Thalidomide: Clinical Implications in Oral Mucosal Lesions - An Update
2 Amity Institute of Public Health, Amity University, Noida (UP), India
3 Department of CTVS, RIMS, Ranchi Jharkhand, India
4 Department of Oral Medicine and Radiology, Kalinga Institute of Dental Sciences, KIIT University, Bhubaneswar, Odisha, India
5 Department of Oral Medicine and Radiology, Institute of Dental Sciences, SOA University, Bhubaneswar, Odisha, India
Citation: Hasan S, et al. Thalidomide: Clinical Implications in Oral Mucosal Lesions - An Update. Ann Med Health Sci Res. 2018;8:21-28
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Thalidomide is perhaps one of the most notorious drugs ever to have been used in clinical practice. The distressing teratogenicity resulted in sudden withdrawl of the drug about 55 years back. Recently, thalidomide has revoked the interest of researchers due to demonstrable significant improvement in certain clearly defined disorders. Because of its salient antiinflammatory, immunomodulatory and anti-angiogenic potential, the drug has become extensively significant even in dental clinical practice. Currently, thalidomide is being used as therapeutic entity in severe aphthous stomatitis, Behcet’s syndrome, Erosive lichen planus, and oral features of HIV infection, Marshal Syndrome, orofacial granulomatosis and certain malignancies.
Oral mucosal lesions; Peripheral neuropathy; Teratogenicity; Thalidomide
A Swiss pharmaceutical firm, Chemische Industrie Basel (CIBA) first initiated the manufacture of thalidomide in early 1950’s. Further researches were made by German pharmacy Chemie Grunethal and thalidomide was introduced in 1954 as Contegran.  The drug was considered as one of the safest sedatives because even small doses were effective and acute adverse effects such as motor impairment were not seen. [2,3] Life threatening adverse effects, such as teratogenicity and peripheral neuropathy were soon recognised and led to the drug’s withdrawl in early 1960’s. [4,5] An Israeli practitioner, Sheskin, prescribed previously stored thalidomide supplies to a patient with mania and leprosy, and resulted in remarkable and almost complete remission of the patient’s skin symptoms.  These results were tested in other parts of the world and in 1998, U.S Food and Drug Administration (FDA), accepted the “orphan drug” status of thalidomide in the treatment of Erythema Nodusum Leprosum (ENL). Thalidomide should be prescribed under strict guidelines of System for thalidomide Education and Prescribing Safety (STEPS) program to minimize the risk of devastating teratogenic effects.  The drug’s antitumor necrosis factor-alpha (TNF-α) action and investigational affirmation of anti-angiogenic potential revoked the attention of the researches in the clinical application of the drug. Currently, the drug is in use for many recalcitrant inflammatory conditions and possible malignancies.  This paper aim to highlight the implications and possible mechanism of action of thalidomide in various oral mucosal lesions.
Recurrent Apthous Stomatitis (RAS)
Apthous stomatitis, characterized by recurrent, localized painful ulcers is the most frequently observed disorder of the oral cavity. (Incidence rate of 5-25%).  The condition requires immense clinical consideration because of its multi-factorial etiopathogenesis and various therapeutic protocols with not much of a cure. 
Cell mediated immunity has a role to play in the immunopathogenesis of RAS. TNF-α, produced by T cells, macrophages and mast cells induces mucosal inflammation by causing adhesion of endothelial cells and chemotaxis of neutrophils. 
The immunomodulatory potential of thalidomide and its inhibitory action on TNF-α overproduction signifies the therapeutic role of thalidomide in aphthous stomatitis, although, still the precise mechanism of action of thalidomide in RAS cannot be clearly delineated. [12-14] Table 1 enumerates numerous trials demonstrating the use of thalidomide in RAS. [15-23]
|Author||Year||No. of Patients (n)||Study Details||Clinical Outcome||Remarks|
|Mascaro et al. ||1979||06||100 mg thalidomide/day was given to patients with genital and oral ulcers||Ulcers were painless after 2-3 days, and complete remission was observed in 7-10 days.|
|Torras et al. ||1982||09||100 mg thalidomide/day was given to patients for 10 days||8 patients reported complete resolution from ulcers, minimal pain and diminished recurrence rate.|
|Jenkins et al. ||1984||15||400 mg OD (once a day) thalidomide was prescribed to patients for 5 days, followed by 200 mg for 4 weeks.||14 patients showed complete remission and 1 patient had marked improvement in the lesions within 5-21 days.||Recurrences were seen within a month of therapy cessation.|
|Grinspan et al. ||1985||40||300 mg thalidomide was given to patients with severe aphthae and 100 mg thalidomide was given for patients with less severe aphthae.||Regardless of the thalidomide dose, 75% remission in the symptoms was observed by the patients.||Patients with recurrences were managed with 100 mg thalidomide daily for 12 days.|
|Ramsellar et al. ||1986||67||In this randomized, placebo controlled clinical trial, patients were given 100 mg thalidomide daily or placebo for 2 months each and then switched therapy without a wash out period.||Complete resolution was seen in 48% thalidomide treated group, while only 9% resolution was observed in the placebo group.|
|Revus et al. ||1990||73||In this randomized placebo controlled clinical trial, patients were given 100 mg thalidomide daily or placebo for 2 months||Complete resolution was seen in 44% (32 out of 73) thalidomide treated group, while only 8% resolution was observed in the placebo group.||Therapy cessation was followed by recurrences (within 20 days )|
|Bonnetblanc JM et al. ||1996||25||This retrospective study focussed at assessing how many individuals could undergo therapy cessation or decrease the dose of therapy.||Only a few patients showed a good response and could undergo therapy cessation. A low dose of thalidomide maintenance regimen was aimed to minimize serious side effects.|
|Mimura et al. ||2009||21||Efficacy of the 4 systemic drugs- thalidomide, dapsone, colchicine, and pentoxifylline was assessed.
Initially, patients were given a 2-week course of (0.5 mg/kg/day) prednisone to bring them to a baseline status. Following this, one of the four trial drug was assigned to each patient for a 6 month interval. If adverse effects or unsatisfactory results were seen, the patients were switched to one of the other three drugs and the 6-month limit of the treatment was then reset.
|Thalidomide was the most efficient and best-tolerated drug; 7 out of 8 patients showed complete remission (87.5%). Out of 9 dapsone treated patients, complete resolution occurred in 5 patients, and considerable improvement was noted in 8 patients (89%). Colchicine was prescribed to ten patients. 4 patients showed complete resolution and 9 showed significant improvements (90%).
Out of 5 patients treated with Pentoxyfilline, one patient showed complete remission with benefits observed in three (60%)
|Least recurrences were seen in dapsone treated group. (Remained ulcer free for 9 months)
Thalidomide treated patients showed no relapse for a period of 2-week to 4-month.
This study strengthened the efficacy of thalidomide for RAS treatment, as 5 of 6 major aphthae patients showed major clinical improvements with thalidomide.
|Muriel H et al. ||2010||92 (76 had oral or bipolar aphthosis, and 16 had Behcet disease)||A multicenter retrospective descriptive cohort study was carried at 14 different centres between Jan 2003 to May 2006.
15 patients were subjected to short term thalidomide therapy, because of adverse effects and poor outcome. (less than 3 months)
77 patients were subjected to maintainence therapy more than 3 months
( 60 patients for continuous therapy and 17 patients for intermittent therapy in cases of episodes of ulcerations)
|Thalidomide was rapidly effective: 85% (78/92) entered complete remission (CR) within a median of 14 days.
The median maintenance dose was
100 mg/week, and did not reflect the initial dose (r = 0.18). The
intermittent-treatment group’s median dose was significantly lower and
its median duration of thalidomide intake significantly longer than for
patients on continuous therapy.
After 40 months of follow-up, 60% of patients were receiving
maintenance therapy, according to a continuous or intermittent
regimen, with favorable efficacy/safety ratio, and at
low thalidomide doses (e3 capsules/wk) for most of them
|Mild adverse events occurred in 78% (72/92) of patients. The most frequent were somnolence (36%), paresthesia (19%), constipation (19%), and weight gain.
Adverse events were severe for 21% (19/92) of patients.
No teratogenicity was reported. Peripheral neuropathies
Table 1: Thalidomide in RAS.
As aphthous stomatitis is a self-healing entity, the use of thalidomide should be reserved for severely distressing or intractable orogenital ulcerations. 
Recurrent aphthous stomatitis in immunocompromised individuals (HIV Patient’s)
Aphthous stomatitis is a potentially debilitating disorder in HIV- positive patients, with an incidence rate of approximately 5-15%. Typically, the oral ulcers in HIV patients are larger in size, extremely painful, heal more slowly, and have a higher recurrence rate as compared to those seen in immunocompetent individuals. [25-27] A wide range of therapies including corticosteroids, pentoxyfylline, levimazole, colchicines, and granulocyte-colony stimulating factor (G-CSF) has shown variable responses, and no single drug has shown complete remission from the ulcers. 
|Author||Year||No. of Patients (n)||Study Details||Clinical Outcome||Remarks|
|Youle et al. ||1989||7||Thalidomide 100 mg/day for 2 weeks was prescribed to HIV patients with refractory aphthous ulcers.||Patients reported with speedy resolution in the lesions.|
|Paterson et al. ||1995||20||A retrospective review was conducted for a 4 year period (1989 to 1993 )
Thalidomide (200mg /day for 2 weeks) was given to patients with recalcitrant oropharyngeal, esophageal and genital ulcers.
|Complete resolution was seen in 14 patients and 6 others had marked clinical improvement.||No changes in CD4 + cells were observed during or after therapy.|
|Weidle et al. ||1996||14||Thalidomide therapy (300mg or 600 mg daily) for 7 days was compared with placebo.||75% patients in the thalidomide group responded to therapy, while none responded to placebo treatment.|
|Jacobson et al. ||1997||57||Thalidomide therapy (200mg daily) for 4 weeks was compared with placebo.||16 out of 29 patients (55%) treated with thalidomide showed complete remission, whereas only 2 out of 28 patients (7%) showed complete remission in the placebo group.||Adverse effects of thalidomide were observed. 7 patients reported somnolence and skin rash and 6 patients stopped treatment because of toxic effects.|
|Ramirez-Amador et al. ||1999||16||Thalidomide therapy in 10 patients was compared with placebo therapy in 6 patients. 400 mg oral thalidomide was given initially for 7 days, followed by 200 mg daily for 7 weeks.||9 out of 10 patients (90%) treated with thalidomide showed complete remission, whereas only 2 out of 6 patients (33%) showed complete remission in the placebo group.||Skin rash was reported by 80% patients treated with thalidomide.|
|Jacobson et al. ||2001||49||A multicenter randomized study of thalidomide versus placebo for oral and oesophageal ulcers was conducted. 100 mg thalidomide or placebo 3 times per week for 6 months was prescribed.||14 of 23 patients (61%) treated with thalidomide had recurrence as compared to 11 of 26 patients (42%) in the placebo group.||No difference in plasma levels of HIV RNA, TNF-ALPHA and soluble TNF receptor II at the time of ulcer recurrence.|
Table 2: Thalidomide in RAS (HIV patients).
HIV infection of mucosal cells induces a cascade of an immune mediated mechanism, and results in mucosal inflammation. Thalidomide, by virtue of its anti-inflammatory potential, causes inhibition of mucosal inflammation. 
In 1937, Hulusi Behcet, a Turkish dermatologist, first described Behcet’s disease. It is characterized by recurrent oral and genital ulcers, uveitis and cutaneous lesions. Uncommon multi-systemic manifestations, such as gastrointestinal, central nervous system, vascular and joint infections may also be seen.  Behcet’s syndrome is usually treated symptomatically and empirically, usually with systemic anti-inflammatory or immunomodulatory drugs. [37-39]
An increase in neutrophil chemotactic and migratory activity, along with immune complexes mediated vascular damage may play a role in the etio-pathogenesis of behcet’s syndrome.  The precise mechanism of action of thalidomide in behcet’s syndrome is not clearly delineated. Thalidomide may have an inhibitory action on the formation of superoxide and hydroxyl radicals causing tissue destruction at inflammatory sites.  Due to its anti-inflammotory and immunomodulatory properties, thalidomide decreases neutrophil chemotaxtic action and cell mediated immunity. 
|Authors||Year||No. of Patients (n)||Study Details||Clinical Outcome|
|Saylan T. ||1982||22||Initial 5 days: 400 mg/ day thalidomide was given, followed by 200 mg/day for the next 15-60 days.||Spontaneous healing was observed in oral and genital lesions, with uncommon and milder recurrence rates. However, ocular lesions and arthritis remained non responsive.|
|Gardner et al. ||1994||59||Patients with recalcitrant orogenital ulcerations (OGU) were treated with 400 mg/ day thalidomide for the initial 5 days, followed by tapered thalidomide dose (200 mg/day) for the next 28 days.||81% patients showed complete resolution within one month of treatment with 200 mg thalidomide.
Thalidomide therapy was not required in 20% responding patients, and in the remaining patients improvement was maintained at smaller doses (7-200mg).
|Hamuryudan et al. ||1998||96||In this randomized, placebo controlled trial, patients were given either thalidomide (100 mg/day or 300 mg/day) or placebo for a period of 24 weeks.||complete remission occurred in-
1) 2 out of 32 patients (6%) receiving thalidomide 100 mg/day.
2) 5 out of 31 patients (16%) receiving thalidomide 300 mg/day.
Unsatisfactory outcome was observed in all the placebo treated patients
|Wazieres et al. ||1999||17||Thalidomide was prescribed to seventeen patients with OGU. Thalidomide 1 tablet (50mg/day) was initially given for 1 month. Dose tapering was done after improvement in the lesions (one tablet on alternate days) for 1 month and one tablet every 3 days thereafter. Nerve conduction studies (EMG) were conducted at inclusion in the study and every 6 months thereafter||At 1 month therapy-complete remission in 10 patients and improved condition in rest 7 patients.
At 2 month therapy-Complete remission was observed in six patients.
At 4 month therapy-
one patient showed complete remission the study showed that a initial dose of 50-mg/day is an effective therapy in OGU.
Prescribing one tablet every 2 or 3 days is successful in more than 60% of the patients to maintain remission.
Table 3: Thalidomide in Behcets syndrome.
Lichen planus (LP) is a chronic muco-cutaneous disease of the stratified squamous epithelium, frequently involving mucous membranes of the oral and genital region, skin, scalp, and nails. 
Lichen planus, an auto-immune disorder, is mediated by T CD 8 + cells, macrophages and Langerhan’s cells. Immune mechanisms trigger apoptosis resulting in cell destruction and the appearance of characteristic histological changes. 
At present, the therapeutic regimen is aimed to reduce mucosal inflammation, ulcerations and minimize the symptoms during disease activity and possibly increase the disease remission period.  However, no single therapy has proven beneficial in the management of oral lichen planus.
Thalidomide applicability in lichen planus can be justified based on its re-epitheliazation tendency and immunomodulatory potential. Keratinocyte proliferation and their movement are the two significant and crucial stages in the re-epithelialization of skin wounds. A 2-3 fold enhancement in both the proliferative activity and migratory activity of keratinocytic cells has been observed at therapeutic concentration of thalidomide. 
Naafs and Faber were the first to utilize the salient properties of thalidomide in managing lichen planus lesions. 
|Authors||Year||No. of Patients (n)||Study Details||Clinical Outcome||Remarks|
|Yun Wu et al. ||2010||69||The randomized clinical trial was conducted to evaluate the short term efficiency and safety of topical thalidomide for erosive lichen planus.
1% thalidomide paste was given to 37 patients and dexamethasone paste was prescribed to 32 patients for a week.
After 7 days of treatment, recurrences were looked for in patients free from erosions, whereas patients with ongoing erosions were prescribed same therapy for 3 more weeks.
Erosion size, visual analogue scale (VAS), 3 months recurrence rate and adverse effects at 1 year were the parameters.
|After a week of therapy
A noteworthy decrease in erosive areas and VAS scores was reported by patients in both groups.
18 patients out of 33 (54.5%) in thalidomide group showed complete remission, whereas 17 patients out of 30 (56.7%) in the dexamethasone group showed complete remission. Erosive area size and VAS score were similar in the two groups.
After 1 month therapy
Complete remission was seen in 24 patients out of 33 (66.7%) in Thalidomide group, and in 22 patients out of 30 (73.3) in the dexamethasone group.
At 3 month follow up
The two groups did not show any major difference in recurrence rate.
At 1 year follow up
Side effects were not reported.
|Topical thalidomide was considered as efficient as dexamethasone in the management of erosive oral lichen planus.|
Table 4: Thalidomide in lichen planus.
Marshall Syndrome is also known as PFAPA syndrome (periodic fever, adenitis, pharyngitis, aphthae). It is characterized by recurrent febrile episodes, accompanied by aphthous ulcers, pharyngitis and cervical adenitis. [58,59]
Numerous controlled studies have recommended different therapeutic regimens. However, the mainstay of treatment of PFAPA syndrome still remains controversial.  The disease usually shows self-remission after several years, although some adults have also reported with persistent attacks.  Utilizing the proven anti-inflammatory and immunomodulatory potential, Marque et al. were the first to report successful management of a refractory case of PFAPA syndrome with thalidomide. 
Thalidomide as an anti-cancer agent
The pioneer observation of thalidomide’s anti-angiogenic properties by D-Amato and colleagues revoked the interest of clinicians to use it as an anticancer agent.  The antiangiogenic potential of thalidomide was further highlighted by studies in rabbit cornea model and isolated rat aorta model. [64-66] Angiogenesis is a complex mechanism that involves various growth factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and plateletderived growth factor (PDGF).  An in vitro study on chicken embryonic chorioallantoic membrane (CAM) was conducted and it was observed that thalidomide has an inhibitory action on VEGF plus bFGF-mediated vessel formation. This antiangiogenic outcome was amplified by preincubation with human microsomes. 
Thalidomide’s anti-angiogenic potential and also the fact that anti-angiogenesis was a suitable target for cancer therapy, justifies the role of thalidomide in the treatment of multiple myeloma (MM) and Kaposi’s sarcoma. 
Thalidomide showed significant efficacy in cases where human herpes virus-8 (HHV-8) was demonstrable both in skin and serum of patients.  A study by Jin X et al. detailed the remedial benefits of thalidomide in OLP and chronic discoid lupus erythematosus (CDLE) and recommended the application of thalidomide as a potential therapeutic regimen for potentially malignant lesions of the oral cavity. 
Orofacial granulomatosis (OFG) is a general terminology that encompasses a variety of disorders, including Melkersson- Rosenthal syndrome, granulomatosis cheilitis, Crohn’s disease, sarcoidosis, and infectious entities such as tuberculosis. It is characterized by non-necrotizing granulomatous inflammation of the oral and maxillofacial region. The condition clinically manifests as perioral and/or mucosal swelling, labial enlargement, oral mucosal ulcerations, and gingivitis.  Few published case reports have shown the role of thalidomide as a successful therapeutic regimen for severe orofacial granulomatosis. [72-74]
Table 5 depicts the role of thalidomide in Orofacial granulomatosis.
|Authors||Year||No. of Patients (n)||Study Details||Clinical Outcome||Remarks|
|Odeka EB, Miller V
|1997||01||oral thalidomide (100 mg daily, later reduced to 50 mg daily was given to a 8 year old male patient with oral Crohn's Disease Refractory to Conventional Medical Treatment (oral prednisolone (2-maximum 60 mg/kg daily and combination of azathioprine and prednisolone).||The pain eased within days, and the ulcers disappeared within 2 weeks.||The patient had longer ulcer-free intervals, and ulcers respond to ad hoc use of TLD 50 mg daily.|
|Hegarty A, Hodgson T, Porter S||2003||05||Low dose thalidomide was given to 5 orofacial granulomatosis patients recalcitrant to recognized immunosuppressant therapy.||All patients had clinical resolution of their symptoms and signs. Transient somnolence was the only reported adverse effect. Remission was maintained by extending the period between thalidomide doses.||Thalidomide should be considered an effective therapy for the short-term treatment of severe orofacial granulomatosis in appropriately counseled patients.|
|Eustace K, Clowry J, Kirby B, Lally A.
|2014||01||100 mg OD (once a day) thalidomide was prescribed to refractory orofacial granulomatosis patient for 8 weeks||Remission was seen following thalidomide therapy.|
Table 5: Thalidomide in orofacial granulomatosis.
Thalidomide is categorized as pregnancy category X drug.
Teratogenicity is the most serious and devastating side effect. 
According to McBride, the teratogenic effects may be categorized as: 
• Abnormalities of the extremity: Amelia (absent limbs), flipper hands and feet (phocomelia), hypoplastic or even absent bones.
• Anomalies of the eyes and ears: absent ears, absent or small auditory canal, absence of one or both eyes (anophthalmia), abnormally small eyes with anatomical malformations (microphthalmia), with or without accompanied facial palsy.
• Internal organ deformities: congenital heart defects, malformed gastrointestinal and urinary tract.
Peripheral neuropathy is another significant adverse effect which should be given a consideration in cases where thalidomide needs to be prescribed.  The most commonly observed neuropathic manifestations include senso-motor symptoms (lack of sensation, prickling, painful extremities, or fatigue), with or without hindrance in daily activities. The condition is usually managed either with dose reduction or cessation of therapy. However, in few individuals, even the treatment cessation could not reverse the condition. [78-80] Table 6 summarizes the various adverse effects of thalidomide.
|Severe||Common ||Uncommon |
Table 6: Adverse effects of thalidomide.
Hence, a number of conducted trials and case studies have established the efficacy of thalidomide in a wide range of clinical entities, resistant to conventional treatment modalities. With its salient immunomodulatory, anti-inflammatory, and anti-angiogenic potential, the drug holds a promising future for the management of variety of medical and dental conditions.
We are grateful to Department of Oral Medicine and Radiology for the support.
Conflict of Interest
All authors disclose that there was no conflict of interest.
- Randall T. Thalidomide has 37-year history. J Am Med Assoc. 1990; 263:1474.
- Stirling D, Sherman M, Strauss S. Thalidomide. A surprising recovery. J Am Pharm Assoc. 1997; NS37: 306-313.
- Grosshans E, Illy G. Thalidomide therapy for inflammatory dermatoses. Int J Dermatol. 1984;25: 598-602.
- McBride WG. Thalidomide and congenital abnormalities. Lancet. 1962;2:1358.
- Fullerton PM, Kremer M. Neuropathy after intake of thalidomide (Distival). Br Med J. 1961; 2:853-858.
- Sheskin J. Further observation with thalidomide in lepra reactions. Lepr Rev. 1965;36:183-187.
- Faver IR, Guerra SG, Su WPD, El-Azhary R. Thalidomide for dermatology: A review of clinical uses and adverse effects. Int J Dermatol. 2005;44:61-67.
- Mubeen K, Siddiq MA, Jigna VR. Thalidomide: An emerging drug in oral mucosal lesions. Clin J Gastroenterol. 2009;2:149-155.
- Hutton KP, Rodgers RS. Recurrent aphthous stomatitis. Dermatol. 1987;5:761-768.
- Ship JA, Arbor A. Recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:141-147.
- Natah SS, HÃ¤yrinen-Immonen R, Hietanen J, MalmstrÃ¶m M, Konttinen YT. Immunolocalization of tumor necrosis factor-a expressing cells in recurrent aphthous ulcer lesions (RAU). Journal of Oral Pathology & Medicine. 2000;29:19-25.
- Paterson DL, Georghiou PR, Allworth AM, Kemp RJ. Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection. Clin Infect Dis. 1995;20:250-254.
- Gardner-Medwin JM, Smith NJ, Powell RJ. Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as BehÃ§et's disease: The use of neurophysiological studies to detect thalidomide neuropathy. Ann Rheum Dis. 1994;53:828-832.
- Thompson C. Thalidomide effective for AIDS-related oral ulcers. Lancet. 1995;346:1289.
- Mascaro JM, Lecha M, Torras H. Thalidomide in the treatment of recurrent, necrotic, and giant mucocutaneous aphthae and aphthosis. Arch Dermatol. 1979;115:636-637.
- Torras H, Lecha M, Mascaro JM. Thalidomide treatment of recurrent necrotic giant mucocutaneous aphthae and aphthosis. Arch Dermatol. 1982;118:875.
- Jenkins JS, Powell RJ, Allen BR, Littlewood SM, Maurice PDL, Smith NJ. Thalidomide in severe orogenital ulceration. Lancet. 1984;2:1424-1426
- Grinspan D. Significant response of oral aphthosis to thalidomide treatment. J Am Acad Dermatol. 1985;12:85-90.
- Ramselaar CG, Boone RM, Kluin-Nelemens HC. Thalidomide in the treatment of neuro-BehÃ§et syndrome. Brit J Dermatol. 1986;115:367-370.
- Revuz J, Guillaume JC, Janier M, Hans P, Marchand C, Souteyrand P, et al. Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis. Archives of Dermatology. 1990;126:923-927.
- Bonnetblanc JM, Royer C, Bedane C. Thalidomide and recurrent aphthous stomatitis: A follow-up study. Dermatology. 1996;193:321-323.
- Mimura MA, Hirota SK, Sugaya NN, Sanches Jr JA, Migliari DA. Systemic treatment in severe cases of recurrent aphthous stomatitis: an open trial. Clinics. 2009;64:193-198.
- Hello M, Barbarot S, Bastuji-Garin S, Revuz J, Chosidow O. Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis. Medicine (Baltimore). 2010;89:176-182.
- Bowers PW, Powell RJ. Effect of thalidomide on orogenital ulceration. BMJ. 1983;287:799-800.
- Sircus W, Church R, Kelleher J. Recurrent aphthous ulceration of the mouth; a study of the natural history, aetiology, and treatment. Q J Med. 1957;26:235-249.
- Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. 2005;49:31-47.
- Natah SS, Konttinen YT, Enattah NS, Ashammakhi N, Sharkey KA, HÃ¤yrinen-Immonen R. Recurrent aphthous ulcers today: A review of the growing knowledge. Int J Oral Maxillofac Surg. 2004;33:221-234.
- Youle M, Clarbour J, Farthing C, Connolly M, Hawkins D, Staughton R, et al. Treatment of resistant aphthous ulceration with thalidomide in patients positive for HIV antibody. BMJ: British Medical Journal. 1989;298:432.
- Weidle PJ. Thalidomide for aphthous ulcers in patients infected with the human immunodeficiency virus. Am J Health Syst Pharm. 1996;53:371-378.
- Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med. 1997;336:1487-1493.
- Ramirez-Amador VA, Esquivel-Pedraza L, Ponce-de-Leon S, Reyes-Teran G, Gonzalez-Guevara M, Ponce-de-Leon S, et al. Thalidomide as therapy for human immunodeficiency virus-related oral ulcers: a double-blind placebo-controlled clinical trial. Clin Infect Dis. 1999;28:892-894.
- Jacobson JM, Greenspan JS, Spritzler J, Fox L, Fahey JL, Jackson JB et al. Thalidomide in low intermittent doses does not prevent recurrence of human immunodeficiency virus-associated aphthous ulcers. J Infect Dis. 2001;183:343-346.
- Nicolau DP, West TE. Thalidomide: Treatment of severe recurrent aphthous stomatitis in patients with AIDS. DICP. 1990;24:1054-1056.
- Shetty K. Thalidomide in the concurrent management of recurrent aphthous ulcerations and Kaposi sarcoma in HIV patients with severe immunosuppression. Oral Oncology extra 2006; 42:26-31.
- Nasca MR, Micali G, Cheigh NH, West LE, West DP. Dermatologic and nondermatologic uses of thalidomide. Annals of Pharmacotherapy. 2003;37:1307-1320.
- H. BehÃ§et. Uber rezidivierende, aphtose, durch ein Virus verursachte GeschwÃ¼re am Mund, am auge und an den Genitalien. Dermatol Wochensch . 1937;105:1152-1157.
- Mendes D, Correia M, Barbedo M, Vaio T, Mota M, GonÃ§alves O, et al. BehÃ§etâs diseaseâA contemporary review. J Autoimmun. 2009;32:178-188.
- Sfikakis PP, Markomichelakis N, Alpsoy E, Assaad-Khalil S, Bodaghi B, Gul A, et al. Anti-TNF therapy in the management of behÃ§etâs disease-review and basis for recommendations. Rheumatology (Oxford) 2007;46:736-741.
- Sfikakis PP. BehÃ§etâs disease: a new target for anti-tumor necrosis factor treatment. Ann Rheum Dis. 2002;61:51-53.
- Hamza MH.Treatment of BehÃ§et's disease with thalidomide. Clin Rheumatol. 1986;5:365-371.
- Jorizzo JL, Schmalstieg FC, Solomon AR Jr, Cavallo T, Taylor RS 3rd, Rudloff HB et al. Thalidomide effects in BehÃ§et's syndrome and pustular vasculitis. Arch Intern Med. 1986;146:878-881.
- Saylan T, Saltik I. Thalidomide in the treatment of Behcet's syndrome. Arch Dermatol. 1982;118:536.
- Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome: A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine. 1998;128:443-450.
- De WaziÃ¨res B, Gil H, Magy N, Berthier S, Vuitton DA, Dupond JL. Treatment of recurrent oro-genital ulceration with low dose of thalidomide. Pilot study in 17 patients. Revue de Medecine Interne. 1999;20:567-570.
- Shek LP, Lee YS, Lee BW, Lehman TJ. Thalidomide responsiveness in an infant with BehÃ§et's syndrome. successfully treated an infant with Behcetâs syndrome. Pediatrics. 1999;103:1295-1297.
- Powell RJ, Allen BR, Jenkins JS, Steele L, Hunneyball I, Maurice PD et al. Investigation and treatment of orogenital ulceration; studies on a possible mode of action of thalidomide. Br J Dermatol 1985;113:141-144.
- Canto AM, MÃ¼ller H, Freitas RR, Santos PS. Oral lichen planus (OLP): Clinical and complementary diagnosis. An Bras Dermatol 2010;85:669-675.
- Sugerman PB, Savage NW, Walsh LJ, Zhao ZZ, Zhou XJ, Khan A, et al. The pathogenesis of oral lichen planus. Crit Rev Oral Biol Med. 2002;13:350-365.
- Patil S, Khandelwal S, Sinha N, Kaswan S, Rahman F, Tipu S. Treatment modalities of oral lichen planus: an update. Journal of Oral Diagnosis. 2016;1.
- Nasca MR, Oâtoole EA, Palicharia P, West DP, Woodley DT. Thalidomide increase human keratinocyte migration and proliferation. J Invest Dermatol 1999;113:720-724.
- Naafs B, Faber WR. Thalidomide therapy: An open trial. Int J Dermatol. 1985;24131-24134.
- Wu Y, Zhou G, Zeng H, Xiong CR, Lin M, Zhou HM. A randomized double-blind, positive-control trial of topical thalidomide in erosive oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;110:188-195.
- Camisa C, Popovsky JL Effective treatment of oral erosive lichen planus with thalidomide. Arch Dermatol 2000;1361442-1361443.
- Perez Alfonzo R, Weiss E, Piquero Martin J, Rondon Lugo A. Generalized lichen planus with erosive lesions of the penis, treated with thalidomide. Report of a case and review of the literature. Med Cutan Ibero Lat Am. 1987;15:321-326.
- Dereure O, Basset-Seguin N, Guilhou JJ. Erosive lichen planus: dramatic response to thalidomide. Arch Dermatol. 1996;118:536.
- Macario-Barrel, X. Balguerie, P. Joly. Treatment of erosive oral lichen planus with thalidomide. Ann Dermatol Venereol. 2003;130:1109-1112.
- Torti DC, Jorizzo JL, McCarty MA. Oral lichen planus: A case series with emphasis on therapy. Arch Dermatol. 2007;143:511-515.
- Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphtous stomatitis. J Pediatr. 1987;110:43-46.
- Thomas KT, Feder HM, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. 1999;135:15-21.
- Leong SCL, Karkos PD, Apostolidou MT. Is there a role for the otolaryngologist in PFAPA syndrome? A systematic review. Int J Pediatr Otolaryngol 2006;11.
- Ridder GJ, Fradis M, Berner R, Lohle E. PFAPA syndrome: Current standard of knowledge and relevance for the ENT specialist. Laryngorhinootologie 2002; 81:635-639.
- Marque M, Guillot B, Bessis D. Thalidomide for treatment of PFAPA syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103:306-307.
- Folkman J. Tumor Angiogenesis: Therapeutic Implications. N Engl J Med 1971;285:1182-1186.
- Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol. 1998;55:1827-1834.
- D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082-4085.
- Kenyon BM, Browne F, D'Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res. 1997;64:971-978.
- Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature. 2005;438:937-945.
- Marks MG, Shi J, Fry MO, Xiao Z, Trzyna M, Pokala V, et al. Effects of putative hydroxylated thalidomide metabolites on blood vessel density in the chorioallantoic membrane (CAM) assay and on tumor and endothelial cell proliferation. Biol Pharm Bull 2002;25:597-604.
- Viejo-Borbolla A, Schultz TF. Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV8): Key Aspects of Epidemiology and Pathogenesis. AIDS Rev 2003;5:222-229.
- Jin X, Lu S, Xing X, Wang L, Mu D, He M, et al. Thalidomide: features and potential significance in oral precancerous conditions and oral cancer. J Oral Pathol Med. 2013;42:355-362.
- Rana AP. Orofacial granulomatosis: A case report with review of literature. J Indian Soc Periodontol 2012;16:469-474.
- Odeka EB, Miller V. Thalidomide in oral Crohnâs disease refractory to conventional medical treatment. J Pediatr Gastroenterol Nutr 1997;25:250-251.
- Hegarty A, Hodgson T, Porter S. Thalidomide for the treatment of recalcitrant oral Crohnâs disease and orofacial granulomatosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:576-585.
- Eustace K, Clowry J, Kirby B, Lally A. Thalidomide in the treatment of refractory orofacial granulomatosis. Br J Dermatol 2014;171:423-425.
- Randomsky CL, Levine N. Thalidomide. Dermatol Clinics 2001;19:87-103.
- McBride W. Thalidomide embryopathy. Teratology. 1977;16:79-82.
- Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol. 1996;35:969-979.
- Rajkumar SV, Gertz MA, Kyle RA, Greipp PR. Thalidomide- induced neuropathyâin reply. Mayo Clinic Proc. 2002; 77:1395.
- Ghobrial IM, Rajkumar SV. Management of thalidomide toxicity. J Support Oncol 2003;1:194-205.
- Sadau Y, Adelaiye AB, Magaji RA, Ayo JO, Mabrouk MA, Isa AI. Role of selenium and vitamin E on gastric mucosal damage induced by water-immersion restraint stress in wistar rats. IOSR J. Pharm. Biol. Sci. 2015;10:34-39.