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Other Rheumatologic Diseases TABLE 42. lnternational Criteria for Behqet Disease Rela psing Polychond ritis Manifestations Points" Relapsing polychondritis is a rare condition (annual incidence, Recurrent oral ulcers 2 3.5 cases/l million) characterized by inflammation and Recu rrent genital ulcers 2 destruction of cartilage. The most apparent involvement of relapsing polychondritis is in the helix and antihelix of the Pathergy external eari the initial presentation there is redness and Skin lesions (pseudofolliculitis; skin ulcers; erythema nodosum) swelling, but it may progress to structural collapse and a floppy appearance (Figure 59). Middle ear involvement may cause Eye lesions (anterior uveitis; posterior uveitis; 2 retinalvasculitis) hearing loss. Other cartilaginous structures that can be affected include the bridge of the nose and articular cartilage, Central nervous system lesions Ieading to inflammatory arthritis. Involvement of the tracheal Vascular lesions (arterial thrombosis; large-vein thrombosis; phlebitis) rings can cause airway obstruction, requiring surgical inter vention. Other connective tissue structures involving the eyes, 'Four or more points are needed for the diagnosis of Behget syndrome. tendons, heart valves, and skin may be affected. Pathogenesis of relapsing polychondritis is poorly under- stood. An association with HLA-DR4 supports an autoimmune cause, and antibodies to various cartilage components are sometimes present. On biopsy specimens, cartilage shows a polymorphic inflammatory cell infiltrate. Diagnosis is made clinicallyi biopsies are rarely necessary. Tracheobronchial involvement mandates an aggressive evalu- ation, including imaging (typically CT), pulmonary function testing, and, in some cases, tracheobronchoscopy. In 30'7, of cases, relapsing polychondritis may be associated with other autoimmune diseases, including ANCA-associated vasculitis. The MAGIC (mouth and genital ulcerations with inflamed cartilage) syndrome appears to represent a confluence of F I G UR E 5 8. Pathergy associated with Behget syndrome, characterized by relapsing polychondritis and Behqet syndrome. pustular-appearing skin lesions occuning 48 hours after skin pricking with a sterile Management depends on severity. For mild symptoms, need le. NSAIDs and dapsone may be considered. For acute and/or severe involvement, high-dose glucocorticoids are the initial ulcers in Behget syndrome. Thalidomide and colchicine are management. Oral immunosuppressants (e.9., methotrexate) both accepted treatments; colchicine may be better for may be added. The tumor necrosis factor inhibitors infliximab arthritis than for oral ulcers. Topical and/or oral 5-aminosali and adalimumab have been used to good effect. The anti cylic acid derivatives may be used for gastrointestinal interleukin-6 agent tocilizumab may also be effective. involvement. For resistant severe ulcers, or for vascular, oph thalmologic, or central nervous system involvement, oral disease modifying antirheumatic drugs, such as azathio prine and cyclosporine, may be considered; tumor necrosis factor inhibitor therapy, particularly infliximab and adali- mumab, is frequently effective. In severe cases, cyclophos phamide may be an option. Acute thrombosis should be treated with immunosuppressives rather than anticoagulants because the cause of the thrombosis is inflammatory rather than thrombotic.

TABLE 42. lnternational Criteria for Behqet Disease Rela psing Polychond ritis Manifestations Points" Relapsing polychondritis is a rare condition (annual incidence, Recurrent oral ulcers 2 3.5 cases/l million) characterized by inflammation and Recu rrent genital ulcers 2 destruction of cartilage. The most apparent involvement of relapsing polychondritis is in the helix and antihelix of the Pathergy external eari the initial presentation there is redness and Skin lesions (pseudofolliculitis; skin ulcers; erythema nodosum) swelling, but it may progress to structural collapse and a floppy appearance (Figure 59). Middle ear involvement may cause Eye lesions (anterior uveitis; posterior uveitis; 2 retinalvasculitis) hearing loss. Other cartilaginous structures that can be affected include the bridge of the nose and articular cartilage, Central nervous system lesions Ieading to inflammatory arthritis. Involvement of the tracheal Vascular lesions (arterial thrombosis; large-vein thrombosis; phlebitis) rings can cause airway obstruction, requiring surgical inter vention. Other connective tissue structures involving the eyes, 'Four or more points are needed for the diagnosis of Behget syndrome. tendons, heart valves, and skin may be affected. Pathogenesis of relapsing polychondritis is poorly under- stood. An association with HLA-DR4 supports an autoimmune cause, and antibodies to various cartilage components are sometimes present. On biopsy specimens, cartilage shows a polymorphic inflammatory cell infiltrate. Diagnosis is made clinicallyi biopsies are rarely necessary. Tracheobronchial involvement mandates an aggressive evalu- ation, including imaging (typically CT), pulmonary function testing, and, in some cases, tracheobronchoscopy. In 30'7, of cases, relapsing polychondritis may be associated with other autoimmune diseases, including ANCA-associated vasculitis. The MAGIC (mouth and genital ulcerations with inflamed cartilage) syndrome appears to represent a confluence of F I G UR E 5 8. Pathergy associated with Behget syndrome, characterized by relapsing polychondritis and Behqet syndrome. pustular-appearing skin lesions occuning 48 hours after skin pricking with a sterile Management depends on severity. For mild symptoms, need le. NSAIDs and dapsone may be considered. For acute and/or severe involvement, high-dose glucocorticoids are the initial ulcers in Behget syndrome. Thalidomide and colchicine are management. Oral immunosuppressants (e.9., methotrexate) both accepted treatments; colchicine may be better for may be added. The tumor necrosis factor inhibitors infliximab arthritis than for oral ulcers. Topical and/or oral 5-aminosali and adalimumab have been used to good effect. The anti cylic acid derivatives may be used for gastrointestinal interleukin-6 agent tocilizumab may also be effective. involvement. For resistant severe ulcers, or for vascular, oph thalmologic, or central nervous system involvement, oral disease modifying antirheumatic drugs, such as azathio prine and cyclosporine, may be considered; tumor necrosis factor inhibitor therapy, particularly infliximab and adali- mumab, is frequently effective. In severe cases, cyclophos phamide may be an option. Acute thrombosis should be treated with immunosuppressives rather than anticoagulants because the cause of the thrombosis is inflammatory rather than thrombotic. TEY POITIS . Behqet syndrome is characterized by recurrent painful oral and genital mucosal ulcerations, inflammatory eye disease, and pathergr. . Vascular, ophthalmologic, and central nervous system involvement requires aggressive treatment with immu- nosuppressive andior tumor necrosis factor inhibitor F IG UR E 5 9. Floppy ear in a patient with relapsing polychondritis. Chronic inflammation of the upper section of the ear eventually results in loss of cartilage therapy. and structural collapse.The ear lobe, which does not contain cartilage, is unaffected.

TEY POITIS . Behqet syndrome is characterized by recurrent painful oral and genital mucosal ulcerations, inflammatory eye disease, and pathergr. . Vascular, ophthalmologic, and central nervous system involvement requires aggressive treatment with immu- nosuppressive andior tumor necrosis factor inhibitor F IG UR E 5 9. Floppy ear in a patient with relapsing polychondritis. Chronic inflammation of the upper section of the ear eventually results in loss of cartilage therapy. and structural collapse.The ear lobe, which does not contain cartilage, is unaffected. 88

Other Rheumatologic Diseases I(EY POII{I arthritis, rash, and sterile peritonitis. Renal amyloidosis may . Relapsing polychondritis is characterized by inflamma- ensue. The cryopyrin-associated periodic fever syndromes result from activation of the NLRP3 inflammasome. In the tion and damage of cartilaginous tissues; tissues most pediatric version, neonatal onset multisystem inflammatory commonly affected include the cartilaginous portions disease, inflammation leads to permanent joint deformity, of the external and middle ear, nose, and tracheal rings. encephalitis, and, ifnot treated, early death. Adult versions of cryopyrin-associated periodic fever syndromes are milder and may be triggered by cold. In TRAPS (tumor necrosis factor Autoi nflam matory Diseases receptor-associated periodic fever syndrome), mutations in Autoinflammatory diseases xre monogenic conditions in the tumor necrosis factor receptor lead it to be persistently which innate immune pathways are activated independently activated on inflammatory cells. Patients have fever, chills, and of any specific known antigen. The result is periodic or chronic severe muscle pain lasting more than 1 week. Other fbrms of inflammation, f'ever, and multiorgan involvement. The best mutations can also lead to periodic fevers, such as through the studied of these conditions result from mutations that cause activation of the signaling molecule nuclear factor rB or enhanced function of inflammasomes. multimolecular com, through the unstimulated production of interferons. plexes that raise the levels ofactivated interleukin 1p. To the extent possible, treatments address the signaling In familial Mediterranean fever, mutations of pyrin, a problem involved. Table 43 lists the features and treatment of protein, lead to inflammasome activation, causing fever, select autoinfl ammatory diseases.

I(EY POII{I arthritis, rash, and sterile peritonitis. Renal amyloidosis may . Relapsing polychondritis is characterized by inflamma- ensue. The cryopyrin-associated periodic fever syndromes result from activation of the NLRP3 inflammasome. In the tion and damage of cartilaginous tissues; tissues most pediatric version, neonatal onset multisystem inflammatory commonly affected include the cartilaginous portions disease, inflammation leads to permanent joint deformity, of the external and middle ear, nose, and tracheal rings. encephalitis, and, ifnot treated, early death. Adult versions of cryopyrin-associated periodic fever syndromes are milder and may be triggered by cold. In TRAPS (tumor necrosis factor Autoi nflam matory Diseases receptor-associated periodic fever syndrome), mutations in Autoinflammatory diseases xre monogenic conditions in the tumor necrosis factor receptor lead it to be persistently which innate immune pathways are activated independently activated on inflammatory cells. Patients have fever, chills, and of any specific known antigen. The result is periodic or chronic severe muscle pain lasting more than 1 week. Other fbrms of inflammation, f'ever, and multiorgan involvement. The best mutations can also lead to periodic fevers, such as through the studied of these conditions result from mutations that cause activation of the signaling molecule nuclear factor rB or enhanced function of inflammasomes. multimolecular com, through the unstimulated production of interferons. plexes that raise the levels ofactivated interleukin 1p. To the extent possible, treatments address the signaling In familial Mediterranean fever, mutations of pyrin, a problem involved. Table 43 lists the features and treatment of protein, lead to inflammasome activation, causing fever, select autoinfl ammatory diseases. TABLE 43. Features and Treatment of Select Autoinflammatory Diseases FMFA TRAPS FCA5U MWSb NOMID/ Schnitzler Syndrome ctNcAb lnheritance AR AD AD AD AD Acquired Gene MEFV TNFRSFlA NtRP3 NtRP3 NLRP3 Unknown Protein furin TNF receptor Cryopyrin Cryopyrin Cryopyrin MGUS (hallmark but type 1 not proven causal) Age at onset 65% <1 0 years 50% <1 0 years <1 year of age Childhood Neonata I Adult(51 +10years) o{ age;907"<20 of age; up to period years of age fifth decade Ethnicity Mediterranean Ail European European All White/European Clinical Ma nifestations

TABLE 43. Features and Treatment of Select Autoinflammatory Diseases FMFA TRAPS FCA5U MWSb NOMID/ Schnitzler Syndrome ctNcAb lnheritance AR AD AD AD AD Acquired Gene MEFV TNFRSFlA NtRP3 NtRP3 NLRP3 Unknown Protein furin TNF receptor Cryopyrin Cryopyrin Cryopyrin MGUS (hallmark but type 1 not proven causal) Age at onset 65% <1 0 years 50% <1 0 years <1 year of age Childhood Neonata I Adult(51 +10years) o{ age;907"<20 of age; up to period years of age fifth decade Ethnicity Mediterranean Ail European European All White/European Clinical Ma nifestations Attack duration 12-72 hours Days to weeks 12-24 hours 1-2 days Continuous Daily Abdominal Pain; serositis Pain; serositis Nausea Pain Pleuritis Common Common Rare Rare M usculoskeleta I Monoarthritis Large joints Arthralgia Arthralgia; Epiphyseal Arthralgia; arth ritis; of lower oligoarthritis overgrowth; bone pain extremities co ntractu res

M usculoskeleta I Monoarthritis Large joints Arthralgia Arthralgia; Epiphyseal Arthralgia; arth ritis; of lower oligoarthritis overgrowth; bone pain extremities co ntractu res Rash Erysipeloid on Migratory with Cold- Urticaria-like U rticaria-like Urticarial rash lower legs underlying induced; myalgia urticaria-like Oth er High risk for Conjunctivitis; Conjunctivitis; Sensorineural Sensorineural Leukocytosis; amyloidosis periorbital headache; deafness; deafness; lymphadenopathy; edema amyloidosis; conjunctivitis; aseptic hepatosplenomega ly; sensorineural amyloidosis meningitis; MGUS (usually lgM r); deafness mental may later develop retardation; Waldenstrom amyloidosis macrog lobu linem ia Treatment Colchicine Glucocorticoids; lL-1 0 rL 1p lL-1 B lL-1Ra or lL-1B TNF inhibitors inh ibition inhibition inh ibition inhibition AD=autosoma dominant;AR=autosomalrecessive;CINCA=chronicinfantileneurologic,cutaneous,articularsyndrome;FCAS=familialcoldautoinflammatorysyndrome; syndrome;NOMID=neonatalonsetmultisysteminflammatorydisease;TNF=tumornecrosisfactor;TRAPS=tumornecrosisfactorreceptor associatedperiodicsyndrome. i "FMF is the most common autoin{lammatory disease.

Rash Erysipeloid on Migratory with Cold- Urticaria-like U rticaria-like Urticarial rash lower legs underlying induced; myalgia urticaria-like Oth er High risk for Conjunctivitis; Conjunctivitis; Sensorineural Sensorineural Leukocytosis; amyloidosis periorbital headache; deafness; deafness; lymphadenopathy; edema amyloidosis; conjunctivitis; aseptic hepatosplenomega ly; sensorineural amyloidosis meningitis; MGUS (usually lgM r); deafness mental may later develop retardation; Waldenstrom amyloidosis macrog lobu linem ia Treatment Colchicine Glucocorticoids; lL-1 0 rL 1p lL-1 B lL-1Ra or lL-1B TNF inhibitors inh ibition inhibition inh ibition inhibition AD=autosoma dominant;AR=autosomalrecessive;CINCA=chronicinfantileneurologic,cutaneous,articularsyndrome;FCAS=familialcoldautoinflammatorysyndrome; syndrome;NOMID=neonatalonsetmultisysteminflammatorydisease;TNF=tumornecrosisfactor;TRAPS=tumornecrosisfactorreceptor associatedperiodicsyndrome. i "FMF is the most common autoin{lammatory disease. I disease (chronic infantiie neurologic, cutaneous, afticuiar syndrome). 89

Other Rheumatologic Diseases rtY Potxl multiple organs and tissues. Although sarcoidosis most com o Autoinflammatory diseases are characterized by epi- monly affects the lungs (see MKSAP 19 Pulmonary and Critical Care Medicine), approximately 50% of patients have sodic and/or persistent inflammation and involve extrapulmonary involvement, arrd 2"/,, have only extrapulmo inherited or spontaneous mutation ofgenes that encode nary involvement. The cause of sarcoidosis is unknown; the for inflammatory responses. primacy of lung involvement suggests an initial respiratory exposure. ln the United States, Black persons are affected more commonly and more severely than White persons. Adult-Onset Still Disease Rheumatologic manifestations of sarcoidosis include Adult onset Still disease is a rare systemic condition (preva arthritis involving multiple joints that may develop erosive lence, 1 10 cases/l million) characterized by fever with daily damage, deformity, and dactylitis. Myopathy may also occur. evening spikes, evanescent salmon colored macular or macu Bone involvement, reported in up to 15'X, of patients. is associ lopapular rashes that peak with the fever, arthritis or arthral ated r,r,ith a chronic course and poorer prognosis (Figure 60). gia, and elevated leukocyte counts. Other manifestations include sore throat; lymphadenopathy; splenomegaly: and inflammation of the lungs, heart, and liver. The Yamaguchi criteria fbr adult-onset Still disease con- sist of tbur major and four minor criteria. Diagnosis requires the presence of at least five criteria, including at least two major criteria. Major criteria are (1) daily evening spiking fever to temperature of 39.0 'C (102.2 "F), (2) arthralgia/ arthritis fbr more than 2 weeks, (3) nonpruritic salmon colored macular/maculopapular rash on trunk or extremities, and (4) leukocyte count greater than 10.000/pL (10 x 10e/L), with more than B0'2, neutrophils. Minor criteria are (t) lym phadenopathy and/or splenomegaly, (2) elevated aspartate aminotransferase, alanine aminotransferase, or lactate dehy drogenase levels, and (3) negativig for antinuclear antibodies or rheumatoid factor. Erythrocyte sedimentation rate and C reactive protein levels are elevatedl I'erritin levels are often extremely high. Adult onset Still disease is thought to represent an overex pression ofinterleukin-lB and other cytokines, and as such it is sometimes conceptualized as a polygenic autoinflammatory syndrome. The differential diagnosis is broad, including infec- tious. malignant, and systemic autoimmune diseases. Adult- onset Still disease may present as a single episode; be recurrent; or, most commonly, be chronic and progressive (zs"t, ol"t, of aflected patients). Past treatment options, including glucocorticoids and methotrexate, were frequently inadequate. The use of interleukin-B directed biologic thera pies, including anakinra and canakinumab, has been success ful. Anti-interleukin 6 therapies have shown promise in clinical reports. I(EY POItrI . Adult-onset Still disease is characterized by fever with daily evening spikes, evanescent salmon-colored rash, arthritis, and leukocytosis.

rtY Potxl multiple organs and tissues. Although sarcoidosis most com o Autoinflammatory diseases are characterized by epi- monly affects the lungs (see MKSAP 19 Pulmonary and Critical Care Medicine), approximately 50% of patients have sodic and/or persistent inflammation and involve extrapulmonary involvement, arrd 2"/,, have only extrapulmo inherited or spontaneous mutation ofgenes that encode nary involvement. The cause of sarcoidosis is unknown; the for inflammatory responses. primacy of lung involvement suggests an initial respiratory exposure. ln the United States, Black persons are affected more commonly and more severely than White persons. Adult-Onset Still Disease Rheumatologic manifestations of sarcoidosis include Adult onset Still disease is a rare systemic condition (preva arthritis involving multiple joints that may develop erosive lence, 1 10 cases/l million) characterized by fever with daily damage, deformity, and dactylitis. Myopathy may also occur. evening spikes, evanescent salmon colored macular or macu Bone involvement, reported in up to 15'X, of patients. is associ lopapular rashes that peak with the fever, arthritis or arthral ated r,r,ith a chronic course and poorer prognosis (Figure 60). gia, and elevated leukocyte counts. Other manifestations include sore throat; lymphadenopathy; splenomegaly: and inflammation of the lungs, heart, and liver. The Yamaguchi criteria fbr adult-onset Still disease con- sist of tbur major and four minor criteria. Diagnosis requires the presence of at least five criteria, including at least two major criteria. Major criteria are (1) daily evening spiking fever to temperature of 39.0 'C (102.2 "F), (2) arthralgia/ arthritis fbr more than 2 weeks, (3) nonpruritic salmon colored macular/maculopapular rash on trunk or extremities, and (4) leukocyte count greater than 10.000/pL (10 x 10e/L), with more than B0'2, neutrophils. Minor criteria are (t) lym phadenopathy and/or splenomegaly, (2) elevated aspartate aminotransferase, alanine aminotransferase, or lactate dehy drogenase levels, and (3) negativig for antinuclear antibodies or rheumatoid factor. Erythrocyte sedimentation rate and C reactive protein levels are elevatedl I'erritin levels are often extremely high. Adult onset Still disease is thought to represent an overex pression ofinterleukin-lB and other cytokines, and as such it is sometimes conceptualized as a polygenic autoinflammatory syndrome. The differential diagnosis is broad, including infec- tious. malignant, and systemic autoimmune diseases. Adult- onset Still disease may present as a single episode; be recurrent; or, most commonly, be chronic and progressive (zs"t, ol"t, of aflected patients). Past treatment options, including glucocorticoids and methotrexate, were frequently inadequate. The use of interleukin-B directed biologic thera pies, including anakinra and canakinumab, has been success ful. Anti-interleukin 6 therapies have shown promise in clinical reports. I(EY POItrI . Adult-onset Still disease is characterized by fever with daily evening spikes, evanescent salmon-colored rash, arthritis, and leukocytosis. Sarcoidosis Sarcoidosis is an inflammatory disease of unknown cause F I G UR E 6 0. Hand radiograph showing the typical cystic lesions (red anow) and characterized by fbrmation of noncaseating granulomas in a lacy pattern (green arrow\ characteristic of sarcoidosis.

rtY Potxl multiple organs and tissues. Although sarcoidosis most com o Autoinflammatory diseases are characterized by epi- monly affects the lungs (see MKSAP 19 Pulmonary and Critical Care Medicine), approximately 50% of patients have sodic and/or persistent inflammation and involve extrapulmonary involvement, arrd 2"/,, have only extrapulmo inherited or spontaneous mutation ofgenes that encode nary involvement. The cause of sarcoidosis is unknown; the for inflammatory responses. primacy of lung involvement suggests an initial respiratory exposure. ln the United States, Black persons are affected more commonly and more severely than White persons. Adult-Onset Still Disease Rheumatologic manifestations of sarcoidosis include Adult onset Still disease is a rare systemic condition (preva arthritis involving multiple joints that may develop erosive lence, 1 10 cases/l million) characterized by fever with daily damage, deformity, and dactylitis. Myopathy may also occur. evening spikes, evanescent salmon colored macular or macu Bone involvement, reported in up to 15'X, of patients. is associ lopapular rashes that peak with the fever, arthritis or arthral ated r,r,ith a chronic course and poorer prognosis (Figure 60). gia, and elevated leukocyte counts. Other manifestations include sore throat; lymphadenopathy; splenomegaly: and inflammation of the lungs, heart, and liver. The Yamaguchi criteria fbr adult-onset Still disease con- sist of tbur major and four minor criteria. Diagnosis requires the presence of at least five criteria, including at least two major criteria. Major criteria are (1) daily evening spiking fever to temperature of 39.0 'C (102.2 "F), (2) arthralgia/ arthritis fbr more than 2 weeks, (3) nonpruritic salmon colored macular/maculopapular rash on trunk or extremities, and (4) leukocyte count greater than 10.000/pL (10 x 10e/L), with more than B0'2, neutrophils. Minor criteria are (t) lym phadenopathy and/or splenomegaly, (2) elevated aspartate aminotransferase, alanine aminotransferase, or lactate dehy drogenase levels, and (3) negativig for antinuclear antibodies or rheumatoid factor. Erythrocyte sedimentation rate and C reactive protein levels are elevatedl I'erritin levels are often extremely high. Adult onset Still disease is thought to represent an overex pression ofinterleukin-lB and other cytokines, and as such it is sometimes conceptualized as a polygenic autoinflammatory syndrome. The differential diagnosis is broad, including infec- tious. malignant, and systemic autoimmune diseases. Adult- onset Still disease may present as a single episode; be recurrent; or, most commonly, be chronic and progressive (zs"t, ol"t, of aflected patients). Past treatment options, including glucocorticoids and methotrexate, were frequently inadequate. The use of interleukin-B directed biologic thera pies, including anakinra and canakinumab, has been success ful. Anti-interleukin 6 therapies have shown promise in clinical reports. I(EY POItrI . Adult-onset Still disease is characterized by fever with daily evening spikes, evanescent salmon-colored rash, arthritis, and leukocytosis. Sarcoidosis Sarcoidosis is an inflammatory disease of unknown cause F I G UR E 6 0. Hand radiograph showing the typical cystic lesions (red anow) and characterized by fbrmation of noncaseating granulomas in a lacy pattern (green arrow\ characteristic of sarcoidosis. 90