1066
References 1 Swetter SM, Pollitt RA, Johnson TM et al. Behavioral determinants of successful early melanoma detection: role of self and physician skin examination. Cancer 2012; 118: 3725–3734. 2 Lamerson CL, Eaton K, Sax JL et al. Comparing melanoma invasiveness in dermatologist-versus patient-detected lesions: a retrospective chart review. J Skin Cancer 2012; 2012: 187963. 3 Terushkin V, Halpern AC. Melanoma early detection. Hematol Oncol Clin North Am 2009; 23: 481–500. 4 Federman DG, Kravetz JD, Kirsner RS. Skin cancer screening by dermatologists: prevalence and barriers. J Am Acad Dermatol 2002; 46: 710–714. 5 Geller AC, Koh HK, Miller DR et al. Use of health services before the diagnosis of melanoma: implications for early detection and screening. J Gen Intern Med 1992; 7: 154–157. 6 Argenziano G, Zalaudek I, Hofmann-Wellenhof R et al. Total body skin examination for skin cancer screening in patients with focused symptoms. J Am Acad Dermatol 2012; 66: 212–219. 7 Oliveria SA, Heneghan MK, Cushman LF et al. Skin cancer screening by dermatologists, family practitioners, and internists: barriers and facilitating factors. Arch Dermatol 2011; 147: 39–44. 8 Geller AC, Johnson TM, Miller DR et al. Factors associated with physician discovery of early melanoma in middle-aged and older men. Arch Dermatol 2009; 145: 409–414. 9 Zalaudek I, Kittler H, Marghoob AA et al. Time required for a complete skin examination with and without dermoscopy: a prospective, randomized multicenter study. Arch Dermatol 2008; 144: 509– 513. DOI: 10.1111/jdv.13113
Tofacitinib, a novel JAK3 inhibitor, as a potential cause of distal symmetric polyneuropathy Sir A 35-year-old man suffering from psoriasis vulgaris since 1997 participated in a multi-centre phase 3 clinical trial to evaluate the efficacy and safety of tofacitinib in the treatment of psoriasis. Tofacitinib is a novel small molecule drug for the treatment of chronic inflammatory diseases. The orally active, highly selective, Janus-activated kinase-3 (JAK3) inhibitor has been licensed for treatment of rheumatoid arthritis in the USA and Russia, and is still in the testing phase for diseases such as psoriasis and psoriasis arthritis. JAK3 is essential for cytokine signal transduction, which manages lymphocyte survival, proliferation, differentiation and apoptosis.1 In phase II, III and long-term extension studies, the most frequent reported adverse events were respiratory infections, nausea, mild headache, increases in LDL-C and HDL-C levels, and a decrease in neutrophil counts.2,3 The patient took part in the randomized placebo-controlled dose-ranging study from January 2012 till January 2013; he had no other comorbidity and was not taking any other drugs. He was randomized to the dose of tofacitinib 10 mg BID. During
JEADV 2016, 30, 1025–1067
Letters to the Editor
treatment, the Psoriasis Area and Severity Index (PASI) decreased from 29.1 to 3.6 points, the affected body surface area from 34.0 to 3.0%. During the study, he suffered no adverse events except once a common cold and mild bronchitis. In January 2013, he was switched to the open-label follow-up study, which was also a multicentre, but not placebo-controlled, clinical trial for evaluating the efficacy and safety of tofacitinib in two dosages. He continued to take a dose of 10 mg BID. Four months after entering the open-label phase, the patient suffered from infection of the upper respiratory tract. Two months later, he complained of tremor in his hands as also vegetative changes such as increased sweating in his hands. He also reported distinct muscular weakness of the extremities and sensory disturbances. In addition, he felt as if his hands and feet were severely constricted during the night. Neurological examination showed loss of deep ankle reflexes, hyperesthaesia, paraesthesia and allodynia in his hands and feet. A mild 6–7 Hz tremor of upper extremities was observed. Motor and sensory neurography of the median, ulnar sural, peroneal and tibial nerve was normal. Sensoryevoked potentials (SEP) of the upper extremities were normal and those of the lower extremities showed a delay; motor-evoked potentials were normal. Skin biopsy was taken from lesional skin (plantar) and immunostained for protein gene product 95. According to the guideline of the European Federation of Neurological Societies, the intraepidermal nerve fibre density (IENF) per millimetre was determined. Skin biopsy showed decreased IENF density (0.6 f/mm), and small fibre neuropathy as a variant of distal symmetric polyneuropathy (DSP) was diagnosed (Fig. 1). To exclude other causes of DSP, chest X-ray, ultrasound of the abdomen and thyroid, extensive laboratory investigations
Figure 1 Cutaneous dermal nerve fibres stain for PGP 9.5 (arrows) but do not cross basement membrane (insert, arrow) and are not present in the epidermis (star) except single nerve fibres in the whole specimen (intraepidermal nerve fibre density 0.6–1.1 F/mm).
© 2015 European Academy of Dermatology and Venereology
Letters to the Editor
(blood serology parameters including liver and renal values, thyroid stimulating hormone, HbA1c, ferritin, differential blood count, vitamin B12, folic acid, serologies for infectious diseases such as HIV and borrelia, tumour markers [CEA], serum protein and immunoelectrophoresis/immunofixation, antinuclear antibodies) were performed. However, the tests did not show any abnormalities. As a whole, there was no evidence for an internistic cause of the patient’s complaints. Therefore, tofacitinib was suspected to be the culprit that was responsible for inducing DSP and was immediately stopped. Therapy with pregabalin was proposed, but not accepted by the patient due to fear of potential sideeffects. After 3 months, first reduction in clinical symptoms of DSP was noticed. At a follow-up visit 11 months later, all symptoms had normalized including the delay in SEP. Control of skin punch biopsy 10 months after termination of tofacitinib showed improvement in IENF density from 0.6 f/mm to 1.1 f/mm but normal ranges were not found. This is the first report of the development of DSP during treatment with tofacitinib. DSP in this case was established by clinical and technical procedures such as SEP and skin biopsy. In our patient, remission of DSP took almost 1 year as is often observed in toxic DSP.4 According to the information from the Investigator‘s Brochure (IB), only the appearance of paresthaesia has been rarely described (uncommon and rare: >1/1000 to
References 1 Swetter SM, Pollitt RA, Johnson TM et al. Behavioral determinants of successful early melanoma detection: role of self and physician skin examination. Cancer 2012; 118: 3725–3734. 2 Lamerson CL, Eaton K, Sax JL et al. Comparing melanoma invasiveness in dermatologist-versus patient-detected lesions: a retrospective chart review. J Skin Cancer 2012; 2012: 187963. 3 Terushkin V, Halpern AC. Melanoma early detection. Hematol Oncol Clin North Am 2009; 23: 481–500. 4 Federman DG, Kravetz JD, Kirsner RS. Skin cancer screening by dermatologists: prevalence and barriers. J Am Acad Dermatol 2002; 46: 710–714. 5 Geller AC, Koh HK, Miller DR et al. Use of health services before the diagnosis of melanoma: implications for early detection and screening. J Gen Intern Med 1992; 7: 154–157. 6 Argenziano G, Zalaudek I, Hofmann-Wellenhof R et al. Total body skin examination for skin cancer screening in patients with focused symptoms. J Am Acad Dermatol 2012; 66: 212–219. 7 Oliveria SA, Heneghan MK, Cushman LF et al. Skin cancer screening by dermatologists, family practitioners, and internists: barriers and facilitating factors. Arch Dermatol 2011; 147: 39–44. 8 Geller AC, Johnson TM, Miller DR et al. Factors associated with physician discovery of early melanoma in middle-aged and older men. Arch Dermatol 2009; 145: 409–414. 9 Zalaudek I, Kittler H, Marghoob AA et al. Time required for a complete skin examination with and without dermoscopy: a prospective, randomized multicenter study. Arch Dermatol 2008; 144: 509– 513. DOI: 10.1111/jdv.13113
Tofacitinib, a novel JAK3 inhibitor, as a potential cause of distal symmetric polyneuropathy Sir A 35-year-old man suffering from psoriasis vulgaris since 1997 participated in a multi-centre phase 3 clinical trial to evaluate the efficacy and safety of tofacitinib in the treatment of psoriasis. Tofacitinib is a novel small molecule drug for the treatment of chronic inflammatory diseases. The orally active, highly selective, Janus-activated kinase-3 (JAK3) inhibitor has been licensed for treatment of rheumatoid arthritis in the USA and Russia, and is still in the testing phase for diseases such as psoriasis and psoriasis arthritis. JAK3 is essential for cytokine signal transduction, which manages lymphocyte survival, proliferation, differentiation and apoptosis.1 In phase II, III and long-term extension studies, the most frequent reported adverse events were respiratory infections, nausea, mild headache, increases in LDL-C and HDL-C levels, and a decrease in neutrophil counts.2,3 The patient took part in the randomized placebo-controlled dose-ranging study from January 2012 till January 2013; he had no other comorbidity and was not taking any other drugs. He was randomized to the dose of tofacitinib 10 mg BID. During
JEADV 2016, 30, 1025–1067
Letters to the Editor
treatment, the Psoriasis Area and Severity Index (PASI) decreased from 29.1 to 3.6 points, the affected body surface area from 34.0 to 3.0%. During the study, he suffered no adverse events except once a common cold and mild bronchitis. In January 2013, he was switched to the open-label follow-up study, which was also a multicentre, but not placebo-controlled, clinical trial for evaluating the efficacy and safety of tofacitinib in two dosages. He continued to take a dose of 10 mg BID. Four months after entering the open-label phase, the patient suffered from infection of the upper respiratory tract. Two months later, he complained of tremor in his hands as also vegetative changes such as increased sweating in his hands. He also reported distinct muscular weakness of the extremities and sensory disturbances. In addition, he felt as if his hands and feet were severely constricted during the night. Neurological examination showed loss of deep ankle reflexes, hyperesthaesia, paraesthesia and allodynia in his hands and feet. A mild 6–7 Hz tremor of upper extremities was observed. Motor and sensory neurography of the median, ulnar sural, peroneal and tibial nerve was normal. Sensoryevoked potentials (SEP) of the upper extremities were normal and those of the lower extremities showed a delay; motor-evoked potentials were normal. Skin biopsy was taken from lesional skin (plantar) and immunostained for protein gene product 95. According to the guideline of the European Federation of Neurological Societies, the intraepidermal nerve fibre density (IENF) per millimetre was determined. Skin biopsy showed decreased IENF density (0.6 f/mm), and small fibre neuropathy as a variant of distal symmetric polyneuropathy (DSP) was diagnosed (Fig. 1). To exclude other causes of DSP, chest X-ray, ultrasound of the abdomen and thyroid, extensive laboratory investigations
Figure 1 Cutaneous dermal nerve fibres stain for PGP 9.5 (arrows) but do not cross basement membrane (insert, arrow) and are not present in the epidermis (star) except single nerve fibres in the whole specimen (intraepidermal nerve fibre density 0.6–1.1 F/mm).
© 2015 European Academy of Dermatology and Venereology
Letters to the Editor
(blood serology parameters including liver and renal values, thyroid stimulating hormone, HbA1c, ferritin, differential blood count, vitamin B12, folic acid, serologies for infectious diseases such as HIV and borrelia, tumour markers [CEA], serum protein and immunoelectrophoresis/immunofixation, antinuclear antibodies) were performed. However, the tests did not show any abnormalities. As a whole, there was no evidence for an internistic cause of the patient’s complaints. Therefore, tofacitinib was suspected to be the culprit that was responsible for inducing DSP and was immediately stopped. Therapy with pregabalin was proposed, but not accepted by the patient due to fear of potential sideeffects. After 3 months, first reduction in clinical symptoms of DSP was noticed. At a follow-up visit 11 months later, all symptoms had normalized including the delay in SEP. Control of skin punch biopsy 10 months after termination of tofacitinib showed improvement in IENF density from 0.6 f/mm to 1.1 f/mm but normal ranges were not found. This is the first report of the development of DSP during treatment with tofacitinib. DSP in this case was established by clinical and technical procedures such as SEP and skin biopsy. In our patient, remission of DSP took almost 1 year as is often observed in toxic DSP.4 According to the information from the Investigator‘s Brochure (IB), only the appearance of paresthaesia has been rarely described (uncommon and rare: >1/1000 to
