging to each group (Group × Time interaction) and determines if a statistical difference exists between the groups during the follow-up [10].
The minimum significance level for all the statistical tests was set at P < 0.05.
Results
At baseline, the two groups of study were homogeneous for age, weight, height, VAS, SF-36 Health Survey and IKDC Subjective Knee Evaluation score (Table 1).
Table 1Characteristics of the groups at baselinePlacebo #29I-ONE #31PMeanSEMeanSEAge29.61.632.51.40.17Weight7227330.73Height175117420.59VAS2.40.33.20.50.27SF-36 Health Survey3723720.95IKDC Subjective Knee Evaluation Form4834730.90
Average daily treatment was the same in both groups: 3.92 ± 0.5 h/die versus 3.13 ± 0.3 h/die in the I-ONE group and the placebo group, respectively (P = n.s.).
The average pain was modest and almost absent at 6 months’ follow-up: 0.7 ± 0.2 cm among placebo and 0.9 ± 0.2 cm among active. At 30 days, less patients in the active group used NSAIDs: 8% in the I-ONE group versus 27% in the placebo group (P < 0.05).
The SF-36 Health Survey score decreased significantly at 30 days, in both groups (P < 0.0005). At 60 days the mean SF-36 Health Survey score in the I-ONE patients already exceeded the initial value (by 3.2 points), whereas in the patients of the placebo group SF-36 Health Survey score was slightly below the initial mean value (by −0.7 units). At 6 months a significant (P < 0.005) increase was observed for SF-36 Health Survey average values in both groups; the patients of the I-ONE group were above the initial values by 10.1 units, while the placebo group exceeds the baseline value by 7.2 units. The mean changes of SF-36 Health Survey score in the I-ONE group are systematically higher with respect to placebo during follow-up, P < 0.05 (Fig. 2).
Fig. 2Mean changes of SF-36 Health Survey (±SE) versus baseline in the two groups (P < 0.05)
The IKDC Subjective Knee Evaluation score increased over 6 months and did not show significant differences between the two groups at any follow-up visit.
The IKDC Knee Examination Form outlined both groups including subjects with joint swelling before surgery (one in placebo and two in I-ONE group, P = n.s.) and at 30 days’ follow-up (five in placebo and six in I-ONE group, P = n.s.). On day 60, joint swelling was observed in the placebo group (two patients) only. Joint swelling was not observed any more at 6 months’ follow-up. Limitation in the passive range of motion of the knee was more frequent in the placebo group than in the I-ONE group (P < 0.05) (Fig. 3).
Fig. 3Patients with limitation in passive range of motion in the two groups, P < 0.05
Finally, the generalized linear mixed effects analysis revealed a significantly different trend (group × time interaction, P < 0.0001) between the two groups for SF-36 Health Survey score, IKDC Subjective Knee Evaluation score and for VAS, showing a positive effect of I-ONE treatment. The estimate coefficients and significance of independent variables for three models are displayed in Table 2.
Table 2Generalized linear mixed effects models in which the dependent variables considered are: SF-36 Health Survey score, IKDC Subjective Knee Evaluation score and VAS, respectivelyCoefficientStd. err.z testP < SF-36 Health Survey  Group0.3612.6900.130.893 Hours of treatment−0.0140.008−1.790.073 Sex−8.3484.810−1.740.083 Weight−0.4230.171−2.480.013 Height0.2200.2540.870.386 Age−0.2120.137−1.550.120 Smoking status0.7682.0750.370.711 Use of NSAIDs−4.6672.726−1.710.087 Time0.1250.0344.580.000 Group × Time0.0510.0143.670.0001 Constant37.94040.3020.940.347IKDC Subjective Knee Evaluation Group−1.4993.417−0.440.661 Hours of treatment−0.0070.011−0.620.533 Sex−19.3906.172−3.140.002 Weight−0.5780.216−2.680.007 Height0.1500.3220.470.642 Age−0.7540.185−4.080.000 Smoking status−2.2142.783−0.800.426 Use of NSAIDs−2.9413.805−0.770.440 Time0.1450.0512.890.000 Group × Time0.1670.0315.370.000 Constant94.56151.3821.840.066VAS  Group0.7990.4551.760.079 Hours of treatment−0.0000.001−0.220.824 Sex1.5830.8061.960.050 Weight0.0200.0290.670.505 Height0.0270.0430.640.524 Age0.0330.0221.50.133 Smoking status0.2460.3370.730.464 Use of NSAIDs−0.8250.434−1.900.058 Time−0.4410.2443.890.000 Group × Time−0.0090.002−4.000.000 Constant−5.5936.721−0.830.405The Group × Time interaction term describes the different trend between the groups
At the 2-year follow-up interview 86% of the patients in the I-ONE group and 75% in the placebo group reported complete functional recovery, no knee pain and return to sport activity.
ACL reconstruction and meniscectomy
When the cohort of patients, undergoing both ACL reconstruction and meniscectomy, was analysed separately, the SF-36 Health Survey score confirmed the faster recovery trend among I-ONE treated patients compared to placebo, P < 0.05 (Fig. 4). At 6 months, SF-36 Health Survey average score increase was 11.4 in the I-ONE group (P < 0.005 vs. baseline) and 7.1 in placebo group (P = ns vs. baseline). Further, the average values of SF-36 Health Survey were significantly higher in the I-ONE group compared to the placebo (45.2 ± 1.5 vs. 37 ± 2.7, P < 0.05).
Fig. 4Patients undergoing ACL and meniscectomy: mean changes of SF-36 Health Survey (±SE) versus baseline in the two groups (P < 0.05)
The percent of patients with limitation in the passive range of motion was lower in the I-ONE group compared to the placebo one (34% I-ONE vs. 50% placebo at day 30 and 4% I-ONE vs. 17% placebo at day 60, P < 0.05).
Discussion
Arthroscopic surgery has gained a large success and led to a significant increase in its use: about 650,000 procedures are performed in the USA each year [14]. However, the access into the joint space is always associated to an inflammatory reaction that may jeopardize the benefits expected from surgery. Joint inflammation has a catabolic effect on extracellular matrix and inhibits chondrocyte activity; thus, all means capable of locally controlling the inflammation should be adopted to prevent the onset and limit the progression of cartilage damage. Furthermore, unlike bone tissue after damage, the cartilage will not completely recover its competence: once lost, the articular cartilage does not reform [13].
Many efforts are made to develop strategies able to control joint inflammation and to favour the anabolic activities of chondrocytes; these are challenging objectives, and up to now the pharmacological approaches based on the use of drugs, whether by systemic or by local route, have not yet been able to demonstrate a genuine chondroprotective effect in humans [19].
Pre-clinical studies have shown PEMFs to have a chondroprotective effect, mediated by the control of inflammation and by the stimulation of chondrocyte activity; thus, we hypothesized that after arthroscopic surgery PEMFs treatment can be used for articular cartilage protection and ultimately joint preservation.
This prospective, randomized and double-blind study investigated whether and to what extent the employment of I-ONE, by controlling joint reaction to arthroscopy, could accelerate functional recovery in patients undergoing ACL reconstruction. The I-ONE treatment was well tolerated by the patients and no adverse side effects were observed. The results show that, at 30 days after surgery, in I-ONE group significantly fewer patients used NSAIDs to control pain, compared to patients in the placebo group; afterwards, the use of NSAIDs was not necessary in either group.
When IKDC Subjective Knee Evaluation average scores were analysed, we found no statistically significant difference between the I-ONE and placebo group; this is in agreement with the findings of other authors who reported that this parameter does not correlate with the other clinical information collected using the SF-36 Health Survey form [1]. However, when the results of the two groups were analysed by generalized linear mixed effects model, which takes into account the trend of each patient in both groups and the effect of confounding factors, we could evidence a positive significant effect of I-ONE treatment also in the Subjective Knee Evaluation (Table 2).
The SF-36 Health Survey average scores at baseline were the same in the I-ONE and placebo groups; however, the high standard deviation testify the large distribution of initial score values. To monitor patient’s recovery after ACL reconstruction, we considered the SF-36 Health Survey score changes with respect to baseline for each individual subject. At 2 and 6 months SF-36 Health Survey increase is undoubtedly higher in I-ONE group than in the placebo group. This result indicates a faster recovery in the treated patients. This positive effect of I-ONE treatment is confirmed by the generalized linear mixed effects analysis. Further, when the cohort of patients who underwent both ACL reconstruction and meniscectomy was analysed, we observed that the average increase of SF-36 Health Survey at 60 days in the I-ONE group was the same as that of placebo group at 6 months (6.0 vs. 7.1, P = n.s.).
The IKDC Knee Examination Form showed how in the placebo group the resolution of joint swelling and the recovery of complete range of motion occur later compared to the I-ONE group; no significant difference in scoring was observed among centres.
The study end-points were thus demonstrated: fewer patients in the I-ONE group required the use of NSAIDs and their functional recovery was faster.
At 2-year follow-up no statistically significant difference was observed between two groups, although the percent of patients with complete recovery was slightly higher in the I-ONE group.
In this study we applied a statistical analysis specifically developed for longitudinal studies that allows to calculate the group × time interaction. This test, that considers individual patient’s score at different time points and the possible influence of confounding factors, supports the positive effect of I-ONE treatment on the recovery of patients undergoing ACL reconstruction.
Our data confirm the results reported by Zorzi et al. [22] in a group of patients treated with I-ONE following an arthroscopic treatment for cartilage lesions. To the authors’ knowledge, there are no other reports of use of biophysical stimulation after surgical procedures of the knee.
Biophysical stimulation allows treating individual joints, permeating the whole cartilage surface and thickness, the synovia and the subchondral bone. The effectiveness of biophysical stimulation is not limited by considerations such as diffusion ability and concentration gradient, which are present and important in the dynamic of a pharmacological intervention; joint tissues are paramagnetic, they do not attenuate the biophysical signal and thus are all homogenously exposed to the treatment efficacy. Biophysical stimulation is an effective therapeutic intervention to control the detrimental consequences of the inflammation over articular cartilage in the absence of negative side effects.
I-ONE should always be considered after ACL reconstruction, particularly in professional athletes, to shorten the recovery time, to limit joint inflammatory reaction and ultimately for joint preservation.

anterior cruciate ligament
pulsed electromagnetic fields
joint preservation
chondroprotection
biophysical stimuli