Article

Psoriasis is an inflammatory skin condition affecting 1% to 5% of the world population. ¹ Guttate psoriasis is a subgroup of psoriasis that most commonly presents as raindroplike, erythematous, silvery, scaly papules. There have been limited reports of guttate psoriasis caused by rhinovirus and COVID-19 infection, but a PubMed search of articles indexed for MEDLINE using the term COVID-19 guttate psoriasis yielded only 3 documented cases of a psoriatic flare secondary to SARS-CoV-2 infection. ^1-4 Herein, we detail a case in which a patient with mild SARS-CoV-2 infection who did not have a personal or family history of psoriasis experienced a moderate psoriatic flare 3 weeks after diagnosis of COVID-19.

Case Report

A 55-year-old woman was diagnosed with COVID-19 after SARS-CoV-2 RNA was detected from a nasopharyngeal swab. She reported moderate fatigue but no other symptoms. At the time of infection, she was not taking medications and reported neither a personal nor family history of psoriasis.

Three weeks after the COVID-19 diagnosis, she reported erythematous scaly papules only on the trunk and backs of the legs. Two months after the COVID-19 diagnosis, she was evaluated in our practice and diagnosed with guttate psoriasis. The patient refused biopsy. Physical examination revealed that the affected body surface area had increased to 5%; erythematous, silvery, scaly papules were found on the trunk, anterior and posterior legs, and lateral thighs (Figure). At the time of evaluation, she did not report joint pain or nail changes.

The patient was treated with triamcinolone acetonide cream 0.1% twice daily for 2 to 4 weeks. The guttate psoriasis resolved.

Comment

A sudden psoriatic flare can be linked to dysregulation of the innate immune response. Guttate psoriasis and generalized plaque-type psoriasis are postulated to have similar pathogenetic mechanisms, but guttate psoriasis is the only type of psoriasis that originates from viral infection. Initially, viral RNA will stimulate the toll-like receptor 3 protein, leading to increased production of the pathogenic cytokine IL-36γ and pathogenic chemokine CXCL8 (also known as IL-8), both of which are biomarkers for psoriasis.¹ Specifically, IL-36γ and CXCL8 are known to further stimulate the proinflammatory cascade during the innate immune response displayed in guttate psoriasis.^5,6

Our patient had a mild case of COVID-19, and she first reported the erythematous and scaly papules 3 weeks after infection. Dysregulation of proinflammatory cytokines must have started in the initial stages—within 7 days—of the viral infection. Guttate psoriasis arises within 3 weeks of infection with other viral and bacterial triggers, most commonly with streptococcal infections.¹

Rodríguez et al⁷ described a phenomenon in which both SARS-CoV-2 and Middle East respiratory syndrome, both caused by a coronavirus, can lead to a reduction of type I interferon, which in turn leads to failure of control of viral replication during initial stages of a viral infection. This triggers an increase in proinflammatory cytokines and chemokines, including IL‐36γ and CXCL8. This pathologic mechanism might apply to SARS-CoV-2, as demonstrated in our patient’s sudden psoriatic flare 3 weeks after the COVID-19 diagnosis. However, further investigation and quantification of the putatively involved cytokines is necessary for confirmation.

Psoriasis, a chronic inflammatory skin condition, has been linked predominantly to genetic and environmental factors. Guttate psoriasis as a secondary reaction after streptococcal tonsillar and respiratory infections has been reported.¹

Our case is the fourth documented case of guttate psoriasis secondary to COVID-19 infection.^2-4 However, it is the second documented case of a patient with a diagnosis of guttate psoriasis secondary to COVID-19 infection who had neither a personal nor family history of psoriasis.

Because SARS-CoV-2 is a novel virus, the long-term effects of COVID-19 remain unclear. We report this case and its findings to introduce a novel clinical manifestation of SARS-CoV-2 infection. 

Psoriasis is an inflammatory skin condition affecting 1% to 5% of the world population. ¹ Guttate psoriasis is a subgroup of psoriasis that most commonly presents as raindroplike, erythematous, silvery, scaly papules. There have been limited reports of guttate psoriasis caused by rhinovirus and COVID-19 infection, but a PubMed search of articles indexed for MEDLINE using the term COVID-19 guttate psoriasis yielded only 3 documented cases of a psoriatic flare secondary to SARS-CoV-2 infection. ^1-4 Herein, we detail a case in which a patient with mild SARS-CoV-2 infection who did not have a personal or family history of psoriasis experienced a moderate psoriatic flare 3 weeks after diagnosis of COVID-19.

Case Report

A 55-year-old woman was diagnosed with COVID-19 after SARS-CoV-2 RNA was detected from a nasopharyngeal swab. She reported moderate fatigue but no other symptoms. At the time of infection, she was not taking medications and reported neither a personal nor family history of psoriasis.

Three weeks after the COVID-19 diagnosis, she reported erythematous scaly papules only on the trunk and backs of the legs. Two months after the COVID-19 diagnosis, she was evaluated in our practice and diagnosed with guttate psoriasis. The patient refused biopsy. Physical examination revealed that the affected body surface area had increased to 5%; erythematous, silvery, scaly papules were found on the trunk, anterior and posterior legs, and lateral thighs (Figure). At the time of evaluation, she did not report joint pain or nail changes.

The patient was treated with triamcinolone acetonide cream 0.1% twice daily for 2 to 4 weeks. The guttate psoriasis resolved.

Comment

A sudden psoriatic flare can be linked to dysregulation of the innate immune response. Guttate psoriasis and generalized plaque-type psoriasis are postulated to have similar pathogenetic mechanisms, but guttate psoriasis is the only type of psoriasis that originates from viral infection. Initially, viral RNA will stimulate the toll-like receptor 3 protein, leading to increased production of the pathogenic cytokine IL-36γ and pathogenic chemokine CXCL8 (also known as IL-8), both of which are biomarkers for psoriasis.¹ Specifically, IL-36γ and CXCL8 are known to further stimulate the proinflammatory cascade during the innate immune response displayed in guttate psoriasis.^5,6

Our patient had a mild case of COVID-19, and she first reported the erythematous and scaly papules 3 weeks after infection. Dysregulation of proinflammatory cytokines must have started in the initial stages—within 7 days—of the viral infection. Guttate psoriasis arises within 3 weeks of infection with other viral and bacterial triggers, most commonly with streptococcal infections.¹

Rodríguez et al⁷ described a phenomenon in which both SARS-CoV-2 and Middle East respiratory syndrome, both caused by a coronavirus, can lead to a reduction of type I interferon, which in turn leads to failure of control of viral replication during initial stages of a viral infection. This triggers an increase in proinflammatory cytokines and chemokines, including IL‐36γ and CXCL8. This pathologic mechanism might apply to SARS-CoV-2, as demonstrated in our patient’s sudden psoriatic flare 3 weeks after the COVID-19 diagnosis. However, further investigation and quantification of the putatively involved cytokines is necessary for confirmation.

Psoriasis, a chronic inflammatory skin condition, has been linked predominantly to genetic and environmental factors. Guttate psoriasis as a secondary reaction after streptococcal tonsillar and respiratory infections has been reported.¹

Our case is the fourth documented case of guttate psoriasis secondary to COVID-19 infection.^2-4 However, it is the second documented case of a patient with a diagnosis of guttate psoriasis secondary to COVID-19 infection who had neither a personal nor family history of psoriasis.

Because SARS-CoV-2 is a novel virus, the long-term effects of COVID-19 remain unclear. We report this case and its findings to introduce a novel clinical manifestation of SARS-CoV-2 infection. 

Psoriasis is an inflammatory skin condition affecting 1% to 5% of the world population. ¹ Guttate psoriasis is a subgroup of psoriasis that most commonly presents as raindroplike, erythematous, silvery, scaly papules. There have been limited reports of guttate psoriasis caused by rhinovirus and COVID-19 infection, but a PubMed search of articles indexed for MEDLINE using the term COVID-19 guttate psoriasis yielded only 3 documented cases of a psoriatic flare secondary to SARS-CoV-2 infection. ^1-4 Herein, we detail a case in which a patient with mild SARS-CoV-2 infection who did not have a personal or family history of psoriasis experienced a moderate psoriatic flare 3 weeks after diagnosis of COVID-19.

Case Report

A 55-year-old woman was diagnosed with COVID-19 after SARS-CoV-2 RNA was detected from a nasopharyngeal swab. She reported moderate fatigue but no other symptoms. At the time of infection, she was not taking medications and reported neither a personal nor family history of psoriasis.

Three weeks after the COVID-19 diagnosis, she reported erythematous scaly papules only on the trunk and backs of the legs. Two months after the COVID-19 diagnosis, she was evaluated in our practice and diagnosed with guttate psoriasis. The patient refused biopsy. Physical examination revealed that the affected body surface area had increased to 5%; erythematous, silvery, scaly papules were found on the trunk, anterior and posterior legs, and lateral thighs (Figure). At the time of evaluation, she did not report joint pain or nail changes.

The patient was treated with triamcinolone acetonide cream 0.1% twice daily for 2 to 4 weeks. The guttate psoriasis resolved.

Comment

A sudden psoriatic flare can be linked to dysregulation of the innate immune response. Guttate psoriasis and generalized plaque-type psoriasis are postulated to have similar pathogenetic mechanisms, but guttate psoriasis is the only type of psoriasis that originates from viral infection. Initially, viral RNA will stimulate the toll-like receptor 3 protein, leading to increased production of the pathogenic cytokine IL-36γ and pathogenic chemokine CXCL8 (also known as IL-8), both of which are biomarkers for psoriasis.¹ Specifically, IL-36γ and CXCL8 are known to further stimulate the proinflammatory cascade during the innate immune response displayed in guttate psoriasis.^5,6

Our patient had a mild case of COVID-19, and she first reported the erythematous and scaly papules 3 weeks after infection. Dysregulation of proinflammatory cytokines must have started in the initial stages—within 7 days—of the viral infection. Guttate psoriasis arises within 3 weeks of infection with other viral and bacterial triggers, most commonly with streptococcal infections.¹

Rodríguez et al⁷ described a phenomenon in which both SARS-CoV-2 and Middle East respiratory syndrome, both caused by a coronavirus, can lead to a reduction of type I interferon, which in turn leads to failure of control of viral replication during initial stages of a viral infection. This triggers an increase in proinflammatory cytokines and chemokines, including IL‐36γ and CXCL8. This pathologic mechanism might apply to SARS-CoV-2, as demonstrated in our patient’s sudden psoriatic flare 3 weeks after the COVID-19 diagnosis. However, further investigation and quantification of the putatively involved cytokines is necessary for confirmation.

Psoriasis, a chronic inflammatory skin condition, has been linked predominantly to genetic and environmental factors. Guttate psoriasis as a secondary reaction after streptococcal tonsillar and respiratory infections has been reported.¹

Our case is the fourth documented case of guttate psoriasis secondary to COVID-19 infection.^2-4 However, it is the second documented case of a patient with a diagnosis of guttate psoriasis secondary to COVID-19 infection who had neither a personal nor family history of psoriasis.

Because SARS-CoV-2 is a novel virus, the long-term effects of COVID-19 remain unclear. We report this case and its findings to introduce a novel clinical manifestation of SARS-CoV-2 infection. 

Central centrifugal cicatricial alopecia (CCCA), traction alopecia, and acquired proximal trichorrhexis nodosa are 3 forms of alopecia that disproportionately affect women of African descent.¹ Central centrifugal cicatricial alopecia is characterized by a shiny smooth patch of hair loss over the vertex of the scalp that spreads centrifugally (Figure 1).^1-4 Traction alopecia results from prolonged or repeated tension on the hair root that causes mechanical damage, hair loss, and shortening of hairs along the frontotemporal line (the so-called fringe sign)(Figure 2).^1,3,5 Acquired proximal trichorrhexis nodosa, a result of trauma, is identified by a substantial number of hairs breaking off midshaft during a hair pull test.¹ By understanding the unique structural properties and grooming methods of hair in women of African descent, physicians can better manage and stop the progression of hair loss before it becomes permanent.^1,4,5

The characterization of hair between and within ethnic groups is challenging and lies on a spectrum.^6,7 Many early studies broadly differentiated hair in 3 ethnic subgroups: African, Asian, and Caucasian^6-8; older descriptions of hair texture also included terms such as straight, wavy, curly, and kinky.⁶ However, defining hair texture should be based on an approach that is more objective than an inaccurate ethnicity-based classification or the use of subjective, ill-defined, and overlapping descriptive terms.⁷ The segmentation tree analysis method (STAM) is an objective classification system that, when applied to hair, yields 8 curl-type groups (I=straight; VIII=tightly curly) based on curve diameter, curl index, number of waves, and twists.^6-9 (We discuss the “tightly coiled” [group VII] through “tight, interwoven small curls” [group VIII] groups in the STAM classification of hair.)

Highly textured hair has been found to be more susceptible to breakage than other hair types because of an increased percentage of spirals and relatively fewer elastic fibers anchoring hair follicles to the dermis.^1-4,10,11 In a cross-section, the hair shaft of individuals of African descent tends to be more elliptical and kidney shaped than the hair shaft of Asian individuals, which is round and has a large diameter, and the hair shaft of Caucasian individuals, which structurally lies between African and Asian hair.^1,2,4,11 This axial asymmetry and section size contributes to points of lower tensile strength and increased fragility, which are exacerbated by everyday combing and grooming. Curvature of the hair follicle leads to the characteristic curly and spiral nature of African hair, which can lead to increased knotting.^2,4

Practice Gap

Among women of African descent, a variety of hairstyles and hair treatments frequently are employed to allow for ease of management and self-expression.¹ Many of these practices have been implicated as risk factors for alopecia. Simply advising patients to avoid tight hairstyles is ineffective because tension is subjective and difficult to quantify.⁵ Furthermore, it might be unreasonable to ask a patient to discontinue a hairstyle or treatment when they are unaware of less damaging alternatives.^3,5

We provide an overview of hairstyles for patients who have highly textured hair so that physicians can better identify high-risk hairstyles and provide individualized recommendations for safer alternatives.^1,3,5

Techniques for Hair Straightening

Traditional thermal straightening uses a hot comb or flat iron^1,2,4,12 to temporarily disrupt hydrogen bonds within the hair shafts, which is reversible with exposure to moisture.^1,2,4,5 Patients repeat this process every 1 or 2 weeks to offset the effects of normal perspiration and environmental humidity.^5,12 Thermal straightening techniques can lead to increased fragility of the hair shaft and loss of tensile strength.¹¹

Alternate methods of hair straightening use lye (sodium hydroxide) or nonlye (lithium and guanidine hydroxide) “relaxers” to permanently disrupt hydrogen and disulfide bonds in the hair shaft, which can damage and weaken hair.^1-5,11,12 Touch-ups to the roots often are performed every 6 to 8 weeks.^1,2

Chemical relaxers historically have been associated with CCCA but have not been definitively implicated as causative.^2,3,4,13 Most studies have not demonstrated a statistically significant association between chemical relaxers and CCCA because, with a few exceptions,¹³ studies have either been based on surveys or have not employed trichoscopy or scalp biopsy. In one of those studies, patients with CCCA were determined to be 12.37 times more likely to have used a chemical relaxer in the past (P<.001).¹³ In another study of 39 women in Nigeria, those who had frequent and prolonged use of a chemical relaxer developed scarring alopecia more often than those who did not use a chemical relaxer (P<.0001). However, it is now known that the pathogenesis of CCCA may be related to an upregulation in genes implicated in fibroproliferative disorders (FPDs), a group of conditions characterized by aberrant wound healing, low-grade inflammation and irritation, and excessive fibrosis.¹⁴ They include systemic sclerosis, keloids, atherosclerosis, and uterine fibroids. The risk for certain FPDs is increased in individuals of African descent, and this increased risk is thought to be secondary to the protective effect that profibrotic alleles offer against helminths found in sub-Saharan Africa. A study of 5 patients with biopsy-proven CCCA found that there was increased expression of platelet-derived growth factor gene, PDGF; collagen I gene, COL I; collagen III gene, COL III; matrix metallopeptidase 1 gene, MMP1; matrix metallopeptidase 2 gene, MMP2; matrix metallopeptidase 7 gene, MMP7; and matrix metallopeptidase 9 gene, MMP9, in an affected scalp compared with an unaffected scalp.¹⁴ Still, chemical relaxers weaken the hair shaft and follicle structure, increasing the possibility of hair breakage and allowing for inflammation and trauma to render negative follicular effects.^3,13

The following interventions can be recommended to patients who thermally or chemically treat their hair to prevent hair damage:

• Decrease the frequency of thermal straightening.
• Use lower heat settings on flat irons and blow-dryers.
• Thermally straighten only clean dry hair.
• Regularly trim split ends.
• Use moisturizing shampoos and conditioners.
• Have a trained professional apply a chemical relaxer, if affordable.
• Consider decreasing (1) the frequency of chemical relaxer touch-up (to every 8 to 10 weeks) and (2) the overall manipulation of hair. There is a fine balance between not treating often enough and treating too often: The transition point between chemically processed hair and grown-out roots is a high-tension breakage point.
• Apply a thick protective emollient (known as scalp basing) to the scalp before applying a relaxer^1,5; this protects the scalp from irritation.

Techniques for Braids, Weaves, and Twists

Braids and cornrows, sewn-in or glued-on extensions and weaves, and twists are popular hairstyles. When applied improperly, however, they also can lead to alopecia.^1-5,11,12 When braids are too tight, the patient might complain of headache. Characteristic tenting—hair pulled so tight that the scalp is raised—might be observed.^3,5 Twists are achieved by interlocking 2 pieces of hair, which are held together by styling gel.^1,4 When twists remain over many months, hair eventually knots or tangles into a permanent locking pattern (also known as dreadlocks, dreads, or locs).^1,2,4 In some cases, the persistent weight of dreadlocks results in hair breakage.^1,3,5

The following recommendations can be made to patients who style their hair with braids or cornrows, extensions or weaves, twists, or dreadlocks:

• Apply these styles with as little traction as possible.
• Change the direction in which braids and cornrows are styled frequently to avoid constant tension over the same areas.
• Opt for larger-diameter braids and twists.
• Leave these styles in place no longer than 2 or 3 months; consider removing extensions and weaves every 3 or 4 weeks.
• Remove extensions and weaves if they cause pain or irritation.
• Avoid the use of glue; opt for loosely sewn-in extensions and weaves.
• Consider the alternative of crochet braiding; this is a protective way to apply extensions to hair and can be worn straight, curly, braided, or twisted.^5,12

Techniques for Other Hairstyling Practices

Low-hanging ponytails or buns, wigs, and natural hairstyles generally are considered safe when applied correctly.^1,5 The following recommendations can be made to patients who have a low-hanging ponytail, bun, wig, or other natural hairstyle:

• Before a wig is applied, hold the hair against the scalp with a cotton, nylon, or satin wig cap and with clips, tapes, or bonds. Because satin does not cause constant friction or absorb moisture, it is the safest material for a wig cap.⁵
• Achieve a natural hairstyle by cutting off chemically processed hair and allowing hair to grow out.⁵
• Hair that has not been thermally or chemically processed better withstands the stresses of traction, pulling, and brushing.⁵
• For women with natural hair, wash hair at least every 2 weeks and moisturize frequently.^5,12
• Caution patients that adding synthetic or human hair (ie, extensions, weaves) to any hairstyle to increase volume or length using glue or sewing techniques^1-4,11 can cause problems. The extra weight and tension of extensions and weaves can lead to alopecia. Glue can trigger an irritant or allergic reaction, especially in women who have a latex allergy.^1,4,5,11

Practice Implications

Women of African descent might be more susceptible to alopecia because of the distinctive structural properties of their hair and the various hair treatments and styles they often employ. Physicians should be knowledgeable when counseling these patients on their hair care practices. It also is important to understand that it might not be feasible for a patient to completely discontinue a hair treatment or style. In that situation, be prepared to make recommendations for safer hairstyling practices.

Central centrifugal cicatricial alopecia (CCCA), traction alopecia, and acquired proximal trichorrhexis nodosa are 3 forms of alopecia that disproportionately affect women of African descent.¹ Central centrifugal cicatricial alopecia is characterized by a shiny smooth patch of hair loss over the vertex of the scalp that spreads centrifugally (Figure 1).^1-4 Traction alopecia results from prolonged or repeated tension on the hair root that causes mechanical damage, hair loss, and shortening of hairs along the frontotemporal line (the so-called fringe sign)(Figure 2).^1,3,5 Acquired proximal trichorrhexis nodosa, a result of trauma, is identified by a substantial number of hairs breaking off midshaft during a hair pull test.¹ By understanding the unique structural properties and grooming methods of hair in women of African descent, physicians can better manage and stop the progression of hair loss before it becomes permanent.^1,4,5

The characterization of hair between and within ethnic groups is challenging and lies on a spectrum.^6,7 Many early studies broadly differentiated hair in 3 ethnic subgroups: African, Asian, and Caucasian^6-8; older descriptions of hair texture also included terms such as straight, wavy, curly, and kinky.⁶ However, defining hair texture should be based on an approach that is more objective than an inaccurate ethnicity-based classification or the use of subjective, ill-defined, and overlapping descriptive terms.⁷ The segmentation tree analysis method (STAM) is an objective classification system that, when applied to hair, yields 8 curl-type groups (I=straight; VIII=tightly curly) based on curve diameter, curl index, number of waves, and twists.^6-9 (We discuss the “tightly coiled” [group VII] through “tight, interwoven small curls” [group VIII] groups in the STAM classification of hair.)

Highly textured hair has been found to be more susceptible to breakage than other hair types because of an increased percentage of spirals and relatively fewer elastic fibers anchoring hair follicles to the dermis.^1-4,10,11 In a cross-section, the hair shaft of individuals of African descent tends to be more elliptical and kidney shaped than the hair shaft of Asian individuals, which is round and has a large diameter, and the hair shaft of Caucasian individuals, which structurally lies between African and Asian hair.^1,2,4,11 This axial asymmetry and section size contributes to points of lower tensile strength and increased fragility, which are exacerbated by everyday combing and grooming. Curvature of the hair follicle leads to the characteristic curly and spiral nature of African hair, which can lead to increased knotting.^2,4

Practice Gap

Among women of African descent, a variety of hairstyles and hair treatments frequently are employed to allow for ease of management and self-expression.¹ Many of these practices have been implicated as risk factors for alopecia. Simply advising patients to avoid tight hairstyles is ineffective because tension is subjective and difficult to quantify.⁵ Furthermore, it might be unreasonable to ask a patient to discontinue a hairstyle or treatment when they are unaware of less damaging alternatives.^3,5

We provide an overview of hairstyles for patients who have highly textured hair so that physicians can better identify high-risk hairstyles and provide individualized recommendations for safer alternatives.^1,3,5

Techniques for Hair Straightening

Traditional thermal straightening uses a hot comb or flat iron^1,2,4,12 to temporarily disrupt hydrogen bonds within the hair shafts, which is reversible with exposure to moisture.^1,2,4,5 Patients repeat this process every 1 or 2 weeks to offset the effects of normal perspiration and environmental humidity.^5,12 Thermal straightening techniques can lead to increased fragility of the hair shaft and loss of tensile strength.¹¹

Alternate methods of hair straightening use lye (sodium hydroxide) or nonlye (lithium and guanidine hydroxide) “relaxers” to permanently disrupt hydrogen and disulfide bonds in the hair shaft, which can damage and weaken hair.^1-5,11,12 Touch-ups to the roots often are performed every 6 to 8 weeks.^1,2

Chemical relaxers historically have been associated with CCCA but have not been definitively implicated as causative.^2,3,4,13 Most studies have not demonstrated a statistically significant association between chemical relaxers and CCCA because, with a few exceptions,¹³ studies have either been based on surveys or have not employed trichoscopy or scalp biopsy. In one of those studies, patients with CCCA were determined to be 12.37 times more likely to have used a chemical relaxer in the past (P<.001).¹³ In another study of 39 women in Nigeria, those who had frequent and prolonged use of a chemical relaxer developed scarring alopecia more often than those who did not use a chemical relaxer (P<.0001). However, it is now known that the pathogenesis of CCCA may be related to an upregulation in genes implicated in fibroproliferative disorders (FPDs), a group of conditions characterized by aberrant wound healing, low-grade inflammation and irritation, and excessive fibrosis.¹⁴ They include systemic sclerosis, keloids, atherosclerosis, and uterine fibroids. The risk for certain FPDs is increased in individuals of African descent, and this increased risk is thought to be secondary to the protective effect that profibrotic alleles offer against helminths found in sub-Saharan Africa. A study of 5 patients with biopsy-proven CCCA found that there was increased expression of platelet-derived growth factor gene, PDGF; collagen I gene, COL I; collagen III gene, COL III; matrix metallopeptidase 1 gene, MMP1; matrix metallopeptidase 2 gene, MMP2; matrix metallopeptidase 7 gene, MMP7; and matrix metallopeptidase 9 gene, MMP9, in an affected scalp compared with an unaffected scalp.¹⁴ Still, chemical relaxers weaken the hair shaft and follicle structure, increasing the possibility of hair breakage and allowing for inflammation and trauma to render negative follicular effects.^3,13

The following interventions can be recommended to patients who thermally or chemically treat their hair to prevent hair damage:

• Decrease the frequency of thermal straightening.
• Use lower heat settings on flat irons and blow-dryers.
• Thermally straighten only clean dry hair.
• Regularly trim split ends.
• Use moisturizing shampoos and conditioners.
• Have a trained professional apply a chemical relaxer, if affordable.
• Consider decreasing (1) the frequency of chemical relaxer touch-up (to every 8 to 10 weeks) and (2) the overall manipulation of hair. There is a fine balance between not treating often enough and treating too often: The transition point between chemically processed hair and grown-out roots is a high-tension breakage point.
• Apply a thick protective emollient (known as scalp basing) to the scalp before applying a relaxer^1,5; this protects the scalp from irritation.

Techniques for Braids, Weaves, and Twists

Braids and cornrows, sewn-in or glued-on extensions and weaves, and twists are popular hairstyles. When applied improperly, however, they also can lead to alopecia.^1-5,11,12 When braids are too tight, the patient might complain of headache. Characteristic tenting—hair pulled so tight that the scalp is raised—might be observed.^3,5 Twists are achieved by interlocking 2 pieces of hair, which are held together by styling gel.^1,4 When twists remain over many months, hair eventually knots or tangles into a permanent locking pattern (also known as dreadlocks, dreads, or locs).^1,2,4 In some cases, the persistent weight of dreadlocks results in hair breakage.^1,3,5

The following recommendations can be made to patients who style their hair with braids or cornrows, extensions or weaves, twists, or dreadlocks:

• Apply these styles with as little traction as possible.
• Change the direction in which braids and cornrows are styled frequently to avoid constant tension over the same areas.
• Opt for larger-diameter braids and twists.
• Leave these styles in place no longer than 2 or 3 months; consider removing extensions and weaves every 3 or 4 weeks.
• Remove extensions and weaves if they cause pain or irritation.
• Avoid the use of glue; opt for loosely sewn-in extensions and weaves.
• Consider the alternative of crochet braiding; this is a protective way to apply extensions to hair and can be worn straight, curly, braided, or twisted.^5,12

Techniques for Other Hairstyling Practices

Low-hanging ponytails or buns, wigs, and natural hairstyles generally are considered safe when applied correctly.^1,5 The following recommendations can be made to patients who have a low-hanging ponytail, bun, wig, or other natural hairstyle:

• Before a wig is applied, hold the hair against the scalp with a cotton, nylon, or satin wig cap and with clips, tapes, or bonds. Because satin does not cause constant friction or absorb moisture, it is the safest material for a wig cap.⁵
• Achieve a natural hairstyle by cutting off chemically processed hair and allowing hair to grow out.⁵
• Hair that has not been thermally or chemically processed better withstands the stresses of traction, pulling, and brushing.⁵
• For women with natural hair, wash hair at least every 2 weeks and moisturize frequently.^5,12
• Caution patients that adding synthetic or human hair (ie, extensions, weaves) to any hairstyle to increase volume or length using glue or sewing techniques^1-4,11 can cause problems. The extra weight and tension of extensions and weaves can lead to alopecia. Glue can trigger an irritant or allergic reaction, especially in women who have a latex allergy.^1,4,5,11

Practice Implications

Women of African descent might be more susceptible to alopecia because of the distinctive structural properties of their hair and the various hair treatments and styles they often employ. Physicians should be knowledgeable when counseling these patients on their hair care practices. It also is important to understand that it might not be feasible for a patient to completely discontinue a hair treatment or style. In that situation, be prepared to make recommendations for safer hairstyling practices.

Central centrifugal cicatricial alopecia (CCCA), traction alopecia, and acquired proximal trichorrhexis nodosa are 3 forms of alopecia that disproportionately affect women of African descent.¹ Central centrifugal cicatricial alopecia is characterized by a shiny smooth patch of hair loss over the vertex of the scalp that spreads centrifugally (Figure 1).^1-4 Traction alopecia results from prolonged or repeated tension on the hair root that causes mechanical damage, hair loss, and shortening of hairs along the frontotemporal line (the so-called fringe sign)(Figure 2).^1,3,5 Acquired proximal trichorrhexis nodosa, a result of trauma, is identified by a substantial number of hairs breaking off midshaft during a hair pull test.¹ By understanding the unique structural properties and grooming methods of hair in women of African descent, physicians can better manage and stop the progression of hair loss before it becomes permanent.^1,4,5

The characterization of hair between and within ethnic groups is challenging and lies on a spectrum.^6,7 Many early studies broadly differentiated hair in 3 ethnic subgroups: African, Asian, and Caucasian^6-8; older descriptions of hair texture also included terms such as straight, wavy, curly, and kinky.⁶ However, defining hair texture should be based on an approach that is more objective than an inaccurate ethnicity-based classification or the use of subjective, ill-defined, and overlapping descriptive terms.⁷ The segmentation tree analysis method (STAM) is an objective classification system that, when applied to hair, yields 8 curl-type groups (I=straight; VIII=tightly curly) based on curve diameter, curl index, number of waves, and twists.^6-9 (We discuss the “tightly coiled” [group VII] through “tight, interwoven small curls” [group VIII] groups in the STAM classification of hair.)

Highly textured hair has been found to be more susceptible to breakage than other hair types because of an increased percentage of spirals and relatively fewer elastic fibers anchoring hair follicles to the dermis.^1-4,10,11 In a cross-section, the hair shaft of individuals of African descent tends to be more elliptical and kidney shaped than the hair shaft of Asian individuals, which is round and has a large diameter, and the hair shaft of Caucasian individuals, which structurally lies between African and Asian hair.^1,2,4,11 This axial asymmetry and section size contributes to points of lower tensile strength and increased fragility, which are exacerbated by everyday combing and grooming. Curvature of the hair follicle leads to the characteristic curly and spiral nature of African hair, which can lead to increased knotting.^2,4

Practice Gap

Among women of African descent, a variety of hairstyles and hair treatments frequently are employed to allow for ease of management and self-expression.¹ Many of these practices have been implicated as risk factors for alopecia. Simply advising patients to avoid tight hairstyles is ineffective because tension is subjective and difficult to quantify.⁵ Furthermore, it might be unreasonable to ask a patient to discontinue a hairstyle or treatment when they are unaware of less damaging alternatives.^3,5

We provide an overview of hairstyles for patients who have highly textured hair so that physicians can better identify high-risk hairstyles and provide individualized recommendations for safer alternatives.^1,3,5

Techniques for Hair Straightening

Traditional thermal straightening uses a hot comb or flat iron^1,2,4,12 to temporarily disrupt hydrogen bonds within the hair shafts, which is reversible with exposure to moisture.^1,2,4,5 Patients repeat this process every 1 or 2 weeks to offset the effects of normal perspiration and environmental humidity.^5,12 Thermal straightening techniques can lead to increased fragility of the hair shaft and loss of tensile strength.¹¹

Alternate methods of hair straightening use lye (sodium hydroxide) or nonlye (lithium and guanidine hydroxide) “relaxers” to permanently disrupt hydrogen and disulfide bonds in the hair shaft, which can damage and weaken hair.^1-5,11,12 Touch-ups to the roots often are performed every 6 to 8 weeks.^1,2

Chemical relaxers historically have been associated with CCCA but have not been definitively implicated as causative.^2,3,4,13 Most studies have not demonstrated a statistically significant association between chemical relaxers and CCCA because, with a few exceptions,¹³ studies have either been based on surveys or have not employed trichoscopy or scalp biopsy. In one of those studies, patients with CCCA were determined to be 12.37 times more likely to have used a chemical relaxer in the past (P<.001).¹³ In another study of 39 women in Nigeria, those who had frequent and prolonged use of a chemical relaxer developed scarring alopecia more often than those who did not use a chemical relaxer (P<.0001). However, it is now known that the pathogenesis of CCCA may be related to an upregulation in genes implicated in fibroproliferative disorders (FPDs), a group of conditions characterized by aberrant wound healing, low-grade inflammation and irritation, and excessive fibrosis.¹⁴ They include systemic sclerosis, keloids, atherosclerosis, and uterine fibroids. The risk for certain FPDs is increased in individuals of African descent, and this increased risk is thought to be secondary to the protective effect that profibrotic alleles offer against helminths found in sub-Saharan Africa. A study of 5 patients with biopsy-proven CCCA found that there was increased expression of platelet-derived growth factor gene, PDGF; collagen I gene, COL I; collagen III gene, COL III; matrix metallopeptidase 1 gene, MMP1; matrix metallopeptidase 2 gene, MMP2; matrix metallopeptidase 7 gene, MMP7; and matrix metallopeptidase 9 gene, MMP9, in an affected scalp compared with an unaffected scalp.¹⁴ Still, chemical relaxers weaken the hair shaft and follicle structure, increasing the possibility of hair breakage and allowing for inflammation and trauma to render negative follicular effects.^3,13

The following interventions can be recommended to patients who thermally or chemically treat their hair to prevent hair damage:

• Decrease the frequency of thermal straightening.
• Use lower heat settings on flat irons and blow-dryers.
• Thermally straighten only clean dry hair.
• Regularly trim split ends.
• Use moisturizing shampoos and conditioners.
• Have a trained professional apply a chemical relaxer, if affordable.
• Consider decreasing (1) the frequency of chemical relaxer touch-up (to every 8 to 10 weeks) and (2) the overall manipulation of hair. There is a fine balance between not treating often enough and treating too often: The transition point between chemically processed hair and grown-out roots is a high-tension breakage point.
• Apply a thick protective emollient (known as scalp basing) to the scalp before applying a relaxer^1,5; this protects the scalp from irritation.

Techniques for Braids, Weaves, and Twists

Braids and cornrows, sewn-in or glued-on extensions and weaves, and twists are popular hairstyles. When applied improperly, however, they also can lead to alopecia.^1-5,11,12 When braids are too tight, the patient might complain of headache. Characteristic tenting—hair pulled so tight that the scalp is raised—might be observed.^3,5 Twists are achieved by interlocking 2 pieces of hair, which are held together by styling gel.^1,4 When twists remain over many months, hair eventually knots or tangles into a permanent locking pattern (also known as dreadlocks, dreads, or locs).^1,2,4 In some cases, the persistent weight of dreadlocks results in hair breakage.^1,3,5

The following recommendations can be made to patients who style their hair with braids or cornrows, extensions or weaves, twists, or dreadlocks:

• Apply these styles with as little traction as possible.
• Change the direction in which braids and cornrows are styled frequently to avoid constant tension over the same areas.
• Opt for larger-diameter braids and twists.
• Leave these styles in place no longer than 2 or 3 months; consider removing extensions and weaves every 3 or 4 weeks.
• Remove extensions and weaves if they cause pain or irritation.
• Avoid the use of glue; opt for loosely sewn-in extensions and weaves.
• Consider the alternative of crochet braiding; this is a protective way to apply extensions to hair and can be worn straight, curly, braided, or twisted.^5,12

Techniques for Other Hairstyling Practices

Low-hanging ponytails or buns, wigs, and natural hairstyles generally are considered safe when applied correctly.^1,5 The following recommendations can be made to patients who have a low-hanging ponytail, bun, wig, or other natural hairstyle:

• Before a wig is applied, hold the hair against the scalp with a cotton, nylon, or satin wig cap and with clips, tapes, or bonds. Because satin does not cause constant friction or absorb moisture, it is the safest material for a wig cap.⁵
• Achieve a natural hairstyle by cutting off chemically processed hair and allowing hair to grow out.⁵
• Hair that has not been thermally or chemically processed better withstands the stresses of traction, pulling, and brushing.⁵
• For women with natural hair, wash hair at least every 2 weeks and moisturize frequently.^5,12
• Caution patients that adding synthetic or human hair (ie, extensions, weaves) to any hairstyle to increase volume or length using glue or sewing techniques^1-4,11 can cause problems. The extra weight and tension of extensions and weaves can lead to alopecia. Glue can trigger an irritant or allergic reaction, especially in women who have a latex allergy.^1,4,5,11

Practice Implications

Women of African descent might be more susceptible to alopecia because of the distinctive structural properties of their hair and the various hair treatments and styles they often employ. Physicians should be knowledgeable when counseling these patients on their hair care practices. It also is important to understand that it might not be feasible for a patient to completely discontinue a hair treatment or style. In that situation, be prepared to make recommendations for safer hairstyling practices.

Lin Chang, MD, serves as the Co-Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA. She is also Program Director of the UCLA Gastroenterology Fellowship Program. Dr. Chang’s expertise is in disorders of gut-brain interaction (also known as functional gastrointestinal disorders), particularly irritable bowel syndrome (IBS). She has recently served as the Clinical Research Councilor of the AGA Governing Board. She previously served as President of the American Neurogastroenterology and Motility Society (ANMS) and is a member of the Rome Foundation Board of Directors.

As a gastroenterologist focused on the pathophysiology of IBS related to stress, sex differences, and neuroendocrine alterations, and the treatment of IBS, Dr. Chang, what exactly is IBS-C and how is CIC defined differently?

Dr. Chang: IBS-C is irritable bowel syndrome with predominantly constipation which is a type of IBS. IBS is a symptom-based diagnosis for a chronic or recurrent gastrointestinal condition where patients have abdominal pain that's associated with constipation, diarrhea, or both. IBS is subtyped by bowel habit predominance into IBS with constipation, IBS with diarrhea, and IBS with mixed bowel habits. With IBS-mixed, one of the subgroups of IBS, they have diarrhea as well as constipation.

Patients will present with abdominal pain for usually one day, a week or even more. Sometimes, a little less. But when they have pain, it's associated with a change in stool frequency, a change in stool form, and/or the pain is related to defecation, meaning that when a patient has a bowel movement, they'll either have more pain or they'll have some pain relief, which is more common.

Now, CIC is Chronic Idiopathic Constipation and that's the term used for chronic constipation where abdominal pain is not a predominant symptom. The main difference between IBS-C and CIC is that abdominal pain is not a predominant or frequent symptom.

Patients with CIC can occasionally get abdominal pain, particularly if they haven't had a bowel movement for a prolonged period of time. However, in patients with IBS-C, they can have some normalization of their bowel habits or their constipation with treatment, although they can still have abdominal pain and discomfort. So, these patients have an element of visceral hypersensitivity where the gut is more sensitive than usual.

Very interesting Dr. Chang, and are the causes of IBS-C and CIC different? And then if so, in what ways?

Dr. Chang: Well, IBS is a multifactorial disorder and is known as a functional GI disorder. It has been redefined as a disorder of gut-brain interaction, which is a term people are starting to use and hear more.

There's a lot of scientific evidence that has demonstrated that IBS and other similar conditions, including chronic constipation and functional dyspepsia, where there is no structural and biochemical abnormality that you can readily determine, but there's scientific evidence to support that there’s an alteration in the brain-gut communication associated with symptoms. Altered brain-gut interactions are manifested by one or more of the following, which is visceral hypersensitivity, immune function, gut microbiota, gut motility, and central nervous system processing of visceral information. So, this really is a true brain-gut disorder.

There are multiple risk factors when it comes to IBS. It could be infection, or it could be stressful life events, in childhood and/or as an adult. Evidence shows that there can be some familial or genetic predisposition. Food and stress are the main triggers of IBS. Whereas, CIC can be considered a brain-gut disorder, but there's been more focus on gut function, including abnormal motility and defecation. There are three main subtypes of chronic idiopathic constipation.

There are six signs or symptoms that are the diagnostic criteria for CIC and the patient, or the individual, must meet two out of the six criteria, which I ask patients who report having constipation.

The subtypes of CIC are slow transit constipation where the transit time of stool through the colon is slower than normal which can be measured. Then there's normal transit constipation where the transit time of stool through the colon is normal. This group has not been studied that well and it's not completely understood why these patients have constipation, but it could be that they have a greater perception of constipation even though the transit time of stool in the colon is not slow.

And then there's the third group--defecatory disorders. The transit time of stool through the colon of stool can be normal or slow, but coexisting with that, a patient can have a defecation disorder. A common one is called dyssynergic defecation where the pelvic floor and the anal sphincter muscles don't relax appropriately when trying to evacuate stool. In this case, the rectum cannot straighten as much, the pelvic floor doesn't relax and descend, and stool is not easily evacuated.

There are also other conditions such as a significant large rectocele and rectal prolapse. Those are examples of defecatory disorders. So, when you see a patient with CIC, you want to first rule out secondary constipation where another condition or medication is causing constipation, such as hypothyroidism, diabetes, or a neurodegenerative disorder, or medications like opioids or anticholinergics.

CIC means that there isn't another cause of constipation, that is it is not a secondary condition. It's a primary chronic idiopathic constipation.

Let’s talk about the symptoms you're looking for and how they present themselves differently for IBS-C and CIC, at different times, depending on the diagnosis.

Dr. Chang: Sure! I mentioned what the symptom criteria of IBS was, which is having pain of a certain frequency that is associated with altered bowel habits. To determine the bowel habit subtype of IBS, you must assess the predominant stool form. We use the Bristol Stool Form Scale which is a validated stool form scale that's well known. It's publicly available.

The investigators did a survey years ago and they looked at the general population and found that the description of stool really could be encompassed in seven types, and those seven types of stool form correlate with transit time through the bowel. There's type 1 to type 7. Type 1 and 2 are the constipation type stool form where there's harder, drier pellet-like stools and that's associated with slower transit time through the colon. Types 3, 4 and 5 are more within the normal range. Types 6 and 7 are the loose or watery stools are suggestive of faster stool transit and considered indicative of diarrhea.

In patients with IBS-C,  at least 25% of their bowel movements are the type 1 or 2, which is the harder, drier stool and less than 25% of bowel movements are loose watery. For diarrhea, it's opposite. IBS-mixed bowel habits, at least 25% of bowel movements are type 1 or 2 and at least 25% are type 6 or 7.

Now, to meet the diagnostic criteria of CIC, you must meet two out of the six criteria. All but one of the criteria must be present with at least 25% of bowel movements. There’s a straining, sensation of incomplete evacuation, use of manual maneuvers to help facilitate stool evacuation, sensation of anorectal blockage, and a Bristol Stool Form Scale of type 1 or 2. The remaining criterion is less than three bowel movements per week. If a patient reports, or endorses, at least two of those six symptoms and signs, then their symptoms meet criteria.

Both IBS-C and CIC are chronic conditions. For the diagnosis of both IBS-C and CIC, symptoms are present for at least three months and started at least six months ago.

What's interesting is that if you ask health care providers and physicians what constipation is and  what symptoms define constipation, most of them will say having less than three bowel movements per week or infrequent bowel movements. But it turns out that in chronic constipation patients, they'll report decreased bowel movement frequency. About only a third of them will report that. They'll report the other symptoms of a constipation.

They could have multiple symptoms, but straining is a very common symptom as is hard stools. Even after a bowel movement, they don't feel completely evacuated. That's called sensation of incomplete evacuation. In fact, patients will present with different types of symptoms.

Constipation is often considered a symptom and a diagnosis. And it's fine to use it as a diagnosis, but you really want to delve into what symptoms of constipation they’re experiencing. Are they experiencing straining? Hard stools? Are they not having a bowel movement frequently? That's really part of the history taking so you can determine what the patient perceives as constipation and which symptom are bothersome to them.

So once diagnosed, how different are the treatments for each of the diseases?

Dr. Chang: In both IBS-C and CIC, treatments can include diet, exercise or ambulating more. Often, I will make sure they're drinking plenty of fluids. Those are dietary recommendations such as increasing fiber with foods and/or fiber supplementation. When looking at the difference between IBS-C and CIC, the one thing I should say is that they really exist along a spectrum, so we shouldn't really think of them as two separate diagnoses.

This goes back to the idea we touched on earlier that patients can move back and forth between the different diagnoses. At one point, a patient could have frequent abdominal pain and constipation and the symptoms would meet the criteria for IBS-C. But in the future, the pain gets better or resolves, but there’s still constipation. Their symptoms are more indicative of CIC. So, these conditions really exist along a spectrum.

Because both patients will have constipation symptoms, medications or treatments that help improve constipation can be used for both IBS-C and CIC. The key difference with IBS-C is that in addition to having altered gut motility where they're not moving stool effectively through the bowel, they also have visceral hypersensitivity which manifests as abdominal pain, bloating, and discomfort. Although there may be a modest correlation with bowel habits and IBS, sometimes, they don't correlate that well.

There are some treatments that help pain and constipation and those are the treatments that you want to think about in those patients with IBS-C where they're reporting both pain and constipation.

Now, it's very reasonable to use similar treatments in patients with mild symptoms, whether it's IBS or CIC. But if someone's having more severe IBS-C and they're having a fair amount of pain associated with constipation, you really want to think about treatments that can help reduce pain and constipation and not just constipation.

Treatments can include fiber such as psyllium and osmotic laxatives like polyethylene glycol, which is called MiraLAX, and magnesium-based regimens. These help constipation symptoms, but they don't significantly relieve abdominal pain. If someone came to me with IBS-C and they said, well, I do have pain, but it is mild, maybe a 2 or 3 out of 10, I could probably give them any one of the treatments I just mentioned. But in patients who say that their pain is 8 out of 10 or that it is their predominant symptom, I wouldn't necessarily prescribe the same treatment and would more likely opt for a treatment that has been shown to effectively reduce abdominal pain and constipation.

When you’re looking at the data, are their studies that might show a focus on the treatments and how they might impact the patients differently for IBS-C compared to CIC?

Dr. Chang: Well, the primary study endpoints that are used to determine efficacy of treatment in clinical trials differ in studies of CIC and IBS-C. However, studies also assess individual gastrointestinal symptoms that can be similar in both studies.

So, I would say that treatments that have been shown to be efficacious both in IBS-C and CIC likely relieve constipation symptoms similarly in both groups assuming that the severity of symptoms is comparable. It's just that in the CIC patient population, abdominal pain is not evaluated as much as it is in IBS-C.

Lin Chang, MD, serves as the Co-Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA. She is also Program Director of the UCLA Gastroenterology Fellowship Program. Dr. Chang’s expertise is in disorders of gut-brain interaction (also known as functional gastrointestinal disorders), particularly irritable bowel syndrome (IBS). She has recently served as the Clinical Research Councilor of the AGA Governing Board. She previously served as President of the American Neurogastroenterology and Motility Society (ANMS) and is a member of the Rome Foundation Board of Directors.

As a gastroenterologist focused on the pathophysiology of IBS related to stress, sex differences, and neuroendocrine alterations, and the treatment of IBS, Dr. Chang, what exactly is IBS-C and how is CIC defined differently?

Dr. Chang: IBS-C is irritable bowel syndrome with predominantly constipation which is a type of IBS. IBS is a symptom-based diagnosis for a chronic or recurrent gastrointestinal condition where patients have abdominal pain that's associated with constipation, diarrhea, or both. IBS is subtyped by bowel habit predominance into IBS with constipation, IBS with diarrhea, and IBS with mixed bowel habits. With IBS-mixed, one of the subgroups of IBS, they have diarrhea as well as constipation.

Patients will present with abdominal pain for usually one day, a week or even more. Sometimes, a little less. But when they have pain, it's associated with a change in stool frequency, a change in stool form, and/or the pain is related to defecation, meaning that when a patient has a bowel movement, they'll either have more pain or they'll have some pain relief, which is more common.

Now, CIC is Chronic Idiopathic Constipation and that's the term used for chronic constipation where abdominal pain is not a predominant symptom. The main difference between IBS-C and CIC is that abdominal pain is not a predominant or frequent symptom.

Patients with CIC can occasionally get abdominal pain, particularly if they haven't had a bowel movement for a prolonged period of time. However, in patients with IBS-C, they can have some normalization of their bowel habits or their constipation with treatment, although they can still have abdominal pain and discomfort. So, these patients have an element of visceral hypersensitivity where the gut is more sensitive than usual.

Very interesting Dr. Chang, and are the causes of IBS-C and CIC different? And then if so, in what ways?

Dr. Chang: Well, IBS is a multifactorial disorder and is known as a functional GI disorder. It has been redefined as a disorder of gut-brain interaction, which is a term people are starting to use and hear more.

There's a lot of scientific evidence that has demonstrated that IBS and other similar conditions, including chronic constipation and functional dyspepsia, where there is no structural and biochemical abnormality that you can readily determine, but there's scientific evidence to support that there’s an alteration in the brain-gut communication associated with symptoms. Altered brain-gut interactions are manifested by one or more of the following, which is visceral hypersensitivity, immune function, gut microbiota, gut motility, and central nervous system processing of visceral information. So, this really is a true brain-gut disorder.

There are multiple risk factors when it comes to IBS. It could be infection, or it could be stressful life events, in childhood and/or as an adult. Evidence shows that there can be some familial or genetic predisposition. Food and stress are the main triggers of IBS. Whereas, CIC can be considered a brain-gut disorder, but there's been more focus on gut function, including abnormal motility and defecation. There are three main subtypes of chronic idiopathic constipation.

There are six signs or symptoms that are the diagnostic criteria for CIC and the patient, or the individual, must meet two out of the six criteria, which I ask patients who report having constipation.

The subtypes of CIC are slow transit constipation where the transit time of stool through the colon is slower than normal which can be measured. Then there's normal transit constipation where the transit time of stool through the colon is normal. This group has not been studied that well and it's not completely understood why these patients have constipation, but it could be that they have a greater perception of constipation even though the transit time of stool in the colon is not slow.

And then there's the third group--defecatory disorders. The transit time of stool through the colon of stool can be normal or slow, but coexisting with that, a patient can have a defecation disorder. A common one is called dyssynergic defecation where the pelvic floor and the anal sphincter muscles don't relax appropriately when trying to evacuate stool. In this case, the rectum cannot straighten as much, the pelvic floor doesn't relax and descend, and stool is not easily evacuated.

There are also other conditions such as a significant large rectocele and rectal prolapse. Those are examples of defecatory disorders. So, when you see a patient with CIC, you want to first rule out secondary constipation where another condition or medication is causing constipation, such as hypothyroidism, diabetes, or a neurodegenerative disorder, or medications like opioids or anticholinergics.

CIC means that there isn't another cause of constipation, that is it is not a secondary condition. It's a primary chronic idiopathic constipation.

Let’s talk about the symptoms you're looking for and how they present themselves differently for IBS-C and CIC, at different times, depending on the diagnosis.

Dr. Chang: Sure! I mentioned what the symptom criteria of IBS was, which is having pain of a certain frequency that is associated with altered bowel habits. To determine the bowel habit subtype of IBS, you must assess the predominant stool form. We use the Bristol Stool Form Scale which is a validated stool form scale that's well known. It's publicly available.

The investigators did a survey years ago and they looked at the general population and found that the description of stool really could be encompassed in seven types, and those seven types of stool form correlate with transit time through the bowel. There's type 1 to type 7. Type 1 and 2 are the constipation type stool form where there's harder, drier pellet-like stools and that's associated with slower transit time through the colon. Types 3, 4 and 5 are more within the normal range. Types 6 and 7 are the loose or watery stools are suggestive of faster stool transit and considered indicative of diarrhea.

In patients with IBS-C,  at least 25% of their bowel movements are the type 1 or 2, which is the harder, drier stool and less than 25% of bowel movements are loose watery. For diarrhea, it's opposite. IBS-mixed bowel habits, at least 25% of bowel movements are type 1 or 2 and at least 25% are type 6 or 7.

Now, to meet the diagnostic criteria of CIC, you must meet two out of the six criteria. All but one of the criteria must be present with at least 25% of bowel movements. There’s a straining, sensation of incomplete evacuation, use of manual maneuvers to help facilitate stool evacuation, sensation of anorectal blockage, and a Bristol Stool Form Scale of type 1 or 2. The remaining criterion is less than three bowel movements per week. If a patient reports, or endorses, at least two of those six symptoms and signs, then their symptoms meet criteria.

Both IBS-C and CIC are chronic conditions. For the diagnosis of both IBS-C and CIC, symptoms are present for at least three months and started at least six months ago.

What's interesting is that if you ask health care providers and physicians what constipation is and  what symptoms define constipation, most of them will say having less than three bowel movements per week or infrequent bowel movements. But it turns out that in chronic constipation patients, they'll report decreased bowel movement frequency. About only a third of them will report that. They'll report the other symptoms of a constipation.

They could have multiple symptoms, but straining is a very common symptom as is hard stools. Even after a bowel movement, they don't feel completely evacuated. That's called sensation of incomplete evacuation. In fact, patients will present with different types of symptoms.

Constipation is often considered a symptom and a diagnosis. And it's fine to use it as a diagnosis, but you really want to delve into what symptoms of constipation they’re experiencing. Are they experiencing straining? Hard stools? Are they not having a bowel movement frequently? That's really part of the history taking so you can determine what the patient perceives as constipation and which symptom are bothersome to them.

So once diagnosed, how different are the treatments for each of the diseases?

Dr. Chang: In both IBS-C and CIC, treatments can include diet, exercise or ambulating more. Often, I will make sure they're drinking plenty of fluids. Those are dietary recommendations such as increasing fiber with foods and/or fiber supplementation. When looking at the difference between IBS-C and CIC, the one thing I should say is that they really exist along a spectrum, so we shouldn't really think of them as two separate diagnoses.

This goes back to the idea we touched on earlier that patients can move back and forth between the different diagnoses. At one point, a patient could have frequent abdominal pain and constipation and the symptoms would meet the criteria for IBS-C. But in the future, the pain gets better or resolves, but there’s still constipation. Their symptoms are more indicative of CIC. So, these conditions really exist along a spectrum.

Because both patients will have constipation symptoms, medications or treatments that help improve constipation can be used for both IBS-C and CIC. The key difference with IBS-C is that in addition to having altered gut motility where they're not moving stool effectively through the bowel, they also have visceral hypersensitivity which manifests as abdominal pain, bloating, and discomfort. Although there may be a modest correlation with bowel habits and IBS, sometimes, they don't correlate that well.

There are some treatments that help pain and constipation and those are the treatments that you want to think about in those patients with IBS-C where they're reporting both pain and constipation.

Now, it's very reasonable to use similar treatments in patients with mild symptoms, whether it's IBS or CIC. But if someone's having more severe IBS-C and they're having a fair amount of pain associated with constipation, you really want to think about treatments that can help reduce pain and constipation and not just constipation.

Treatments can include fiber such as psyllium and osmotic laxatives like polyethylene glycol, which is called MiraLAX, and magnesium-based regimens. These help constipation symptoms, but they don't significantly relieve abdominal pain. If someone came to me with IBS-C and they said, well, I do have pain, but it is mild, maybe a 2 or 3 out of 10, I could probably give them any one of the treatments I just mentioned. But in patients who say that their pain is 8 out of 10 or that it is their predominant symptom, I wouldn't necessarily prescribe the same treatment and would more likely opt for a treatment that has been shown to effectively reduce abdominal pain and constipation.

When you’re looking at the data, are their studies that might show a focus on the treatments and how they might impact the patients differently for IBS-C compared to CIC?

Dr. Chang: Well, the primary study endpoints that are used to determine efficacy of treatment in clinical trials differ in studies of CIC and IBS-C. However, studies also assess individual gastrointestinal symptoms that can be similar in both studies.

So, I would say that treatments that have been shown to be efficacious both in IBS-C and CIC likely relieve constipation symptoms similarly in both groups assuming that the severity of symptoms is comparable. It's just that in the CIC patient population, abdominal pain is not evaluated as much as it is in IBS-C.

Lin Chang, MD, serves as the Co-Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA. She is also Program Director of the UCLA Gastroenterology Fellowship Program. Dr. Chang’s expertise is in disorders of gut-brain interaction (also known as functional gastrointestinal disorders), particularly irritable bowel syndrome (IBS). She has recently served as the Clinical Research Councilor of the AGA Governing Board. She previously served as President of the American Neurogastroenterology and Motility Society (ANMS) and is a member of the Rome Foundation Board of Directors.

As a gastroenterologist focused on the pathophysiology of IBS related to stress, sex differences, and neuroendocrine alterations, and the treatment of IBS, Dr. Chang, what exactly is IBS-C and how is CIC defined differently?

Dr. Chang: IBS-C is irritable bowel syndrome with predominantly constipation which is a type of IBS. IBS is a symptom-based diagnosis for a chronic or recurrent gastrointestinal condition where patients have abdominal pain that's associated with constipation, diarrhea, or both. IBS is subtyped by bowel habit predominance into IBS with constipation, IBS with diarrhea, and IBS with mixed bowel habits. With IBS-mixed, one of the subgroups of IBS, they have diarrhea as well as constipation.

Patients will present with abdominal pain for usually one day, a week or even more. Sometimes, a little less. But when they have pain, it's associated with a change in stool frequency, a change in stool form, and/or the pain is related to defecation, meaning that when a patient has a bowel movement, they'll either have more pain or they'll have some pain relief, which is more common.

Now, CIC is Chronic Idiopathic Constipation and that's the term used for chronic constipation where abdominal pain is not a predominant symptom. The main difference between IBS-C and CIC is that abdominal pain is not a predominant or frequent symptom.

Patients with CIC can occasionally get abdominal pain, particularly if they haven't had a bowel movement for a prolonged period of time. However, in patients with IBS-C, they can have some normalization of their bowel habits or their constipation with treatment, although they can still have abdominal pain and discomfort. So, these patients have an element of visceral hypersensitivity where the gut is more sensitive than usual.

Very interesting Dr. Chang, and are the causes of IBS-C and CIC different? And then if so, in what ways?

Dr. Chang: Well, IBS is a multifactorial disorder and is known as a functional GI disorder. It has been redefined as a disorder of gut-brain interaction, which is a term people are starting to use and hear more.

There's a lot of scientific evidence that has demonstrated that IBS and other similar conditions, including chronic constipation and functional dyspepsia, where there is no structural and biochemical abnormality that you can readily determine, but there's scientific evidence to support that there’s an alteration in the brain-gut communication associated with symptoms. Altered brain-gut interactions are manifested by one or more of the following, which is visceral hypersensitivity, immune function, gut microbiota, gut motility, and central nervous system processing of visceral information. So, this really is a true brain-gut disorder.

There are multiple risk factors when it comes to IBS. It could be infection, or it could be stressful life events, in childhood and/or as an adult. Evidence shows that there can be some familial or genetic predisposition. Food and stress are the main triggers of IBS. Whereas, CIC can be considered a brain-gut disorder, but there's been more focus on gut function, including abnormal motility and defecation. There are three main subtypes of chronic idiopathic constipation.

There are six signs or symptoms that are the diagnostic criteria for CIC and the patient, or the individual, must meet two out of the six criteria, which I ask patients who report having constipation.

The subtypes of CIC are slow transit constipation where the transit time of stool through the colon is slower than normal which can be measured. Then there's normal transit constipation where the transit time of stool through the colon is normal. This group has not been studied that well and it's not completely understood why these patients have constipation, but it could be that they have a greater perception of constipation even though the transit time of stool in the colon is not slow.

And then there's the third group--defecatory disorders. The transit time of stool through the colon of stool can be normal or slow, but coexisting with that, a patient can have a defecation disorder. A common one is called dyssynergic defecation where the pelvic floor and the anal sphincter muscles don't relax appropriately when trying to evacuate stool. In this case, the rectum cannot straighten as much, the pelvic floor doesn't relax and descend, and stool is not easily evacuated.

There are also other conditions such as a significant large rectocele and rectal prolapse. Those are examples of defecatory disorders. So, when you see a patient with CIC, you want to first rule out secondary constipation where another condition or medication is causing constipation, such as hypothyroidism, diabetes, or a neurodegenerative disorder, or medications like opioids or anticholinergics.

CIC means that there isn't another cause of constipation, that is it is not a secondary condition. It's a primary chronic idiopathic constipation.

Let’s talk about the symptoms you're looking for and how they present themselves differently for IBS-C and CIC, at different times, depending on the diagnosis.

Dr. Chang: Sure! I mentioned what the symptom criteria of IBS was, which is having pain of a certain frequency that is associated with altered bowel habits. To determine the bowel habit subtype of IBS, you must assess the predominant stool form. We use the Bristol Stool Form Scale which is a validated stool form scale that's well known. It's publicly available.

The investigators did a survey years ago and they looked at the general population and found that the description of stool really could be encompassed in seven types, and those seven types of stool form correlate with transit time through the bowel. There's type 1 to type 7. Type 1 and 2 are the constipation type stool form where there's harder, drier pellet-like stools and that's associated with slower transit time through the colon. Types 3, 4 and 5 are more within the normal range. Types 6 and 7 are the loose or watery stools are suggestive of faster stool transit and considered indicative of diarrhea.

In patients with IBS-C,  at least 25% of their bowel movements are the type 1 or 2, which is the harder, drier stool and less than 25% of bowel movements are loose watery. For diarrhea, it's opposite. IBS-mixed bowel habits, at least 25% of bowel movements are type 1 or 2 and at least 25% are type 6 or 7.

Now, to meet the diagnostic criteria of CIC, you must meet two out of the six criteria. All but one of the criteria must be present with at least 25% of bowel movements. There’s a straining, sensation of incomplete evacuation, use of manual maneuvers to help facilitate stool evacuation, sensation of anorectal blockage, and a Bristol Stool Form Scale of type 1 or 2. The remaining criterion is less than three bowel movements per week. If a patient reports, or endorses, at least two of those six symptoms and signs, then their symptoms meet criteria.

Both IBS-C and CIC are chronic conditions. For the diagnosis of both IBS-C and CIC, symptoms are present for at least three months and started at least six months ago.

What's interesting is that if you ask health care providers and physicians what constipation is and  what symptoms define constipation, most of them will say having less than three bowel movements per week or infrequent bowel movements. But it turns out that in chronic constipation patients, they'll report decreased bowel movement frequency. About only a third of them will report that. They'll report the other symptoms of a constipation.

They could have multiple symptoms, but straining is a very common symptom as is hard stools. Even after a bowel movement, they don't feel completely evacuated. That's called sensation of incomplete evacuation. In fact, patients will present with different types of symptoms.

Constipation is often considered a symptom and a diagnosis. And it's fine to use it as a diagnosis, but you really want to delve into what symptoms of constipation they’re experiencing. Are they experiencing straining? Hard stools? Are they not having a bowel movement frequently? That's really part of the history taking so you can determine what the patient perceives as constipation and which symptom are bothersome to them.

So once diagnosed, how different are the treatments for each of the diseases?

Dr. Chang: In both IBS-C and CIC, treatments can include diet, exercise or ambulating more. Often, I will make sure they're drinking plenty of fluids. Those are dietary recommendations such as increasing fiber with foods and/or fiber supplementation. When looking at the difference between IBS-C and CIC, the one thing I should say is that they really exist along a spectrum, so we shouldn't really think of them as two separate diagnoses.

This goes back to the idea we touched on earlier that patients can move back and forth between the different diagnoses. At one point, a patient could have frequent abdominal pain and constipation and the symptoms would meet the criteria for IBS-C. But in the future, the pain gets better or resolves, but there’s still constipation. Their symptoms are more indicative of CIC. So, these conditions really exist along a spectrum.

Because both patients will have constipation symptoms, medications or treatments that help improve constipation can be used for both IBS-C and CIC. The key difference with IBS-C is that in addition to having altered gut motility where they're not moving stool effectively through the bowel, they also have visceral hypersensitivity which manifests as abdominal pain, bloating, and discomfort. Although there may be a modest correlation with bowel habits and IBS, sometimes, they don't correlate that well.

There are some treatments that help pain and constipation and those are the treatments that you want to think about in those patients with IBS-C where they're reporting both pain and constipation.

Now, it's very reasonable to use similar treatments in patients with mild symptoms, whether it's IBS or CIC. But if someone's having more severe IBS-C and they're having a fair amount of pain associated with constipation, you really want to think about treatments that can help reduce pain and constipation and not just constipation.

Treatments can include fiber such as psyllium and osmotic laxatives like polyethylene glycol, which is called MiraLAX, and magnesium-based regimens. These help constipation symptoms, but they don't significantly relieve abdominal pain. If someone came to me with IBS-C and they said, well, I do have pain, but it is mild, maybe a 2 or 3 out of 10, I could probably give them any one of the treatments I just mentioned. But in patients who say that their pain is 8 out of 10 or that it is their predominant symptom, I wouldn't necessarily prescribe the same treatment and would more likely opt for a treatment that has been shown to effectively reduce abdominal pain and constipation.

When you’re looking at the data, are their studies that might show a focus on the treatments and how they might impact the patients differently for IBS-C compared to CIC?

Dr. Chang: Well, the primary study endpoints that are used to determine efficacy of treatment in clinical trials differ in studies of CIC and IBS-C. However, studies also assess individual gastrointestinal symptoms that can be similar in both studies.

So, I would say that treatments that have been shown to be efficacious both in IBS-C and CIC likely relieve constipation symptoms similarly in both groups assuming that the severity of symptoms is comparable. It's just that in the CIC patient population, abdominal pain is not evaluated as much as it is in IBS-C.

Based on the thickness and size of this irregular lesion, a punch biopsy was performed and confirmed the diagnosis of dermatofibrosarcoma protuberans (DFSP).

DFSPs are usually found on the trunk and proximal extremities; they are most often located on the chest and shoulders. The lesion usually manifests as an asymptomatic, firm, and sometimes nodular plaque that may go undiagnosed for years. DFSP is an uncommon mesenchymal tumor with uncertain etiology. It is thought that prior injury to the affected skin may result in a translocation of chromosomes 17 and 22 in skin cells, as this molecular change characterizes the vast majority of DFSPs.

Black patients are more likely than other ethnic populations to develop DFSP and its variants; there is also a slight female predominance.¹ Known variants of DFSP include violaceous plaques with telangiectatic atrophic skin, and plaques with dark brown pigmentation called Bednar tumors.^1,2

DFSPs are rarely metastatic, but can be locally invasive, so primary treatment consists of wide local excision or Mohs micrographic surgery (MMS). There is a higher probability for cure when MMS is utilized to treat DFSPs with the added benefit of minimizing surgical margins and preserving healthy surrounding skin. In the rarer cases of advanced local, unresectable, or metastatic disease, inhibitor therapy with imatinib or radiation therapy may be considered.² Due to the risk of local recurrence, patients with DFSP should have regular clinical follow-up every 6 months for 5 years, followed by annual lifelong surveillance.¹

This patient was referred for MMS and has not yet returned for follow-up evaluation.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Morgan Haynes, BS, University of New Mexico School of Medicine and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

Based on the thickness and size of this irregular lesion, a punch biopsy was performed and confirmed the diagnosis of dermatofibrosarcoma protuberans (DFSP).

DFSPs are usually found on the trunk and proximal extremities; they are most often located on the chest and shoulders. The lesion usually manifests as an asymptomatic, firm, and sometimes nodular plaque that may go undiagnosed for years. DFSP is an uncommon mesenchymal tumor with uncertain etiology. It is thought that prior injury to the affected skin may result in a translocation of chromosomes 17 and 22 in skin cells, as this molecular change characterizes the vast majority of DFSPs.

Black patients are more likely than other ethnic populations to develop DFSP and its variants; there is also a slight female predominance.¹ Known variants of DFSP include violaceous plaques with telangiectatic atrophic skin, and plaques with dark brown pigmentation called Bednar tumors.^1,2

DFSPs are rarely metastatic, but can be locally invasive, so primary treatment consists of wide local excision or Mohs micrographic surgery (MMS). There is a higher probability for cure when MMS is utilized to treat DFSPs with the added benefit of minimizing surgical margins and preserving healthy surrounding skin. In the rarer cases of advanced local, unresectable, or metastatic disease, inhibitor therapy with imatinib or radiation therapy may be considered.² Due to the risk of local recurrence, patients with DFSP should have regular clinical follow-up every 6 months for 5 years, followed by annual lifelong surveillance.¹

This patient was referred for MMS and has not yet returned for follow-up evaluation.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Morgan Haynes, BS, University of New Mexico School of Medicine and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

Based on the thickness and size of this irregular lesion, a punch biopsy was performed and confirmed the diagnosis of dermatofibrosarcoma protuberans (DFSP).

DFSPs are usually found on the trunk and proximal extremities; they are most often located on the chest and shoulders. The lesion usually manifests as an asymptomatic, firm, and sometimes nodular plaque that may go undiagnosed for years. DFSP is an uncommon mesenchymal tumor with uncertain etiology. It is thought that prior injury to the affected skin may result in a translocation of chromosomes 17 and 22 in skin cells, as this molecular change characterizes the vast majority of DFSPs.

Black patients are more likely than other ethnic populations to develop DFSP and its variants; there is also a slight female predominance.¹ Known variants of DFSP include violaceous plaques with telangiectatic atrophic skin, and plaques with dark brown pigmentation called Bednar tumors.^1,2

DFSPs are rarely metastatic, but can be locally invasive, so primary treatment consists of wide local excision or Mohs micrographic surgery (MMS). There is a higher probability for cure when MMS is utilized to treat DFSPs with the added benefit of minimizing surgical margins and preserving healthy surrounding skin. In the rarer cases of advanced local, unresectable, or metastatic disease, inhibitor therapy with imatinib or radiation therapy may be considered.² Due to the risk of local recurrence, patients with DFSP should have regular clinical follow-up every 6 months for 5 years, followed by annual lifelong surveillance.¹

This patient was referred for MMS and has not yet returned for follow-up evaluation.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Morgan Haynes, BS, University of New Mexico School of Medicine and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?

Continue to the answer...
 

This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)

For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?

Continue to the answer...
 

This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)

For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?

Continue to the answer...
 

This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)

To the Editor:

Trauma from a pencil tip can sometimes result in a fragment of lead being left embedded within the skin. Pencil lead is composed of 66% graphite carbon, 26% aluminum silicate, and 8% paraffin.^1,2 While the toxicity of these individual elements is low, paraffin can cause nonallergic foreign-body reactions, aluminum silicate can induce epithelioid granulomatous reactions, and graphite has been reported to cause chronic granulomatous reactions in the lungs of those who work with graphite.² Penetrating trauma with a pencil can result in the formation of a cutaneous granulomatous reaction that can sometimes occur years to decades after the initial injury.^3,4 Several cases of pencil-core granulomas have been published, with lag times between the initial trauma and lesion growth as long as 58 years.^1-10 The pencil-core granuloma may simulate malignant melanoma, as it presents clinically as a growing, darkly pigmented lesion, thus prompting biopsy. We present a case of a pencil-core granuloma that began to grow 62 years after the initial trauma.

A 72-year-old woman was referred to our clinic for evaluation of a dark nodule on the forehead. The lesion had been present since the age of 10 years, reportedly from an accidental stabbing with a pencil. The lesion had been flat, stable, and asymptomatic since the trauma occurred; however, the patient reported that approximately 9 months prior to presentation, it had started growing and became painful. Physical examination revealed a 1.0-cm, round, bluish-black nodule on the right superior forehead (Figure 1A). No satellite lesions or local lymphadenopathy were noted on general examination.

An elliptical excision of the lesion with 1-cm margins revealed a bluish-black mass extending through the dermis, through the frontalis muscle, and into the periosteum and frontal bone (Figure 1B). A No. 15 blade was then used to remove the remaining pigment from the outer table of the frontal bone. Histopathologic findings demonstrated a sarcoidal granulomatous dermatitis associated with abundant, nonpolarizable, black, granular pigment consistent with carbon tattoo. This foreign material was readily identifiable in large extracellular deposits and also within histiocytes, including numerous multinucleated giant cells (Figure 2). Immunostaining for MART-1 and SOX-10 antigens failed to demonstrate a melanocytic proliferation. These findings were consistent with a sarcoidal foreign-body granulomatous reaction to carbon tattoo following traumatic graphite implantation.

Granulomatous reactions to carbon tattoo may be sarcoidal (foreign-body granulomatous dermatitis), palisading, or rarely tuberculoid (caseating). Sarcoidal granulomatous tattoo reactions may occur in patients with sarcoidosis due to koebnerization, and histology alone is not discriminatory; however, in our patient, the absence of underlying sarcoidosis or clinical or histologic findings of sarcoidosis outside of the site of the pencil-core granuloma excluded that possibility.¹¹ Pencil-core granulomas are characterized by a delayed foreign-body reaction to retained fragments of lead often years following a penetrating trauma with a pencil. Previous reports have described various lag times from injury to lesion growth of up to 58 years.^1-10 Our patient claimed to have noticed the lesion growing and becoming painful only after a 62-year lag time following the initial trauma. To our knowledge, this is the longest lag time between the initial pencil injury and induction of the foreign-body reaction reported in the literature. Clinically, the lesion appeared and behaved very similar to a melanoma, prompting further treatment and evaluation.

It has been suggested that the lag period between the initial trauma and the rapid growth of the lesion may correspond to the amount of time required for the breakdown of the pencil lead to a critical size followed by the dispersal of those particles within the interstitium, where they can induce a granulomatous reaction.^1,2,9 One case described a patient who reported that the growth and clinical change of the pencil-core granuloma only started when the patient accidentally hit the area where the trauma had occurred 31 years prior.¹ This additional trauma may have caused further mechanical breakdown of the lead to set off the tissue reaction. In our case, the patient did not recall any additional trauma to the head prior to the onset of growth of the nodule on the forehead.

Our case indicates that carbon tattoo may be a possible sequela of a penetrating injury from a pencil with retained pencil lead fragments; however, many of these carbon tattoos may remain stable throughout the remainder of the patient’s life. Carbon tattoo alone does not necessitate surgical treatment, but when an evolving lesion has a clinical differential diagnosis that includes a melanocytic neoplasia, biopsy or complete removal for histopathologic evaluation is warranted.

To the Editor:

Trauma from a pencil tip can sometimes result in a fragment of lead being left embedded within the skin. Pencil lead is composed of 66% graphite carbon, 26% aluminum silicate, and 8% paraffin.^1,2 While the toxicity of these individual elements is low, paraffin can cause nonallergic foreign-body reactions, aluminum silicate can induce epithelioid granulomatous reactions, and graphite has been reported to cause chronic granulomatous reactions in the lungs of those who work with graphite.² Penetrating trauma with a pencil can result in the formation of a cutaneous granulomatous reaction that can sometimes occur years to decades after the initial injury.^3,4 Several cases of pencil-core granulomas have been published, with lag times between the initial trauma and lesion growth as long as 58 years.^1-10 The pencil-core granuloma may simulate malignant melanoma, as it presents clinically as a growing, darkly pigmented lesion, thus prompting biopsy. We present a case of a pencil-core granuloma that began to grow 62 years after the initial trauma.

A 72-year-old woman was referred to our clinic for evaluation of a dark nodule on the forehead. The lesion had been present since the age of 10 years, reportedly from an accidental stabbing with a pencil. The lesion had been flat, stable, and asymptomatic since the trauma occurred; however, the patient reported that approximately 9 months prior to presentation, it had started growing and became painful. Physical examination revealed a 1.0-cm, round, bluish-black nodule on the right superior forehead (Figure 1A). No satellite lesions or local lymphadenopathy were noted on general examination.

An elliptical excision of the lesion with 1-cm margins revealed a bluish-black mass extending through the dermis, through the frontalis muscle, and into the periosteum and frontal bone (Figure 1B). A No. 15 blade was then used to remove the remaining pigment from the outer table of the frontal bone. Histopathologic findings demonstrated a sarcoidal granulomatous dermatitis associated with abundant, nonpolarizable, black, granular pigment consistent with carbon tattoo. This foreign material was readily identifiable in large extracellular deposits and also within histiocytes, including numerous multinucleated giant cells (Figure 2). Immunostaining for MART-1 and SOX-10 antigens failed to demonstrate a melanocytic proliferation. These findings were consistent with a sarcoidal foreign-body granulomatous reaction to carbon tattoo following traumatic graphite implantation.

Granulomatous reactions to carbon tattoo may be sarcoidal (foreign-body granulomatous dermatitis), palisading, or rarely tuberculoid (caseating). Sarcoidal granulomatous tattoo reactions may occur in patients with sarcoidosis due to koebnerization, and histology alone is not discriminatory; however, in our patient, the absence of underlying sarcoidosis or clinical or histologic findings of sarcoidosis outside of the site of the pencil-core granuloma excluded that possibility.¹¹ Pencil-core granulomas are characterized by a delayed foreign-body reaction to retained fragments of lead often years following a penetrating trauma with a pencil. Previous reports have described various lag times from injury to lesion growth of up to 58 years.^1-10 Our patient claimed to have noticed the lesion growing and becoming painful only after a 62-year lag time following the initial trauma. To our knowledge, this is the longest lag time between the initial pencil injury and induction of the foreign-body reaction reported in the literature. Clinically, the lesion appeared and behaved very similar to a melanoma, prompting further treatment and evaluation.

It has been suggested that the lag period between the initial trauma and the rapid growth of the lesion may correspond to the amount of time required for the breakdown of the pencil lead to a critical size followed by the dispersal of those particles within the interstitium, where they can induce a granulomatous reaction.^1,2,9 One case described a patient who reported that the growth and clinical change of the pencil-core granuloma only started when the patient accidentally hit the area where the trauma had occurred 31 years prior.¹ This additional trauma may have caused further mechanical breakdown of the lead to set off the tissue reaction. In our case, the patient did not recall any additional trauma to the head prior to the onset of growth of the nodule on the forehead.

Our case indicates that carbon tattoo may be a possible sequela of a penetrating injury from a pencil with retained pencil lead fragments; however, many of these carbon tattoos may remain stable throughout the remainder of the patient’s life. Carbon tattoo alone does not necessitate surgical treatment, but when an evolving lesion has a clinical differential diagnosis that includes a melanocytic neoplasia, biopsy or complete removal for histopathologic evaluation is warranted.

To the Editor:

Trauma from a pencil tip can sometimes result in a fragment of lead being left embedded within the skin. Pencil lead is composed of 66% graphite carbon, 26% aluminum silicate, and 8% paraffin.^1,2 While the toxicity of these individual elements is low, paraffin can cause nonallergic foreign-body reactions, aluminum silicate can induce epithelioid granulomatous reactions, and graphite has been reported to cause chronic granulomatous reactions in the lungs of those who work with graphite.² Penetrating trauma with a pencil can result in the formation of a cutaneous granulomatous reaction that can sometimes occur years to decades after the initial injury.^3,4 Several cases of pencil-core granulomas have been published, with lag times between the initial trauma and lesion growth as long as 58 years.^1-10 The pencil-core granuloma may simulate malignant melanoma, as it presents clinically as a growing, darkly pigmented lesion, thus prompting biopsy. We present a case of a pencil-core granuloma that began to grow 62 years after the initial trauma.

A 72-year-old woman was referred to our clinic for evaluation of a dark nodule on the forehead. The lesion had been present since the age of 10 years, reportedly from an accidental stabbing with a pencil. The lesion had been flat, stable, and asymptomatic since the trauma occurred; however, the patient reported that approximately 9 months prior to presentation, it had started growing and became painful. Physical examination revealed a 1.0-cm, round, bluish-black nodule on the right superior forehead (Figure 1A). No satellite lesions or local lymphadenopathy were noted on general examination.

An elliptical excision of the lesion with 1-cm margins revealed a bluish-black mass extending through the dermis, through the frontalis muscle, and into the periosteum and frontal bone (Figure 1B). A No. 15 blade was then used to remove the remaining pigment from the outer table of the frontal bone. Histopathologic findings demonstrated a sarcoidal granulomatous dermatitis associated with abundant, nonpolarizable, black, granular pigment consistent with carbon tattoo. This foreign material was readily identifiable in large extracellular deposits and also within histiocytes, including numerous multinucleated giant cells (Figure 2). Immunostaining for MART-1 and SOX-10 antigens failed to demonstrate a melanocytic proliferation. These findings were consistent with a sarcoidal foreign-body granulomatous reaction to carbon tattoo following traumatic graphite implantation.

Granulomatous reactions to carbon tattoo may be sarcoidal (foreign-body granulomatous dermatitis), palisading, or rarely tuberculoid (caseating). Sarcoidal granulomatous tattoo reactions may occur in patients with sarcoidosis due to koebnerization, and histology alone is not discriminatory; however, in our patient, the absence of underlying sarcoidosis or clinical or histologic findings of sarcoidosis outside of the site of the pencil-core granuloma excluded that possibility.¹¹ Pencil-core granulomas are characterized by a delayed foreign-body reaction to retained fragments of lead often years following a penetrating trauma with a pencil. Previous reports have described various lag times from injury to lesion growth of up to 58 years.^1-10 Our patient claimed to have noticed the lesion growing and becoming painful only after a 62-year lag time following the initial trauma. To our knowledge, this is the longest lag time between the initial pencil injury and induction of the foreign-body reaction reported in the literature. Clinically, the lesion appeared and behaved very similar to a melanoma, prompting further treatment and evaluation.

It has been suggested that the lag period between the initial trauma and the rapid growth of the lesion may correspond to the amount of time required for the breakdown of the pencil lead to a critical size followed by the dispersal of those particles within the interstitium, where they can induce a granulomatous reaction.^1,2,9 One case described a patient who reported that the growth and clinical change of the pencil-core granuloma only started when the patient accidentally hit the area where the trauma had occurred 31 years prior.¹ This additional trauma may have caused further mechanical breakdown of the lead to set off the tissue reaction. In our case, the patient did not recall any additional trauma to the head prior to the onset of growth of the nodule on the forehead.

Our case indicates that carbon tattoo may be a possible sequela of a penetrating injury from a pencil with retained pencil lead fragments; however, many of these carbon tattoos may remain stable throughout the remainder of the patient’s life. Carbon tattoo alone does not necessitate surgical treatment, but when an evolving lesion has a clinical differential diagnosis that includes a melanocytic neoplasia, biopsy or complete removal for histopathologic evaluation is warranted.

To the Editor:

MYH9-related disorder is an autosomal-dominant disorder characterized by macrothrombocytopenia and neutrophil inclusions secondary to defective myosin-9.¹ We describe a case of lower leg hyperpigmentation secondary to hemosiderin deposition from MYH9-related disorder.

A 31-year-old woman with a history of MYH9-related disorder and mixed connective tissue disease presented to the outpatient dermatology clinic with asymptomatic brown patches on the lower legs (Figure) of 10 years’ duration. She also had epistaxis, hearing loss, renal disease, and menorrhagia secondary to MYH9-related disorder. The patient had been started on hydroxychloroquine 2 years earlier by rheumatology for mixed connective tissue disorder. A biopsy was not performed, given the risk of bleeding from thrombocytopenia. Ammonium lactate lotion was recommended for the leg patches. No further interventions were undertaken. At 6-month follow-up, hyperpigmentation on the lower legs was stable. The patient expressed no desire for cosmetic intervention.

Prior to discovery of a common gene, MYH9-related disorder was classified as 4 overlapping syndromes: May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome.² More than 30 MYH9 mutations have been identified, all of which encode for myosin-9, a subunit of myosin IIA,^1,3 that is a nonmuscle myosin needed for cell movement, shape, and cytokinesis. Although most cells use myosin IIA to IIC, certain cells, such as platelets and neutrophils, use myosin IIA exclusively.

In neutrophils of patients with MYH9-related disorder, nonfunctional myosin-9 clumps to form hallmark inclusion bodies, which are seen on the peripheral blood smear. Macrothrombocytopenia, another hallmark of MYH9-related disorder, also can be seen on the peripheral smear of all affected patients. Approximately 30%of patients develop clinical manifestations of the disorder (eg, bleeding, renal failure, hearing loss, presenile cataracts). Bleeding tendency usually is mild; epistaxis and menorrhagia are the most common hematologic manifestations.⁴

We attribute the lower leg hyperpigmentation in our patient to a severe phenotype of MYH9-related disorder. In addition to hyperpigmentation, our patient had menorrhagia requiring treatment with tranexamic acid, renal failure, and hearing loss, further pointing to a more severe phenotype. Furthermore, it is likely that our patient’s hyperpigmentation was made worse by hydroxychloroquine and a coexisting diagnosis of mixed connective tissue disease, which led to a propensity for increased vessel fragility in the setting of thrombocytopenia.

The workup of suspected MYH9-related disorder includes exclusion of iron-deficiency anemia, which can increase bleeding in patients with the disorder. The presence of small red blood cells (RBCs) in microcytic anemia and large platelets of MYH9-related disorder can lead to a situation in which platelets travel near the center of the lumen of blood vessels, while RBCs travel to the periphery. This decrease in the platelet-endothelium interaction increases the risk for bleeding. Our patient’s hemoglobin level was within reference range, without evidence of iron-deficiency anemia. Correction of iron-deficiency anemia, if applicable, can prevent bleeding brought on by the mechanism of decreased platelet-endothelium interaction and avoid unnecessary antiplatelet medication because of misdiagnosis based on an erroneous platelet count.

The workup of MYH9-related disorder also should include audiography, ophthalmologic examination, and renal function testing for hearing loss, cataracts, and renal disease, respectively. Referral to genetics also may be warranted.

It also is of clinical interest that automated cell counters may underestimate the count of abnormally large platelets in MYH9-related disorder, counting them as RBCs or white blood cells. The platelet count in MYH9-related disorder may be underestimated by 4-fold or greater.^4-7

Treatment of leg hyperpigmentation can prove challenging, given the location of dermal hemosiderin. Topical therapy likely is ineffective. Lasers and intense pulsed light therapy are treatment modalities to consider for the hyperpigmentation of MYH9-related disorder. There have been reports of improved cosmesis in dermal hemosiderin depositional disorders, such as venous stasis.⁴ Our patient was given ammonium lactate lotion to thicken collagen, possibly preventing future bleeding episodes.

To the Editor:

MYH9-related disorder is an autosomal-dominant disorder characterized by macrothrombocytopenia and neutrophil inclusions secondary to defective myosin-9.¹ We describe a case of lower leg hyperpigmentation secondary to hemosiderin deposition from MYH9-related disorder.

A 31-year-old woman with a history of MYH9-related disorder and mixed connective tissue disease presented to the outpatient dermatology clinic with asymptomatic brown patches on the lower legs (Figure) of 10 years’ duration. She also had epistaxis, hearing loss, renal disease, and menorrhagia secondary to MYH9-related disorder. The patient had been started on hydroxychloroquine 2 years earlier by rheumatology for mixed connective tissue disorder. A biopsy was not performed, given the risk of bleeding from thrombocytopenia. Ammonium lactate lotion was recommended for the leg patches. No further interventions were undertaken. At 6-month follow-up, hyperpigmentation on the lower legs was stable. The patient expressed no desire for cosmetic intervention.

Prior to discovery of a common gene, MYH9-related disorder was classified as 4 overlapping syndromes: May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome.² More than 30 MYH9 mutations have been identified, all of which encode for myosin-9, a subunit of myosin IIA,^1,3 that is a nonmuscle myosin needed for cell movement, shape, and cytokinesis. Although most cells use myosin IIA to IIC, certain cells, such as platelets and neutrophils, use myosin IIA exclusively.

In neutrophils of patients with MYH9-related disorder, nonfunctional myosin-9 clumps to form hallmark inclusion bodies, which are seen on the peripheral blood smear. Macrothrombocytopenia, another hallmark of MYH9-related disorder, also can be seen on the peripheral smear of all affected patients. Approximately 30%of patients develop clinical manifestations of the disorder (eg, bleeding, renal failure, hearing loss, presenile cataracts). Bleeding tendency usually is mild; epistaxis and menorrhagia are the most common hematologic manifestations.⁴

We attribute the lower leg hyperpigmentation in our patient to a severe phenotype of MYH9-related disorder. In addition to hyperpigmentation, our patient had menorrhagia requiring treatment with tranexamic acid, renal failure, and hearing loss, further pointing to a more severe phenotype. Furthermore, it is likely that our patient’s hyperpigmentation was made worse by hydroxychloroquine and a coexisting diagnosis of mixed connective tissue disease, which led to a propensity for increased vessel fragility in the setting of thrombocytopenia.

The workup of suspected MYH9-related disorder includes exclusion of iron-deficiency anemia, which can increase bleeding in patients with the disorder. The presence of small red blood cells (RBCs) in microcytic anemia and large platelets of MYH9-related disorder can lead to a situation in which platelets travel near the center of the lumen of blood vessels, while RBCs travel to the periphery. This decrease in the platelet-endothelium interaction increases the risk for bleeding. Our patient’s hemoglobin level was within reference range, without evidence of iron-deficiency anemia. Correction of iron-deficiency anemia, if applicable, can prevent bleeding brought on by the mechanism of decreased platelet-endothelium interaction and avoid unnecessary antiplatelet medication because of misdiagnosis based on an erroneous platelet count.

The workup of MYH9-related disorder also should include audiography, ophthalmologic examination, and renal function testing for hearing loss, cataracts, and renal disease, respectively. Referral to genetics also may be warranted.

It also is of clinical interest that automated cell counters may underestimate the count of abnormally large platelets in MYH9-related disorder, counting them as RBCs or white blood cells. The platelet count in MYH9-related disorder may be underestimated by 4-fold or greater.^4-7

Treatment of leg hyperpigmentation can prove challenging, given the location of dermal hemosiderin. Topical therapy likely is ineffective. Lasers and intense pulsed light therapy are treatment modalities to consider for the hyperpigmentation of MYH9-related disorder. There have been reports of improved cosmesis in dermal hemosiderin depositional disorders, such as venous stasis.⁴ Our patient was given ammonium lactate lotion to thicken collagen, possibly preventing future bleeding episodes.

To the Editor:

MYH9-related disorder is an autosomal-dominant disorder characterized by macrothrombocytopenia and neutrophil inclusions secondary to defective myosin-9.¹ We describe a case of lower leg hyperpigmentation secondary to hemosiderin deposition from MYH9-related disorder.

A 31-year-old woman with a history of MYH9-related disorder and mixed connective tissue disease presented to the outpatient dermatology clinic with asymptomatic brown patches on the lower legs (Figure) of 10 years’ duration. She also had epistaxis, hearing loss, renal disease, and menorrhagia secondary to MYH9-related disorder. The patient had been started on hydroxychloroquine 2 years earlier by rheumatology for mixed connective tissue disorder. A biopsy was not performed, given the risk of bleeding from thrombocytopenia. Ammonium lactate lotion was recommended for the leg patches. No further interventions were undertaken. At 6-month follow-up, hyperpigmentation on the lower legs was stable. The patient expressed no desire for cosmetic intervention.

Prior to discovery of a common gene, MYH9-related disorder was classified as 4 overlapping syndromes: May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome.² More than 30 MYH9 mutations have been identified, all of which encode for myosin-9, a subunit of myosin IIA,^1,3 that is a nonmuscle myosin needed for cell movement, shape, and cytokinesis. Although most cells use myosin IIA to IIC, certain cells, such as platelets and neutrophils, use myosin IIA exclusively.

In neutrophils of patients with MYH9-related disorder, nonfunctional myosin-9 clumps to form hallmark inclusion bodies, which are seen on the peripheral blood smear. Macrothrombocytopenia, another hallmark of MYH9-related disorder, also can be seen on the peripheral smear of all affected patients. Approximately 30%of patients develop clinical manifestations of the disorder (eg, bleeding, renal failure, hearing loss, presenile cataracts). Bleeding tendency usually is mild; epistaxis and menorrhagia are the most common hematologic manifestations.⁴

We attribute the lower leg hyperpigmentation in our patient to a severe phenotype of MYH9-related disorder. In addition to hyperpigmentation, our patient had menorrhagia requiring treatment with tranexamic acid, renal failure, and hearing loss, further pointing to a more severe phenotype. Furthermore, it is likely that our patient’s hyperpigmentation was made worse by hydroxychloroquine and a coexisting diagnosis of mixed connective tissue disease, which led to a propensity for increased vessel fragility in the setting of thrombocytopenia.

The workup of suspected MYH9-related disorder includes exclusion of iron-deficiency anemia, which can increase bleeding in patients with the disorder. The presence of small red blood cells (RBCs) in microcytic anemia and large platelets of MYH9-related disorder can lead to a situation in which platelets travel near the center of the lumen of blood vessels, while RBCs travel to the periphery. This decrease in the platelet-endothelium interaction increases the risk for bleeding. Our patient’s hemoglobin level was within reference range, without evidence of iron-deficiency anemia. Correction of iron-deficiency anemia, if applicable, can prevent bleeding brought on by the mechanism of decreased platelet-endothelium interaction and avoid unnecessary antiplatelet medication because of misdiagnosis based on an erroneous platelet count.

The workup of MYH9-related disorder also should include audiography, ophthalmologic examination, and renal function testing for hearing loss, cataracts, and renal disease, respectively. Referral to genetics also may be warranted.

It also is of clinical interest that automated cell counters may underestimate the count of abnormally large platelets in MYH9-related disorder, counting them as RBCs or white blood cells. The platelet count in MYH9-related disorder may be underestimated by 4-fold or greater.^4-7

Treatment of leg hyperpigmentation can prove challenging, given the location of dermal hemosiderin. Topical therapy likely is ineffective. Lasers and intense pulsed light therapy are treatment modalities to consider for the hyperpigmentation of MYH9-related disorder. There have been reports of improved cosmesis in dermal hemosiderin depositional disorders, such as venous stasis.⁴ Our patient was given ammonium lactate lotion to thicken collagen, possibly preventing future bleeding episodes.

Case Report

A 39-year-old woman who was otherwise healthy presented with fatigue, malaise, a resolving rash, focal lymphadenopathy, increasing distal arthritis, dactylitis, resolving ecchymoses, and acute onycholysis of 1 week’s duration that developed 13 days after initiating ixekizumab. The patient had a history of psoriasis and psoriatic arthritis for more than 10 years. She had been successfully treated in the past for psoriasis with adalimumab for several years; however, adalimumab was discontinued after an episode of Clostridium difficile colitis. The patient had a negative purified protein derivative (tuberculin) test prior to starting biologics as she works in the health care field. Routine follow-up purified protein derivative (tuberculin) test was positive. She discontinued all therapy for psoriasis and psoriatic arthritis prior to being appropriately treated for 6 months under the care of infectious disease physicians. She then had several pregnancies and chose to restart biologic treatment after weaning her third child from breastfeeding, as her skin and joint disease were notably flaring.

Ustekinumab was chosen to shift treatment away from tumor necrosis factor (TNF) α inhibitors. The patient's condition was under relatively good control for 1 year; however, she experienced notable gastrointestinal tract upset (ie, intermittent diarrhea and constipation), despite multiple negative tests for C difficile. The patient was referred to see a gastroenterologist but never followed up. Due to long-term low-grade gastrointestinal problems, ustekinumab was discontinued, and the gastrointestinal symptoms resolved without treatment.

Given the side effects noted with TNF-α and IL-12/23 inhibitors and the fact that the patient’s cutaneous and joint disease were notable, the decision was made to start the IL-17A inhibitor ixekizumab. The patient administered 2 injections, one in each thigh. Within 12 hours, she experienced severe injection-site pain. The pain was so severe that it woke her from sleep the night of the first injections. She then developed severe pain in the right axilla that limited upper extremity mobility. Within 48 hours, she developed an erythematous, nonpruritic, nonscaly, mottled rash on the right breast that began to resolve within 24 hours without treatment. In addition, 3 days after the injections, she developed ecchymoses on the trunk and extremities without any identifiable trauma, severe acute onycholysis in several fingernails (Figure 1) and toenails, dactylitis such that she could not wear her wedding ring, and a flare of psoriatic arthritis in the fingers and ankles.

At the current presentation (2 weeks after the injections), the patient reported malaise, flulike symptoms, and low-grade intermittent fevers. Results from a hematology panel displayed leukopenia at 2.69×10³/μL (reference range, 3.54–9.06×10³/μL) and thrombocytopenia at 114×10³/μL (reference range, 165–415×10³/μL).¹ Her most recent laboratory results before the ixekizumab injections displayed a white blood cell count level at 4.6×10³/μL and platelet count at 159×10³/μL. C-reactive protein and erythrocyte sedimentation rate were within reference range. A shave biopsy of an erythematous nodule on the proximal interphalangeal joint of the fourth finger on the right hand displayed spongiotic dermatitis with eosinophils (Figure 2).

Interestingly, the psoriatic plaques on the scalp, trunk, and extremities had nearly completely resolved after only the first 2 injections. However, given the side effects, the second dose of ixekizumab was held, repeat laboratory tests were ordered to ensure normalization of cytopenia, and the patient was transitioned to pulse-dose topical steroids to control the remaining psoriatic plaques.

One week after presentation (3 weeks after the initial injections), the patient’s systemic symptoms had almost completely resolved, and she denied any further concerns. Her fingernails and toenails, however, continued to show the changes of onycholysis noted at the visit.

Comment

Ixekizumab is a human IgG4 monoclonal antibody that binds to IL-17A, one of the cytokines involved in the pathogenesis of psoriasis. The monoclonal antibody prevents its attachment to the IL-17 receptor, which inhibits the release of further cytokines and chemokines, decreasing the inflammatory and immune response.²

Ixekizumab was approved by the US Food and Drug Administration for plaque psoriasis after 3 clinical trials—UNCOVER-1, UNCOVER-2, and UNCOVER-3—were performed. In UNCOVER-3, the most common side effects that occurred—nasopharyngitis, upper respiratory tract infection, injection-site reaction, arthralgia, headache, and infections (specifically candidiasis)—generally were well tolerated. More serious adverse events included cardiovascular and cerebrovascular events, inflammatory bowel disease, and nonmelanoma skin cancer.³

Notable laboratory abnormalities that have been documented from ixekizumab include elevated liver function tests (eg, alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline phosphatase), as well as leukopenia, neutropenia, and thrombocytopenia.⁴ Although short-term thrombocytopenia, as described in our patient, provides an explanation for the bruising noted on observation, it is unusual to note such notable ecchymoses within days of the first injection.

Onycholysis has not been documented as a side effect of ixekizumab; however, it has been reported as an adverse event from other biologic medications. Sfikakis et al⁵ reported 5 patients who developed psoriatic skin lesions after treatment with 3 different anti-TNF biologics—infliximab, adalimumab, or etanercept—for rheumatoid arthritis; 2 of those patients also developed nail changes consistent with psoriatic onycholysis. In all 5 patients, symptoms of rheumatoid arthritis improved despite the new-onset skin and nail psoriasis.⁵

The exact pathophysiology of these adverse events has not been clearly understood, but it has been proposed that anti-TNF biologics may initiate an autoimmune reaction in the skin and nails, leading to paradoxical psoriasis and nail changes such as onycholysis. Tumor necrosis factor may have a regulatory role in the skin that prevents autoreactive T cells, such as cutaneous lymphocyte antigen–expressing T cells that promote the formation of psoriasiform lesions. By inhibiting TNF, there can be an underlying activation of autoreactive T cells that leads to tissue destruction in the skin and nails.⁶ Anti-TNF biologics also could increase CXCR3, a chemokine receptor that allows autoreactive T cells to enter the skin and cause pathology.⁷

IL-17A and IL-17F also have been shown to upregulate the expression of TNF receptor II in synoviocytes,⁸ which demonstrates that IL-17 works in synergy with TNF-α to promote an inflammatory reaction.⁹ Due to the inhibitory effects of ixekizumab, psoriatic arthritis should theoretically improve. However, if there is an alteration in the inflammatory sequence, then the regulatory role of TNF could be suppressed and psoriatic arthritis could become exacerbated. Additionally, its associated symptoms, such as dactylitis, could develop, as seen in our patient.⁴ Because psoriatic arthritis is closely associated with nail changes of psoriasis, it is conceivable that acute arthritic flares and acute onycholysis are both induced by the same cytokine dysregulation. Further studies and a larger patient population need to be evaluated to determine the exact cause of the acute exacerbation of psoriatic arthritis with concomitant nail changes as noted in our patient.

Acute onycholysis (within 72 hours) is a rare side effect of ixekizumab. It can be postulated that our patient’s severe acute onycholysis associated with a flare of psoriatic arthritis could be due to idiosyncratic immune dysregulation, promoting the activity of autoreactive T cells. The pharmacologic effects of ixekizumab occur through the inhibition of IL-17. We propose that by inhibiting IL-17 with associated TNF alterations, an altered inflammatory cascade could promote an autoimmune reaction leading to the described pathology.

Case Report

A 39-year-old woman who was otherwise healthy presented with fatigue, malaise, a resolving rash, focal lymphadenopathy, increasing distal arthritis, dactylitis, resolving ecchymoses, and acute onycholysis of 1 week’s duration that developed 13 days after initiating ixekizumab. The patient had a history of psoriasis and psoriatic arthritis for more than 10 years. She had been successfully treated in the past for psoriasis with adalimumab for several years; however, adalimumab was discontinued after an episode of Clostridium difficile colitis. The patient had a negative purified protein derivative (tuberculin) test prior to starting biologics as she works in the health care field. Routine follow-up purified protein derivative (tuberculin) test was positive. She discontinued all therapy for psoriasis and psoriatic arthritis prior to being appropriately treated for 6 months under the care of infectious disease physicians. She then had several pregnancies and chose to restart biologic treatment after weaning her third child from breastfeeding, as her skin and joint disease were notably flaring.

Ustekinumab was chosen to shift treatment away from tumor necrosis factor (TNF) α inhibitors. The patient's condition was under relatively good control for 1 year; however, she experienced notable gastrointestinal tract upset (ie, intermittent diarrhea and constipation), despite multiple negative tests for C difficile. The patient was referred to see a gastroenterologist but never followed up. Due to long-term low-grade gastrointestinal problems, ustekinumab was discontinued, and the gastrointestinal symptoms resolved without treatment.

Given the side effects noted with TNF-α and IL-12/23 inhibitors and the fact that the patient’s cutaneous and joint disease were notable, the decision was made to start the IL-17A inhibitor ixekizumab. The patient administered 2 injections, one in each thigh. Within 12 hours, she experienced severe injection-site pain. The pain was so severe that it woke her from sleep the night of the first injections. She then developed severe pain in the right axilla that limited upper extremity mobility. Within 48 hours, she developed an erythematous, nonpruritic, nonscaly, mottled rash on the right breast that began to resolve within 24 hours without treatment. In addition, 3 days after the injections, she developed ecchymoses on the trunk and extremities without any identifiable trauma, severe acute onycholysis in several fingernails (Figure 1) and toenails, dactylitis such that she could not wear her wedding ring, and a flare of psoriatic arthritis in the fingers and ankles.

At the current presentation (2 weeks after the injections), the patient reported malaise, flulike symptoms, and low-grade intermittent fevers. Results from a hematology panel displayed leukopenia at 2.69×10³/μL (reference range, 3.54–9.06×10³/μL) and thrombocytopenia at 114×10³/μL (reference range, 165–415×10³/μL).¹ Her most recent laboratory results before the ixekizumab injections displayed a white blood cell count level at 4.6×10³/μL and platelet count at 159×10³/μL. C-reactive protein and erythrocyte sedimentation rate were within reference range. A shave biopsy of an erythematous nodule on the proximal interphalangeal joint of the fourth finger on the right hand displayed spongiotic dermatitis with eosinophils (Figure 2).

Interestingly, the psoriatic plaques on the scalp, trunk, and extremities had nearly completely resolved after only the first 2 injections. However, given the side effects, the second dose of ixekizumab was held, repeat laboratory tests were ordered to ensure normalization of cytopenia, and the patient was transitioned to pulse-dose topical steroids to control the remaining psoriatic plaques.

One week after presentation (3 weeks after the initial injections), the patient’s systemic symptoms had almost completely resolved, and she denied any further concerns. Her fingernails and toenails, however, continued to show the changes of onycholysis noted at the visit.

Comment

Ixekizumab is a human IgG4 monoclonal antibody that binds to IL-17A, one of the cytokines involved in the pathogenesis of psoriasis. The monoclonal antibody prevents its attachment to the IL-17 receptor, which inhibits the release of further cytokines and chemokines, decreasing the inflammatory and immune response.²

Ixekizumab was approved by the US Food and Drug Administration for plaque psoriasis after 3 clinical trials—UNCOVER-1, UNCOVER-2, and UNCOVER-3—were performed. In UNCOVER-3, the most common side effects that occurred—nasopharyngitis, upper respiratory tract infection, injection-site reaction, arthralgia, headache, and infections (specifically candidiasis)—generally were well tolerated. More serious adverse events included cardiovascular and cerebrovascular events, inflammatory bowel disease, and nonmelanoma skin cancer.³

Notable laboratory abnormalities that have been documented from ixekizumab include elevated liver function tests (eg, alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline phosphatase), as well as leukopenia, neutropenia, and thrombocytopenia.⁴ Although short-term thrombocytopenia, as described in our patient, provides an explanation for the bruising noted on observation, it is unusual to note such notable ecchymoses within days of the first injection.

Onycholysis has not been documented as a side effect of ixekizumab; however, it has been reported as an adverse event from other biologic medications. Sfikakis et al⁵ reported 5 patients who developed psoriatic skin lesions after treatment with 3 different anti-TNF biologics—infliximab, adalimumab, or etanercept—for rheumatoid arthritis; 2 of those patients also developed nail changes consistent with psoriatic onycholysis. In all 5 patients, symptoms of rheumatoid arthritis improved despite the new-onset skin and nail psoriasis.⁵

The exact pathophysiology of these adverse events has not been clearly understood, but it has been proposed that anti-TNF biologics may initiate an autoimmune reaction in the skin and nails, leading to paradoxical psoriasis and nail changes such as onycholysis. Tumor necrosis factor may have a regulatory role in the skin that prevents autoreactive T cells, such as cutaneous lymphocyte antigen–expressing T cells that promote the formation of psoriasiform lesions. By inhibiting TNF, there can be an underlying activation of autoreactive T cells that leads to tissue destruction in the skin and nails.⁶ Anti-TNF biologics also could increase CXCR3, a chemokine receptor that allows autoreactive T cells to enter the skin and cause pathology.⁷

IL-17A and IL-17F also have been shown to upregulate the expression of TNF receptor II in synoviocytes,⁸ which demonstrates that IL-17 works in synergy with TNF-α to promote an inflammatory reaction.⁹ Due to the inhibitory effects of ixekizumab, psoriatic arthritis should theoretically improve. However, if there is an alteration in the inflammatory sequence, then the regulatory role of TNF could be suppressed and psoriatic arthritis could become exacerbated. Additionally, its associated symptoms, such as dactylitis, could develop, as seen in our patient.⁴ Because psoriatic arthritis is closely associated with nail changes of psoriasis, it is conceivable that acute arthritic flares and acute onycholysis are both induced by the same cytokine dysregulation. Further studies and a larger patient population need to be evaluated to determine the exact cause of the acute exacerbation of psoriatic arthritis with concomitant nail changes as noted in our patient.

Acute onycholysis (within 72 hours) is a rare side effect of ixekizumab. It can be postulated that our patient’s severe acute onycholysis associated with a flare of psoriatic arthritis could be due to idiosyncratic immune dysregulation, promoting the activity of autoreactive T cells. The pharmacologic effects of ixekizumab occur through the inhibition of IL-17. We propose that by inhibiting IL-17 with associated TNF alterations, an altered inflammatory cascade could promote an autoimmune reaction leading to the described pathology.

Case Report

A 39-year-old woman who was otherwise healthy presented with fatigue, malaise, a resolving rash, focal lymphadenopathy, increasing distal arthritis, dactylitis, resolving ecchymoses, and acute onycholysis of 1 week’s duration that developed 13 days after initiating ixekizumab. The patient had a history of psoriasis and psoriatic arthritis for more than 10 years. She had been successfully treated in the past for psoriasis with adalimumab for several years; however, adalimumab was discontinued after an episode of Clostridium difficile colitis. The patient had a negative purified protein derivative (tuberculin) test prior to starting biologics as she works in the health care field. Routine follow-up purified protein derivative (tuberculin) test was positive. She discontinued all therapy for psoriasis and psoriatic arthritis prior to being appropriately treated for 6 months under the care of infectious disease physicians. She then had several pregnancies and chose to restart biologic treatment after weaning her third child from breastfeeding, as her skin and joint disease were notably flaring.

Ustekinumab was chosen to shift treatment away from tumor necrosis factor (TNF) α inhibitors. The patient's condition was under relatively good control for 1 year; however, she experienced notable gastrointestinal tract upset (ie, intermittent diarrhea and constipation), despite multiple negative tests for C difficile. The patient was referred to see a gastroenterologist but never followed up. Due to long-term low-grade gastrointestinal problems, ustekinumab was discontinued, and the gastrointestinal symptoms resolved without treatment.

Given the side effects noted with TNF-α and IL-12/23 inhibitors and the fact that the patient’s cutaneous and joint disease were notable, the decision was made to start the IL-17A inhibitor ixekizumab. The patient administered 2 injections, one in each thigh. Within 12 hours, she experienced severe injection-site pain. The pain was so severe that it woke her from sleep the night of the first injections. She then developed severe pain in the right axilla that limited upper extremity mobility. Within 48 hours, she developed an erythematous, nonpruritic, nonscaly, mottled rash on the right breast that began to resolve within 24 hours without treatment. In addition, 3 days after the injections, she developed ecchymoses on the trunk and extremities without any identifiable trauma, severe acute onycholysis in several fingernails (Figure 1) and toenails, dactylitis such that she could not wear her wedding ring, and a flare of psoriatic arthritis in the fingers and ankles.

At the current presentation (2 weeks after the injections), the patient reported malaise, flulike symptoms, and low-grade intermittent fevers. Results from a hematology panel displayed leukopenia at 2.69×10³/μL (reference range, 3.54–9.06×10³/μL) and thrombocytopenia at 114×10³/μL (reference range, 165–415×10³/μL).¹ Her most recent laboratory results before the ixekizumab injections displayed a white blood cell count level at 4.6×10³/μL and platelet count at 159×10³/μL. C-reactive protein and erythrocyte sedimentation rate were within reference range. A shave biopsy of an erythematous nodule on the proximal interphalangeal joint of the fourth finger on the right hand displayed spongiotic dermatitis with eosinophils (Figure 2).

Interestingly, the psoriatic plaques on the scalp, trunk, and extremities had nearly completely resolved after only the first 2 injections. However, given the side effects, the second dose of ixekizumab was held, repeat laboratory tests were ordered to ensure normalization of cytopenia, and the patient was transitioned to pulse-dose topical steroids to control the remaining psoriatic plaques.

One week after presentation (3 weeks after the initial injections), the patient’s systemic symptoms had almost completely resolved, and she denied any further concerns. Her fingernails and toenails, however, continued to show the changes of onycholysis noted at the visit.

Comment

Ixekizumab is a human IgG4 monoclonal antibody that binds to IL-17A, one of the cytokines involved in the pathogenesis of psoriasis. The monoclonal antibody prevents its attachment to the IL-17 receptor, which inhibits the release of further cytokines and chemokines, decreasing the inflammatory and immune response.²

Ixekizumab was approved by the US Food and Drug Administration for plaque psoriasis after 3 clinical trials—UNCOVER-1, UNCOVER-2, and UNCOVER-3—were performed. In UNCOVER-3, the most common side effects that occurred—nasopharyngitis, upper respiratory tract infection, injection-site reaction, arthralgia, headache, and infections (specifically candidiasis)—generally were well tolerated. More serious adverse events included cardiovascular and cerebrovascular events, inflammatory bowel disease, and nonmelanoma skin cancer.³

Notable laboratory abnormalities that have been documented from ixekizumab include elevated liver function tests (eg, alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline phosphatase), as well as leukopenia, neutropenia, and thrombocytopenia.⁴ Although short-term thrombocytopenia, as described in our patient, provides an explanation for the bruising noted on observation, it is unusual to note such notable ecchymoses within days of the first injection.

Onycholysis has not been documented as a side effect of ixekizumab; however, it has been reported as an adverse event from other biologic medications. Sfikakis et al⁵ reported 5 patients who developed psoriatic skin lesions after treatment with 3 different anti-TNF biologics—infliximab, adalimumab, or etanercept—for rheumatoid arthritis; 2 of those patients also developed nail changes consistent with psoriatic onycholysis. In all 5 patients, symptoms of rheumatoid arthritis improved despite the new-onset skin and nail psoriasis.⁵

The exact pathophysiology of these adverse events has not been clearly understood, but it has been proposed that anti-TNF biologics may initiate an autoimmune reaction in the skin and nails, leading to paradoxical psoriasis and nail changes such as onycholysis. Tumor necrosis factor may have a regulatory role in the skin that prevents autoreactive T cells, such as cutaneous lymphocyte antigen–expressing T cells that promote the formation of psoriasiform lesions. By inhibiting TNF, there can be an underlying activation of autoreactive T cells that leads to tissue destruction in the skin and nails.⁶ Anti-TNF biologics also could increase CXCR3, a chemokine receptor that allows autoreactive T cells to enter the skin and cause pathology.⁷

IL-17A and IL-17F also have been shown to upregulate the expression of TNF receptor II in synoviocytes,⁸ which demonstrates that IL-17 works in synergy with TNF-α to promote an inflammatory reaction.⁹ Due to the inhibitory effects of ixekizumab, psoriatic arthritis should theoretically improve. However, if there is an alteration in the inflammatory sequence, then the regulatory role of TNF could be suppressed and psoriatic arthritis could become exacerbated. Additionally, its associated symptoms, such as dactylitis, could develop, as seen in our patient.⁴ Because psoriatic arthritis is closely associated with nail changes of psoriasis, it is conceivable that acute arthritic flares and acute onycholysis are both induced by the same cytokine dysregulation. Further studies and a larger patient population need to be evaluated to determine the exact cause of the acute exacerbation of psoriatic arthritis with concomitant nail changes as noted in our patient.

Acute onycholysis (within 72 hours) is a rare side effect of ixekizumab. It can be postulated that our patient’s severe acute onycholysis associated with a flare of psoriatic arthritis could be due to idiosyncratic immune dysregulation, promoting the activity of autoreactive T cells. The pharmacologic effects of ixekizumab occur through the inhibition of IL-17. We propose that by inhibiting IL-17 with associated TNF alterations, an altered inflammatory cascade could promote an autoimmune reaction leading to the described pathology.

To the Editor:

A 44-year-old man with a history of systemic lupus erythematosus (SLE) complicated by lupus nephritis, end-stage renal disease, and antiphospholipid syndrome was evaluated for progressive skin tightening over the last 3 years, predominantly on the hands but also involving the feet, legs, and arms. Physical examination revealed multiple flesh-colored to hypopigmented, bound-down, indurated, fissured plaques over the distal upper and lower extremities, most prominent over the hands (Figure 1). Yellow plaques appeared on the lateral sclera of both eyes (Figure 2). A diagnosis of nephrogenic systemic fibrosis (NSF) was supported by typical findings on punch biopsy, including a proliferation of dermal fibroblasts with thickened collagen bundles and mucin deposition.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, is characterized by fibrotic plaques and nodules that tend to be bilateral.¹ The chronic course of this disease often is accompanied by flexion contractures. Yellow scleral plaques caused by calcium phosphate deposition are present in up to 75% of cases and are more specific to a diagnosis of NSF in patients younger than 45 years.^1,2 A strong association exists between NSF and gadolinium contrast agents in patients with acute renal failure; our patient later confirmed multiple gadolinium exposures years prior. Deposits of gadolinium have even been found in NSF skin lesions.²

To the Editor:

A 44-year-old man with a history of systemic lupus erythematosus (SLE) complicated by lupus nephritis, end-stage renal disease, and antiphospholipid syndrome was evaluated for progressive skin tightening over the last 3 years, predominantly on the hands but also involving the feet, legs, and arms. Physical examination revealed multiple flesh-colored to hypopigmented, bound-down, indurated, fissured plaques over the distal upper and lower extremities, most prominent over the hands (Figure 1). Yellow plaques appeared on the lateral sclera of both eyes (Figure 2). A diagnosis of nephrogenic systemic fibrosis (NSF) was supported by typical findings on punch biopsy, including a proliferation of dermal fibroblasts with thickened collagen bundles and mucin deposition.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, is characterized by fibrotic plaques and nodules that tend to be bilateral.¹ The chronic course of this disease often is accompanied by flexion contractures. Yellow scleral plaques caused by calcium phosphate deposition are present in up to 75% of cases and are more specific to a diagnosis of NSF in patients younger than 45 years.^1,2 A strong association exists between NSF and gadolinium contrast agents in patients with acute renal failure; our patient later confirmed multiple gadolinium exposures years prior. Deposits of gadolinium have even been found in NSF skin lesions.²

To the Editor:

A 44-year-old man with a history of systemic lupus erythematosus (SLE) complicated by lupus nephritis, end-stage renal disease, and antiphospholipid syndrome was evaluated for progressive skin tightening over the last 3 years, predominantly on the hands but also involving the feet, legs, and arms. Physical examination revealed multiple flesh-colored to hypopigmented, bound-down, indurated, fissured plaques over the distal upper and lower extremities, most prominent over the hands (Figure 1). Yellow plaques appeared on the lateral sclera of both eyes (Figure 2). A diagnosis of nephrogenic systemic fibrosis (NSF) was supported by typical findings on punch biopsy, including a proliferation of dermal fibroblasts with thickened collagen bundles and mucin deposition.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, is characterized by fibrotic plaques and nodules that tend to be bilateral.¹ The chronic course of this disease often is accompanied by flexion contractures. Yellow scleral plaques caused by calcium phosphate deposition are present in up to 75% of cases and are more specific to a diagnosis of NSF in patients younger than 45 years.^1,2 A strong association exists between NSF and gadolinium contrast agents in patients with acute renal failure; our patient later confirmed multiple gadolinium exposures years prior. Deposits of gadolinium have even been found in NSF skin lesions.²