Submitted by - Rajiv Gandhi University of Health … · Web viewin a prospective study of...
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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA
SYNOPSIS OF DISSERTATION
“TO EVALUATE THE EFFICACY OF AUTOLOGOUS SERUM THERAPY IN CHRONIC URTICARIA”
Submitted by
DR.ANKITA GUPTA MBBS
POST GRADUATE STUDENT IN DVL (M.D)
DEPARTMENT OF
DERMATOLOGY, VENEROLOGY & LEPROSY
ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES,
B. G. NAGARA - 571448
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKAANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1 NAME OF THE CANDIDATEAND ADDRESS(in block letters)
DR. ANKITA GUPTAP.G IN DVL,ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G. NAGARA,MANDYA -571448
2. NAME OF THE INSTITUTIONADICHUNCHANAGIRI INSTITUTE OF
MEDICAL SCIENCES, B.G.NAGARA.
3. COURSE OF STUDY AND SUBJECT M.D. IN DVL
4. DATE OF ADMISSION TO COURSE 24.06.2013
5. TITLE OF THE TOPIC “TO EVALUATE THE EFFICACY OF AUTOLOGOUS SERUM THERAPY IN CHRONIC URTICARIA”
6.BRIEF RESUME OF INTENDED WORK6.1 NEED FOR THE STUDY6.2 REVIEW OF LITERATURE6.3 OBJECTIVES OF THE STUDY
APPENDIX-IAPPENDIX-IAAPPENDIX-IBAPPENDIX-IC
7 MATERIALS AND METHODS
7.1 SOURCE OF DATA
7.2 METHOD OF COLLECTION OF DATA : (INCLUDING SAMPLING PROCEDURE IF ANY)
7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER ANIMALS, IF SO PLEASE DESCRIBE BRIEFLY.
7.4 HAS ETHICAL CLEARENCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3
APPENDIX-II
APPENDIX-IIA
APPENDIX-IIB
YESAPPENDIX-IIC
YES
8. LIST OF REFERENCES APPENDIX – IIl
9. SIGNATURE OF THE CANDIDATE
10. REMARKS OF THE GUIDEChronic urticaria is a common distressing dermatosis affecting the quality of life of the patients and poses a therapeutic challenge to the treating dermatologist. Numerous treatment options are currently available but have several limitations like long term treatment and potentially side effects. Hence, there is a need for novel therapeutic modality which is safe, efficaceous and economical option for the patients. In this regard Autologous serum therapy is a promising therapy for treatment of chronic urticaria. In view of very few indian studies and to improve the overall quality of life of the patients, this study has been taken up.
11. NAME AND DESIGNATION (in Block Letters)
11.1 GUIDE DR. H. B. BASAVARAJ MBBS, MDPROFESSOR DEPARTMENT OF DERMATOLOGY,AIMS, B.G. NAGARA-571448
11.2 SIGNATURE OF THE GUIDE
11.3 CO-GUIDE (IF ANY) -
11.4 SIGNATURE -
11.5 HEAD OF DEPARTMENT Dr. B. D. SATHYANARAYANA MD, DVDPROFESSOR AND HEAD,DEPARTMENT OF DERMATOLOGY,AIMS, B.G. NAGARA-571448
11.6 SIGNATURE
12 12.1 REMARKS OF THE CHAIRMAN AND PRINCIPAL
12.2 SIGNATURE
APPENDIX-I
6. BRIEF RESUME OF THE INTENDED WORK
APPENDIX - IA
6.1 NEED FOR THE STUDY:
The name “Urticaria” is derived from the Latin word urtica, meaning to burn or
hives.1 Urticaria is a heterogenous group of diseases defined in common as presence of
short lived, erythematous, edematous, cutaneous swellings secondary to transient dermal
edema and vasodilatation.2 Angioedema (synonym: angioneurotic edema, Quincke’s
edema) is a rapid swelling of the deeper dermis, subcutaneous tissue, mucosa and
submucosal tissue.3 Chronic urticaria is a common distressing dermatosis characterized
by spontaneous occurrence of wheals lasting for less than 24 hours, with or without
angioedema occurring daily or almost daily for more than 6 weeks.4,5
In majority of the patients with chronic urticaria, the exact etiology remains unknown,
hence they have been categorized under the term chronic idiopathic urticaria (50%).3
However in a significant number of patients with chronic urticaria (30-50%), circulating
histamine releasing functional autoantibodies directed either against high affinity IgE
receptor (anti FcɛRIa) on basophils and mast cells or less commonly against the
immunoglobulin E (IgE) have been identified. Thereby the term chronic autoimmune
urticaria has been assigned to these subgroup of patients.1
In rare cases, pseudoallergy (to salicylates, food colour, preservatives, antioxidants),
infections (bowel parasites, H.pylori, intercurrent viral infections, candidiasis of bowel
and chronic sepsis e.g. dental abscess), drugs (NSAIDS and aspirin, opioids, ACE
inhibitors), psychological factors (anxiety, depression, impaired quality of life, significant
discomfort in interpersonal relationships), and implants (metal pin in the femur, metal
dental prosthesis, dental amalgams and nickel allergy), are implicated in chronic
urticaria.3 Overheating and local pressure of belts and clothing aggravates chronic
urticaria and alcohol worsens urticaria by the mechanism of vasodilatation.6
Autologous serum skin test (ASST) is a simple in-vivo intradermal clinical test for the
detection of basophil histamine releasing activity.7 A positive result in the form of an
immediate hypersensitivity reaction (read against a control) signifies the presence of
circulating histamine releasing factors (autoantibodies).8 Hence, ASST is an useful
diagnostic aid in identifying chronic autoimmune urticaria. ASST as an investigative
technique has been found to have a sensitivity of approximately 70 % and a specificity of
80%.9 Though, basophil histamine release assay is the gold standard for detecting
functional autoantibodies, the procedure is lengthy, requires fresh basophils from healthy
donors and skilled expertise is desired. For this reason, the test is generally limited to
research laboratory centers.7,8
Treatments of chronic urticaria possess a therapeutic challenge for the physician and a
protracted, unsatisfactory ordeal for the patient. Chronic urticaria requires long term
treatment with medications having potentially hazardous side effects, without a definite
treatment period and hence, patient compliance and satisfaction is decreased. Moreover,
patients experience restrictions in daily life activities and social life due to unrelenting
symptoms, exhibit psychiatric co-morbidities, sexual difficulties, and reduced
dermatology life quality index.10
Antihistamines form the first line of treatment. They require long term therapy with no
definite treatment time. Doxepin and monteleukast have been tried with variable results.
Prednisolone in tapering dose is used occasionally in severe urticaria and angioedema.
Immunosuppressive drugs like methotrexate and cyclosporine form the third line of
treatment. They cannot be administered safely for a long period as they encompass
serious side effects like bone marrow suppression, hepatotoxicity, hypertension,
nephrotoxicity etc.6
As a result, there is a need for a novel therapeutic modality which is safe, efficacious and
an economical option for patients. Autologous hemotherapy is one such promising
treatment which has been found helpful in chronic urticaria patients. Patients whole blood
or extracted serum is autologously injected (weekly session) to induce tolerance to the
pro-inflammatory signals released in circulation.11 There is no risk of rejection or disease
transmission as it is produced from patient’s own blood. A study by Staubach et al
concluded that autologous whole blood injections were effective in ASST (+ve) patients
in 70% of cases. Conversely, it was not found efficacious in ASST (-ve) patients.12
Autologous serum therapy on the other hand, involves separation of serum from whole
blood, thereby doing away with the cellular components of blood since the autoreactive
histamine releasing factor is present in serum itself. It can be administered with a fine
gauge needle thereby making treatment less painful for the patients without reducing its
efficacy and thereby increasing the compliance. It was found effective in significant
proportion of autologous serum skin test positive patients in chronic urticaria though
some of the autologous serum skin test negative patients also benefited from this
treatment. Urticaria activity score and and patients requirement of antihistamines also
decreased remarkably. Thus, autologous serum therapy is a potentially curative modality
in patients with chronic urticaria.13
Hence the present study is undertaken to evaluate the efficacy of autologous serum
therapy in chronic urticaria patients.
APPENDIX – IB
6.2 REVIEW OF LITERATURE
The following related studies have been conducted by various authors.
Kulthanan K et al carried out a retrospective study of 450 chronic urticaria patients who
attended the department of dermatology, Siriraj hospital, Mahidol University, Bangkok
during the period 2000-2004. 337 (75%) were diagnosed with chronic idiopathic
urticaria. In 61 patients, ASST was done of which 15 patients (24.5%) had positive
results (i.e.) autoimmune urticaria. Antithyroid and antimicrosomal antibodies were
positive in 16% and 12% of chronic idiopathic urticaria patients respectively.14
Kiran V Godse undertook a prospective study in Navi Mumbai in the year 2004 and
reported that out of 45 patients with chronic idiopathic urticaria, 12 patients (26.67%)
showed a positive autologous serum skin test in the form of wheal and flare response of
more than 1.5 mm than the saline control. It was noted that all the 12 ASST (+ve)
patients had clinical features of severe urticaria.8
P. Staubach et al carried out a prospective study involving autologous whole blood
injections to patients with chronic urticaria with a positive autologous serum skin test in
department of dermatology, university of Mainz, Germany in the year 2005 demonstrated
that after repeated injections of autologous whole blood (AWB) in 9 of 13 ASST +ve
chronic urticaria patients, urticaria activity score had a significantly improvement by > 30
% and among all the ASST +ve chronic urticaria patients 70 % showed relevant
improvement, in contrast ASST –ve chronic urticaria patients did not show any
improvement. So it was concluded that ASST +ve chronic urticaria patients are
specifically benefited by the use of autohemotherapy which is a simple, inexpensive,
potentially curative and safe therapy.12
A.K Bajaj et al in a prospective study of autologous serum therapy in chronic urticaria
in Bajaj skin clinic in Allahabad in the year 2007 demonstrated that there was a
significant decrease in total severity score in both ASST (+ve) and ASST (-ve) patients
which continued even after cessation of therapy when assessed at final 21- 25 weeks
follow-up visit. The difference in reduction of total severity score in ASST (+ve) patients
(65%) and ASST (-ve) patients (43%) were not statistically significant at final follow-up.
Antihistamines use declined from 100 % at baseline in both ASST (+ve) and ASST (-ve)
groups to 38.7% of ASST (+ve) patients and 23.1% of ASST (-ve) patients. It was hence
concluded that autologous serum therapy is an effective therapeutic modality to reduce
diseases severity as well as antihistamine requirement. This therapy also prevented
relapse of symptoms for duration as long as 2 years in some patients.13
Surbhi Vohra et al in a prospective clinical study of autologous serum skin test in
dermatology outpatient department in Indira Gandhi medical college, Shimla in the year
2008 and demonstrated that a positive ASST result has a serum induced wheal with
redness score = 2 and diameter of ≥ 1.5mm as evaluated against a saline induced wheal at
30 minutes. Using this criteria, sensitivity and specificity of the autologous serum skin
test for detecting antibodies was found to be 70 % and 80 % respectively. Therefore, it
was concluded that ASST can be used as a predictive clinical test to diagnose
autoimmune urticaria.7
Sharmila Patil, et al in a prospective study of autologous serum therapy in chronic
urticaria in department of dermatology, Dr D.Y Patil medical college and hospital, Navi
Mumbai in the year 2013 noted that of the 20 ASST (+ve) chronic urticaria patients who
were administered autologous serum therapy, 45% of the patients showed excellent
improvement and improved dermatology life quality index (DLQI), 30 % of the patients
did not show satisfactory response and 25 % of the patients showed no response. UAS
(urticaria activity score) also came down within few weeks and patients requirement of
antihistamines also reduced remarkably. 11
APPENDIX – IC
6.3 AIMS AND OBJECTIVES OF THE STUDY
1. To assess autologous serum skin test in patients with chronic urticaria
2. To evaluate the efficacy of autologous serum therapy in patients with chronic
urticaria
APPENDIX-II
7.0 MATERIALS AND METHODS
APPENDIX-II A
7.1 SOURCE OF DATA
This study is being conducted in Department of Dermatology, Venereology
and Leprosy, Sri Adichunchanagiri Hospital and Research Centre, B.G. Nagara, on
out-patient basis, meeting the mentioned inclusion and exclusion criteria.
Study Design : Prospective, non-randomized uncontrolled study
Study Period : 18 months
Sample size : 50 cases
Total number of patients with chronic urticaria who presented to dermatology
outpatient department (OPD) in the past 3 years was retrospectively calculated and the
expected sample size for subsequent years was estimated.
APPENDIX-II B
7.2 METHOD OF COLLECTION OF DATA
INCLUSION CRITERIA
1. Spontaneous appearance of wheals occurring daily or almost daily for more than 6
weeks
2. Patients willing for the study and for weekly follow- up and injections
3. Patients aged above 18 years
EXCLUSION CRITERIA
1. Patients not willing for the study
2. Pregnant and lactating mother
3. Patients on systemic corticosteroids or immunosuppressive medications in the
past 6 weeks
4. Patients on chemotherapy in the past 1 year
PROCEDURE OF THE STUDY:
All patients attending the Dermatology outpatient department and satisfying the
aforementioned inclusion and exclusion criteria will be recruited in the study after
informed consent and ethical committee approval.
A detailed history will be taken as per the prepared questionnaire. Elaborate general and
systemic examination will be done and recorded in standard performa. A total of 50
patients with chronic urticaria will be screened and ASST will be performed in all the
patients followed by 8 weekly intramuscular injections of autologous serum
AUTOLOGOUS SERUM SKIN TEST:
Following are the pre-requisites for doing autologous serum skin test; short acting
antihistamines (chlorpheniramine maleate, brompheniramine maleate, promethazine
hydrochloride) are withdrawn at least 2 to 3 days prior to the test and long acting
antihistamines (cetrizine hydrochloride, loratidine, fexofenadine hydrochloride) ,doxepin
are withdrawn 2 to 6 weeks beforehand. Ethical approval is taken from the appropriate
body. Under aseptic precautions, two milliliters of patients venous blood is taken from
antecubital vein, collected in a sterile glass tube and allowed to clot for 30 minutes at
room temperature.15 The serum is then separated by centrifugation at 2000 rpm for 15
minutes. A site free of lesions is selected as the test area usually the volar aspect of
forearm. Approximately 0.05 ml (equivalent to 2 units on insulin syringe that has 1 ml
marked as 40 units) of autologous serum is injected intradermally over flexor aspect of
the left forearm. Equal amount of normal saline (negative control) is injected
intradermally over flexor aspect of the right forearm. Every time a separate syringe is
used for each solution. The results are read after 30 minutes. The test is considered
positive if the wheal and flare response occurs over the left forearm (serum injection site)
with a diameter of atleast 1.5 mm or more than that of saline induced response.7
AUTOLOGOUS SERUM THERAPY:
After 1 week run in period, baseline disease parameter and urticaria activity score will be
recorded, in intervening period if patients develops wheals then they will be advised to
take long acting antihistamine (levocetrizine 5 mg) orally. Autologous serum therapy is
instituted in all the enrolled patients. Every week for eight consecutive weeks, 5 ml blood
will be drawn, serum separated and 0.05 ml/kg body weight of patients serum is injected
deep intramuscularly in alternate buttocks (upper outer quadrant of the gluteus region) or
upper arms .11 Proper care is taken, so as not to injure nerves and blood vessels (by
withdrawing the plunger and checking for blood). During the treatment period, patient
will be advised to take oral antihistamines (Tab levocetrizine 5 mg) only when they
develop wheals, however if the severity is more (Urticaria Activity Score > 20) patient
will be immediately attended to, managed appropriately and will be withdrawn from the
study.
CLINICAL ASSESSMENT:-
Urticaria total severity score is calculated based on eleven separate parameters on 0-3
scale (Table 1) at week 0 (baseline), week 4, week 8 ( after the end of treatment) and at
the end of 12th week.12 Based on these, 0-33 total severity score (TSS) is generated and
overall disease severity classified as clear (TSS=0), mild (TSS=1-10), moderate
(TSS=11-20) and severe (TSS=21-33). A follow up score of 0 at 12th week will be
considered as complete remission, score of 1-10 marked improvement, a score of 11-20
moderate improvement and score of 21-30 poor or no improvement.13
Table 1: Urticaria activity score12
SYMPTOMS 0 1 2 3
Wheal number (daily average)
None <10 10-50 >50
Wheal size (average diameter)
None <1cm 1-3cm >3cm
Wheal duration (average, h)
None <1 h 1-24 h >24 h
Pruritus intensity (daily average)
None Mild Moderate Severe
Pruritus duration (average, h)
None <1 h 1-24 h >24 h
Erythema number(daily average)
None <10 10-30 >30
Erythema size(average diameter)
None <1 cm 1-3 cm >3 cm
Erythema duration (average, h)
None <1 h 1-24 h >24 h
Angioedema number (daily average)
None 1 2 3
Angioedema size (average diameter)
None <1 cm 1-3 cm >3 cm
Angioedema duration (average, h)
None <1 h 1-24 h >24 h
Outcome measures include:-
1) Decrease in severity of Urticaria activity score at week 12 (week 4 after
termination of treatment)
2) Requirement of antihistamine as rescue medication during the treatment period
and week 12 ( 4 weeks after termination of treatment )
Collected clinic-epidemiological data will then be analyzed using appropriate
stastical method, namely proportion, percentage and chi-square test.
APPENDIX-II C
7.3 Does the study require any investigation or intervention to be conducted on the
patients or animals, if so please describe briefly:
YES
The information elicited from the history and physical examination is used to direct the
selection of laboratory tests.
1) Complete Haemogram
2) Absolute eosinophil count (AEC)
APPENDIX-IID
PROFORMA APPLICATION FOR ETHICS COMMITTEE APPROVAL
SECTION A
a Title of the study“TO EVALUATE THE EFFICACY OF AUTOLOGOUS SERUM THERAPY IN
CHRONIC URTICARIA”
b Principle investigator(Name and Designation)
DR. ANKITA GUPTAPOST GRADUATE IN DERMATOLOGY,ADICHUNCHUNAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G. NAGARA,MANDYA DISTRICT -571448
c Co-investigator(Name and Designation)
Dr. H. B. BASAVARAJ MBBS, MD
PROFESSOR DEPARTMENT OF DERMATOLOGYAIMS, B.G. NAGARA-571448
d Name of the CollaboratingDepartment/Institutions NIL
eWhether permission has been obtained from the heads of the collaborating departments & Institution
NA
Section – B Summary of the Project
APPENDIX ISection – C Objectives of the study
Section – DMethodology
APPENDIX IIB
A Where the proposed study will be undertakenDEPARTMENT OF DERMATOLOGY,
VENEREOLOGY & LEPROSYS.A.H. & R.C., B.G.NAGARA
B Duration of the Project 18 MONTHS
C Nature of the subjects:
Does the study involve Adult patients?
Does the study involve Children?
Does the study involve normal volunteers?
Does the study involve Psychiatric patients?
Does the study involve pregnant women?
YES
NO
NO
NO
NO
D If the study involves health volunteers
I. Will they be institute students?
II. Will they be institute employees?
III. Will they be paid?
IV. If they are to be paid, how much per
session?
NA
E Is the study a part of multi central trial? NO
F If yes, who is the coordinator?
(Name and Designation)
Has the trail been approved by the ethics
Committee of the other centers?
If the study involves the use of drugs please
indicate whether.
I. The drug is marketed in India for the
indication in which it will be used in the study.
II. The drug is marketed in India but not for the
indication in which it will be used in the study
III. The drug is only used for experimental use in
humans.
IV. Clearance of the drugs controller of India
has been obtained for:
Use of the drug in healthy volunteers
Use of the drug in-patients for a new
indication.
NA
-
NA
NA
NA
NA
NA
Phase one and two clinical trials
Experimental use in-patients and healthy
volunteers.
NA
G How do you propose to obtain the drug to be
used in the study?
- Gift from a drug company
- Hospital supplies
- Patients will be asked to purchase
- Other sources (Explain)
NA
H Funding (If any) for the project please state
- None
- Amount
- Source
- To whom payable
NIL
IDoes any agency have a vested interest in the out
come of the Project? NO
JWill data relating to subjects /controls be stored
in a computer?YES
K
Will the data analysis be done by
- The researcher?
- The funding agent
YES
NO
L Will technical / nursing help be required from
the staff of hospital.
If yes, will it interfere with their duties?
Will you recruit other staff for the duration of
the study?
If Yes give details of
I. Designation
YES
NO
NO
II. Qualification
III. Number
IV. Duration of Employment
NA
M Will informed consent be taken? If yes
Will it be written informed consent:
Will it be oral consent?
Will it be taken from the subject themselves?
Will it be from the legal guardian? If no, give
reason:
YES
YES
NO
YES
NA
N Describe design, Methodology and techniques APPENDIX II
Ethical clearance has been accorded.
Chairman,P.G Training Cum-Research Institute,
A.I.M.S., B.G.Nagara.Date:
PS: NA – Not Applicable
APPENDIX-III
8. LIST OF REFERENCES:
1. Sachdeva S, Gupta V, Amin SS, Tahseen M. Chronic urticaria. Indian J Dermatol
2011;56:622-8.
2. Clive EH, Ruth A, Malcom W. Chronic urticaria. J Am Acad Dermatol
2002;46:645-57.
3. Grattan CEH, Black AK. Urticaria and mastocytosis messenger. In: Burns T,
Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of dermatology, 8 th
ed. UK: Wiley-Blackwell; 2010. p. 22.1-26.
4. Godse KV. Urticaria meter. Indian J Dermatol 2012;57:410-1.
5. Tseng JTP, Lee WR, Lin SS, Hsu CH, Yang HH, Wang KH et al. Autologous
serum skin test and autologous whole blood injections to patients with chronic
urticaria: A retrospective analysis. Dermatol Sinica 2009;27:27-36.
6. Godse KV. Chronic urticaria and treatment options. Indian J Dermatol
2009;54:310-2.
7. Vohra S, Sharma NL, Mahajan VK. Autologous serum skin test: Methodology,
interpretation and clinical applications. Indian J Dermatol Venereol Leprol
2009;75:545-8.
8. Godse KV. Autologous serum skin test in chronic idiopathic urticaria. Indian J
Dermatol Venereol Leprol 2004;70:283-4.
9. Sabroe RA, Grattan CE, Francis DM, Barr RM, Kobza BA, Greaves MW. The
autologous serum skin test: A screening test for autoantibodies in chronic
idiopathic urticaria. Br J Dermatol 1999;140:446-52.
10. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of
chronic urticaria on the quality of life. Br J Dermatol 1997;136:197-201.
11. Patil S, Sharma N, Godse K. Autologous serum therapy in chronic urticaria.
Indian J Dermatol 2013;58:225-6.
12. Staubach P, Onnen K, Vonend A, Metz M, Siebenhaar F, Tschentscher I et al.
Autologous whole blood injections to patients with chronic urticaria and a
positive autologous serum skin test: a placebo-controlled trial. Dermatology
2006;212:150-9.
13. Bajaj AK, Saraswat A, Upadhyay A, Damisetty R, Dhar S. Autologous serum
therapy in chronic urticaria: Old wine in a new bottle. Indian J Dermatol Venereol
Leprol 2008;74:109-13.
14. Kulthanan K, Jiamton S, Thumpimukvatana N, Pinkaew S. Chronic idiopathic
urticaria prevalence and clinical course. J Dermatol 2007;34:294-301.
15. Ghosh SK, Ghosh S. Autologous serum skin test. Indian J Dermatol 2009;54:86-
7.