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Table 2 Overview of rare rheumatic diseases

From: The combined prevalence of classified rare rheumatic diseases is almost double that of ankylosing spondylitis

Disease Prevalence Genetics/pathogenesis Diagnostic criteria Clinical features Laboratory findings Therapy Prognosis/ Complications Classification
Buerger's disease (thromboangiitis obliterans) [52,53,54,55,56] Most common in Middle and Far East, estimated prevalence: 5/100,000 (Japan) 0.65/100,000 (Taiwan) → 2.8/100,000 Probably immune-mediated vasculitis, possibly associated with infectious agent; strong association with smoking; segmental occlusive inflammatory vasculitis (mainly small vessels, arteries and veins) Many different diagnostic criteria (e.g., by Shionoya and Olin) Disease onset in middle-aged, predominantly males; ischemic pain in extremities, numbness, skin ulcerations, thrombophlebitis, Raynaud´s phenomenon Inflammatory markers usually normal Smoking cessation, prostaglandin analogs, maximize blood supply, reduce risk of vasoconstriction (avoid coldness. etc.) Remitting-relapsing, life expectancy usually normal, but morbidity increased (e.g., amputations) Vasculitis/ vasculopathy
Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) [57,58,59,60,61,62,63] 17.8/1,000,000 (estimated, Japan) 10.7/1,000,000 (France) 14/1,000,000 (Sweden) → 1.4/100,000 Association with multiple different HLA genotypes, possibly IgG4-related disorder; Th-2 cells and eosinophils seem to play a major role in pathogenesis; small vessel necrotizing vasculitis ACR criteria, Chapel Hill nomenclature definition Disease onset in middle-aged males and females; asthma, weight loss, mononeuritis multiplex, non-erosive sinusitis/polyposis, skin lesions, lung infiltrates, pleural effusion, cardiomyopathy, glomerulonephritis 30 – 40% ANCA-positive (mainly MPO, but proteinase 3 also possible), eosinophilia; depending on organ involvement, elevated renal enzymes possible; elevated IgG4 can be found Corticosteroids, immunosuppressants, rituximab Chronic or remitting-relapsing, main complication with increased mortality is cardiomyopathy but overall mortality low Vasculitis/ vasculopathy
Degos disease (malignant atrophic papulosis) [64,65,66,67] Unknown, less than 200 cases reported, estimate < 1/1,000,000 Unknown; autosomal dominant inheritance discussed; thrombo-obliterative vasculopathy Clinical and histopathological diagnosis Onset usually at age 20–50 years, papular skin lesions with central atrophy and peripheral telangiectatic rim, sudden onset systemic involvement possible with high morbidity and mortality (bowel perforation, thrombosis, hemorrhage) Coagulopathy in some patients Anticoagulants, treprostinil, eculizumab Limited and systemic variant, systemic variant has over 50% mortality within 2–3 years (due to bowel perforation and peritonitis) Vasculitis/ vasculopathy
Hughes-Stovin syndrome (incomplete/ cardiovascular Behcet´s disease) [68, 69] Unknown, ~ 40 cases described, estimate < 1/1,000,000 Unknown; angiodysplasia and infections discussed, maybe variant of Behcet´s disease; absence of oral/genital ulcers important for distinction Clinical and radiographic diagnosis Predominantly young males affected, multiple lung aneurysms cause cough, dyspnea, fever, chest pain, hemoptysis Leukocytosis, anemia, elevated ESR and CRP Corticosteroids, immunosuppressants, anticoagulant/ thrombolytic agents, surgery Poor prognosis, massive hemoptysis and aneurysmal rupture are main causes of death Vasculitis/ vasculopathy
Hypocomplementemic urticarial vasculitis (McDuffie syndrome) [70,71,72,73,74] Unknown, estimate < 1/1,000,000 Mutations in DNASE1L3 described, possible association with SLE; inflammation of dermal capillaries and postcapillary venules; possibly IgG4-related disease Proposed criteria by Schwartz et al. Predominantly in middle-aged females, chronic urticarial exanthema, angioedema, arthralgia/arthritis, ocular inflammation, glomerulonephritis, abdominal pain, angioedema, obstructive pulmonary disease Low complement levels, anti-C1q-antibodies Corticosteroids, immunosuppressants Chronic, prognosis depending on systemic organ involvement (pulmonary, renal, cardiac), mortality low Vasculitis/ vasculopathy
Kawasaki disease (mucocutaneous lymph node syndrome) [18, 75,76,77] Prevalence unknown, incidence ranges from 3.7/100,000 (Australia) to 243/100,000 (Japan) for children < 5 years and increased in previous years, estimate < 1/100,000 Unknown, but genetic predisposition suspected (much more common in Asia), probably infectious trigger (seasonal peaks) causing small and medium vessel vasculitis American Heart Association (AHA) guidelines, but primarily clinical diagnosis, as incomplete presentation is common Predominantly young children until the age of 4 years affected with male predominance; conjunctivitis, exanthema, GI symptoms, fever, oropharynx involvement, lymphadenopathy, cracked lips, erythema of hand and feet, coronary aneurysm Elevated CRP, ESR, leukocytosis, thrombocytosis Intravenous immunoglobulins, high dose aspirin Self-limited, good prognosis if treated, but coronary artery abnormalities occur in 25% if left untreated, leading cause of acquired heart disease in children in developed countries Vasculitis/ vasculopathy
Leukocytoclastic/cutaneous small vessel/hypersensitivity vasculitis [78,79,80] Prevalence unknown, incidence 4.5/1,000,000 estimate < 1/1,000,000 Unknown; more than 50% idiopathic, other possible causes include malignancy, autoimmune diseases, drugs (antibiotics, NSAIDs); neutrophilic inflammation in postcapillary venules Chapel Hill criteria (histopathological) Limited cutaneous variant with palpable purpura and lesions (often on lower extremity), or systemic organ involvement possible (most commonly renal) Anemia, leukocytosis, elevated renal enzymes Corticosteroids, immunosuppressants Variable, commonly remitting-relapsing with treatment, overall survival good Vasculitis/ vasculopathy
Microscopic polyangiitis (microscopic polyarteritis) [58, 59, 81, 82] 25.1/1,000,000 (France) 94/1,000,000 (Sweden) → 6/100,000 Unknown; possibly related to MHC II genes; environmental (silica) and autoimmune influence discussed; small vessel, necrotizing vasculitis with few or no immune deposits, primarily affecting kidneys and lungs Chapel Hill criteria (histopathological) Males slightly more commonly affected than females, onset primarily in elderly (age ≥ 60 years). Dyspnea, cough, hemoptysis, rapidly progressive glomerulonephritis, palpable purpura, GI symptoms, peripheral neuropathy MPO-ANCA, microscopic hematuria Corticosteroids, immunosuppressants (rituximab, cyclophosphamide) Remitting-relapsing with treatment, poor prognosis without therapy, complications include end-stage renal disease, cardiovascular involvement, malignancy, and infections Vasculitis/ vasculopathy
Behçet's disease [41, 83,84,85] Estimated prevalence in Scandinavia: 2/100,000
Europe: 10.5/100,000
Mediterranean: 188/100,000
Others: 15.7/100,000
Not rare in Turkey (80–370/100,000), estimate 5/10,000
Association with HLA-B51; most common along the ancient silk road; infectious or environmental triggers; systemic occlusive vasculitis discussed Many different criteria exist (e.g., New International Criteria of Behçet’s Disease) Peak of disease onset in third decade of life (any age possible), recurrent eye inflammation (iridocyclitis/uveitis), oral and genital ulcers, skin manifestations (erythema nodosum, etc.), arthralgia, thrombosis, neurological symptoms, cardiac involvement Pathergy-phenomenon, leukocytosis Corticosteroids, colchicine, immunosuppressants, biologicals, small molecules, anticoagulants Chronic disease with remitting-relapsing course, increased mortality in case of arterial and neurological involvement, possible cause of blindness Vasculitis/ vasculopathy
Erythema induratum (Bazin disease, nodular vasculitis) [86, 87] Unknown, estimate < 1/1,000,000 Unknown; type III or type IV hypersensitivity reaction suspected; associated with drugs (propylthiouracil), infectious (tuberculosis, hepatitis) or non-infectious diseases (leukemia, RA); diffuse panniculitis with neutrophilic vasculitis   Female predominance, recurrent nodules, usually on posterior lower legs, with focal ulceration and drainage, heal with scarring and post-inflammatory hyperpigmentation Depending on underlying cause Treatment of underlying cause, potassium iodide, NSAIDs, corticosteroids, immunosuppressants Chronic, relapses are common Vasculitis/ vasculopathy
Polyarteritis nodosa (Kussmaul-Maier disease) [58, 59, 88, 89] 30.7/1,000,000 (France) 31/1,000,000 (Sweden) → 3.1/100,000 Early-onset polyarteritis nodosa; mutations in CECR1, leading to deficiency in adenosine deaminase 2 (DADA2); other forms: idiopathic, cutaneous, and infection-associated (HBV); medium vessel, necrotizing vasculitis with segmental, mixed inflammatory infiltrates at branching points and microaneurysms (often in hepatic, renal, and mesenteric arteries), that spares the lung Chapel Hill criteria (histopathological) Male predominance, malaise, weight loss, fever, arthralgia, ulcers, livedo racemosa, myalgia, mononeuritis multiplex, purpura, GI symptoms, kidney infarctions, orchitis, hearing loss; no pulmonary involvement! ESR and CRP elevated, leukocytosis, anemia, occasionally hypereosinophilia, hepatitis serology, liver enzymes, ANCA negative Corticosteroids, immunosuppressant, biologicals (TNFi), antivirals, NSAIDs Variable; chronic, acute, remitting-relapsing (10–20%) course possible; potentially life-threatening, remission can be achieved in many cases, good survival rate if treated early Vasculitis/ vasculopathy
Primary central nervous system vasculitis (PACNS/primary angiitis of the CNS) [90,91,92,93] Prevalence unknown, incidence: 2.4/1,000,000
estimate < 1/1,000,000
Different infectious agents suggested as triggers, segmental inflammation of CNS vessels Proposed criteria by Calabrese and Mallek, histological criteria by Alrawi et al. Disease most common in white males age ≥ 50 years, depending on localization different symptoms occur: headache, stroke, dementia, chronic meningitis, personality changes Because of lack of systemic disease, inflammatory markers in blood are normal, but cerebrospinal fluid should be investigated Corticosteroids + immunosuppressants (e.g., cyclophosphamide) Chronic, controllable with medication, relapses common, fatal in the past, current mortality ~ 15% Vasculitis/ vasculopathy
Henoch-Schonlein purpura (IgA vasculitis) [21, 94, 95] Incidence 3–26.7/100,000 in children, 0.8–1.8/100,000 in adults, estimate 1/100,000 Unknown; several reports describe relationship to different HLA genes and MEFV gene mutations; infectious agent suggested in children (seasonal peak in fall and winter), in adults linked to cancer; small-vessel leukocytoclastic vasculitis ACR criteria, criteria by Michet et al., EULAR pediatric criteria Predominantly male children affected, purpuric rash, abdominal pain, joint pain, edema, renal involvement Increased ESR, CRP, leukocytosis, anemia, proteinuria NSAIDs, corticosteroids, immunoglobulins, immunosuppressants Usually self-limited, but remitting-relapsing course possible, poor prognosis in case of renal involvement, worse prognosis in adults Vasculitis/ vasculopathy
Takayasu arteritis [96,97,98,99,100] 2.82/100,000 (Korea)
4.7/1,000,000 (UK)
22/1,000,000 (Norway)
12.8/1,000,000 (Turkey) → 1.7/100,000
Different candidate genes: HLA variants, FCGR2A/FCGR3A, IL12B; more frequent in Asia; aortic and large vessel vasculitis ACR criteria Female predominance, fever, fatigue, weight loss, headache, differences in blood pressure of extremities, “pulseless disease” Elevated CRP, ESR MMP-3 levels, PTX-3 Corticosteroids, immunosuppressants, biologicals (TNFi, IL-6i) Chronic, good overall survival, cardiovascular disease is most common cause of death (infarction, thrombosis, etc.) Vasculitis/ vasculopathy
Granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis) [29, 58, 59, 101] 160/1,000,000 (Sweden) 23.7/1,000,000 (France) → 9.2/100,000 Different genes suspected: HLA variants, SERPINA1; infectious, environmental (decreasing north–south gradient), and drug-induced triggers suspected; ANCA-associated, small vessel vasculitis ACR criteria, Chapel Hill criteria (histopathological) Malaise, myalgia, arthralgia, anorexia, weight loss, fever, oral ulcers, ear/nose/throat manifestations typical: eye manifestations (scleritis/uveitis, etc.), nasal discharge, epistaxis, upper airway obstructive disease Elevated inflammatory markers, positive ANCA (proteinase 3 in 80%), urine analysis Corticosteroids, immunosuppressants (rituximab, cyclophosphamide, azathioprine) Chronic, relapses are very common, infections are main cause of death Vasculitis/ vasculopathy
Adult-onset Still's disease (AOSD, Wissler's syndrome) [4,5,6, 102, 103] 3.4 – 6.9/100,000 (Norway) 6.77/100,000 (Turkey) 3.9/100,000 (Japan) → 5.3/100,000 Unknown; possibly related to MIF, HLA antigens, MEFV; different triggers suspected (infections, malignancies, medications, vaccinations) Yamaguchi criteria, Fautrel criteria Females slightly more affected, disease onset often at age 17–35 years, fever, maculopapular rash, arthralgia/arthritis (most commonly big joints), lymphadenopathy, hepatosplenomegaly, pleuritis, pericarditis, pneumonitis, eye involvement, abdominal pain, myalgia, alopecia, sore throat, weight loss, cranial nerve palsy Leukocytosis, anemia, hypoalbuminemia, elevated liver enzymes, elevated ESR and CRP; ANA, ACPA and RF usually negative, elevated ferritin, mild proteinuria, increased IgE or elevated β2-microglobulin NSAIDs, corticosteroids, DMARDs, immunosuppressants, biologicals (IL-1i, IL-6i) Variable; 1/3 self-limiting, 1/3 relapsing, 1/3 chronic; overall survival good, complications include MAS Arthritis/ arthropathy
Progressive pseudorheumatoid arthropathy of childhood (PPAC/ PPD/ PPRD/ SEDT-PA) [104,105,106,107,108,109] Maybe not rare, but misdiagnosed as JIA; estimated prevalence < 1/1,000,000 Autosomal recessive; different mutations in WISP3; possible founder effect in Turkey; WISP mediates cell growth and differentiation in chondrocytes Clinical and radiographic diagnosis with genetic confirmation Disease onset usually in childhood (age 3–8 years), progressive joint stiffness, contractures, swelling of finger joints, osteopenia, slow linear growth, short stature, osteopenia, arthritis, difficulty in walking, genu valgum, hip pain, adult height usually below 3rd percentile, normal intelligence No signs of systemic inflammation Symptomatic: NSAIDs Chronic, overall prognosis good because systemic organ involvement is absent Arthritis/ arthropathy
Familial articular chondrocalcinosis (CPPD deposition disease/CCAL1 and CCAL2) [110,111,112,113,114] Unknown, estimate < 1/1,000,000 Most cases autosomal dominant with variable penetrance; CCAL2: mutations in ANKH; CCAL1: chromosome 8 suspected, but gene not yet identified; increased extracellular pyrophosphate levels and formation of CPPD Clinical and radiographic diagnosis Disease onset in early childhood with calcium crystal joint deposition; arthritis/arthralgia, most commonly in knee and other big joints Inflammatory markers may be elevated Symptomatic: Corticosteroids, colchicine, NSAIDs Chronic, usually not life-threatening, but high morbidity Arthritis/ arthropathy
Pigmented villonodular synovitis [25, 115,116,117,118] Incidence: 1.8/1,000,000 (USA), estimate < 1/1,000,000 Unknown; possible association with trauma/surgery, lipometabolism; inflammatory process or benign, tumor-like process suggested Radiographic or histopathological diagnosis Peak of disease onset age 20–40 years, pain/swelling of joints (mainly knee or hip, rarely temporomandibular joint) with “locking phenomenon”, fatigue Elevated ESR and CRP possible Surgical synovectomy, radiotherapy, immunotherapy Chronic or remitting-relapsing, locally aggressive and frequent relapses Arthritis/ arthropathy
Felty syndrome (splenomegaly-neutropenia-rheumatoid arthritis syndrome) [119,120,121,122] 1% of RA = estimated prevalence 1/10,000 HLA-DR4 association (78%), autoantibodies against neutrophil extracellular chromatin traps (NETs), anti-GCSF antibodies Clinical diagnosis More common in females, chronic symmetric arthritis with severe joint destruction (often knee, wrist ankle, MCP, PIP), hepatosplenomegaly, lymphadenopathy, episcleritis, pleuritis, vasculitis, weight loss Anemia, neutropenia, infections, ANA, RF Corticosteroids, DMARDs, biologicals, G-CSF, splenectomy Chronic, increased mortality due to infections Arthritis/ arthropathy
RS3PE (remitting seronegative symmetrical synovitis with pitting edema) [3, 32, 123, 124] Unknown, prevalence in Japan 0.09% (90/100,000 = 1/1,111) for > 50 years (not rare among elderly), estimate 1/100,000 Unknown; associated with other rheumatic conditions, infections, and neoplasms (associated malignancy rate 7% in Asia and 31% in Western countries); VEGF may play a role in pathogenesis Proposed diagnostic criteria by Karmacharya et al. Usually older males affected, symmetrical synovitis of hands and ankles, sudden onset polyarthritis, pitting edema (especially hands or feet) Elevated acute phase reactants, usually RF and autoantibodies negative Usually excellent response to corticosteroids, DMARDs rarely used, treatment of underlying malignancy if present Good, remission can usually be achieved with corticosteroid use only, poor prognosis if malignancy-associated Arthritis/ arthropathy
Multicentric reticulohistiocytosis [37, 125,126,127] Unknown, ~ 300 cases in literature, estimate < 1/1,000,000 Unknown; different triggers suspected (malignancies, autoimmune diseases, infections/tuberculosis); crucial workup for neoplasms necessary; macrophages, cytokines, and osteoclastic activity seem to play a role in pathogenesis Histopathological diagnosis Mainly Caucasian females (3:1) with peak of onset in 4th decade, symmetric erosive polyarthritis or spondylitis with axial involvement (most affected joints: distal interphalangeal joints) with typical papulonodular skin lesions, organ involvement possible (heart, lung), arthritis often precedes skin involvement by years Elevated ESR, CRP, anemia, hyperlipidemia, different autoantibodies may be positive NSAIDs, corticosteroids, DMARDs, biologicals, bisphosphonates, treatment of underlying malignancy if present Variable, may progress rapidly into arthritis mutilans, but most patients achieve remission spontaneously within 10 years Arthritis/ arthropathy
Chronic non-bacterial osteomyelitis (CNO)/CRMO/SAPHO [128,129,130,131,132] Estimated prevalence 40/100,000 No clear association with HLA-B27, possibly related to other genes connected to autoinflammatory disorders; autoimmune process or infection/molecular mimicry (P. acnes) suspected Inclusion and exclusion criteria by Benhamou et al., Kahn et al. Slight female predominance, onset often in children or middle-aged adults; inflammatory, painful, sterile (sometimes P. acnes-positive) osteitis (often in anterior chest wall or axial skeleton) with variety of different skin diseases (most commonly palmoplantar pustulosis), onset can be many years before or after bone and articular involvement (often sacroiliac or sternoclavicular joints) Elevated CRP and ESR (sometimes), different non-specific autoantibodies, sometimes P. acnes NSAIDs, corticosteroids, bisphosphonates, antimicrobial treatment, DMARDs, biologicals Chronic disease, complications or disease-associated death rare Arthritis/ arthropathy
Systemic-onset juvenile idiopathic arthritis (Still`s disease) [133,134,135,136,137,138,139,140,141] Estimated prevalence 10.5/100,000 Association with MEFV and MIF-173 polymorphism; IL-6 and IL-1 play a major role ILAR classification criteria for JIA Systemic inflammation (spiking fever > 39 °C, skin rash, hepatosplenomegaly, lymphadenopathy, serositis, arthritis High levels of serum ferritin, marked polymorphonuclear leukocytosis, thrombocytosis, elevated ESR/CRP NSAIDs, corticosteroids, DMARDs, biologicals (IL-1, IL-6) Variable, chronic, self-limiting or remitting-relapsing, ~ 50% complete recovery, risk of MAS Arthritis/ arthropathy
Whipple's disease [142,143,144,145,146,147,148,149] Unknown, Tropheryma whipplei can be found in ~ 10% (Europe)/20% (Africa) of fecal samples in healthy population, estimate < 1/1,000,000 HLA-B27 involvement discussed; infection with Tropheryma whipplei, predominantly male patients and patients with immune modulatory conditions (alcohol, abuse, chronic disease) affected Histopathological diagnosis or PCR Predominantly males affected, intermittent polyarthritis and gastrointestinal symptoms, any other organ can be affected (neurology, cardiovascular, lungs, eyes, skin), fever, weight loss, abdominal pain, malabsorption, headaches, diarrhea Elevated ESR, CRP, anemia, thrombocytosis, reduced IgM and IgA, leukocytosis, RF, anti-CCP-AB may be present Antibiotics, corticosteroids, DMARDs, biologicals (IL-1) Chronic, lethal if untreated, increased mortality in case of neurological involvement or occurrence of immune reconstitution inflammatory syndrome (IRIS; ~ 10%) Arthritis/ arthropathy
Osteochondritis dissecans [150,151,152] Incidence 6.09/100,000
Estimated 15–29/100,000 → 22/100,000
Unknown; osteonecrosis of subchondral bone; vascular disruption, multiple microtrauma, and genetic predisposition suggested Radiographic diagnosis Predominantly in physically active male children or adolescents. Pain (worsening with exercise), swelling, joint locking, most often in the knee, but any joint can be affected Usually inflammatory markers normal Supportive: NSAIDs, surgery Chronic, prognosis depends on stability of lesion and patient age Arthritis/ arthropathy
Blau syndrome (familial)/early onset sarcoidosis (sporadic)/ pediatric granulomatous arthritis [9, 153,154,155,156,157,158] Unknown, incidence: 0.29/100,000 (Denmark), estimate < 1/1,000,000 Autosomal dominant, sporadic form, gonosomal mosaicism in NOD2/CARD15; NF-κB activation and excessive inflammatory cytokine production Clinical diagnosis, genetic testing, skin biopsy Skin rash in first year of life, later boggy polyarthritis, uveitis, non-caseating epithelioid and giant cell granulomas; fever, lymphadenopathy, neuropathy, renal/hepatic/lung/cardiovascular involvement Leukocytosis, thrombocytosis, elevated ESR, CRP, acute-phase reactants, ACE normal NSAIDs, corticosteroids, immunosuppressants, biologicals, systemic hypertension usually responds to ACE-inhibitors Chronic, prognosis depends on systemic involvement, severe ocular and articular morbidity Autoinflammatory syndrome
CAPS (familial cold autoinflammatory syndrome/familial cold urticaria, Muckle-Wells syndrome, CINCA syndrome/NOMID/IOMID) [38, 39, 159,160,161] 1–2/1,000,000 in US and 1–2/360,000 (= 4.6/1,000,000) in France estimated → 3.05/1,000,000 Autosomal dominant, gain of function mutation in NLRP3/CIAS1 leads to caspase-1 and inflammasome activation with increased IL-1β secretion; mosaicism possible, usually de novo Eurofever clinical diagnostic/ classification Intermittent fever, urticarial rash, chronic inflammation, typical facies in CINCA (frontal bossing, saddle back nose), CNS manifestations, chronic polyarthritis, conjunctivitis, papilledema Elevation of acute phase reactants, leukocytosis, chronic anemia; SAA biomarker for development of AA-amyloidosis Biologicals (IL-1) Chronic, prognosis significantly improved since availability of anti-IL-1-treatment (65–85% complete remission with Anakinra) Autoinflammatory syndrome
Familial Mediterranean fever (familial paroxysmal polyserositis) [38, 162,163,164,165,166] Prevalence highly differs geographically; in eastern Mediterranean 1/500 – 1/1000, Turkey 1/150 – 1/10,000, Ashkenazi Jews 1/73,000 Estimate 1/10,000 Autosomal recessive, mutation in MEFV leading to abnormal function of inflammasome; environmental factors also seem to play a role, as patients from the eastern Mediterranean often have a milder phenotype Multiple criteria: Eurofever clinical diagnostic/classification criteria, Tel-Hashomer, Yalcinkaya-Ozen and Livneh-criteria Disease onset usually in childhood, 90% before age of 20 years, recurrent fever and serositis, myalgia, arthralgia, abdominal pain, vomiting, chest pain, rash, prodromal phase with unspecific symptoms (restlessness, anxiety, irritability), rapid onset of symptoms lasting for at least 12 h Elevated acute phase reactants Colchicine, anti-IL-1 Chronic, remission and fewer relapses can be achieved by therapy, complications include amyloidosis (strongest predictor seems to be country of residence) and MAS Autoinflammatory syndrome
Mevalonate kinase deficiency (hyperimmunoglobulinemia D with periodic fever, HIDS) [38, 167,168,169,170] Unknown, incidence in Germany: 0.39/1,000,000
estimate < 1/1,000,000
Autosomal recessive, mutations in MVK (homozygosity or, most often, compound heterozygosity); MVK essential for cholesterol synthesis; increased production of IL-1β; possible founder effect in the Netherlands Eurofever clinical diagnostic/classification criteria Recurrent fever episodes starting in infancy (most common before end of 1st year of life), fever lasts 4–6 days and can be provoked by physical and psychological stress; lymphadenopathy, splenomegaly, arthralgia, GI symptoms, skin rash, sometimes oral and vaginal aphthous ulcers, neurological symptoms Elevated ESR, CRP, leukocytosis, elevated IgD (> 100 IU/ml), IgA in blood, elevated mevalonic acid in urine HMG-CoA-reductase inhibitors, corticosteroids, immunosuppressants, biologicals (Il-1) Chronic, complications include infections, amyloidosis, peritonitis with abdominal adhesions, MAS, and joint contractures Autoinflammatory syndrome
Nakajo-Nishimura syndrome (NNS) [171,172,173] Unknown, 28 reported cases in Japan until 2010 (19 males, 9 females), estimate < 1/1,000,000 Autosomal recessive, mutation in PSMB8; probably common founder; reduced proteasome activity and accumulation of ubiquitinated and oxidized proteins, leading to increased cytokine levels Distinctive clinical diagnostic criteria for NNS Onset usually at age of 2 months—8 years with pernio-like rash, rash often appears in first winter after birth and reappears every year. Symptoms worsen with cold stimuli; periodic high fever, skin rash, myositis, hepatosplenomegaly, partial lipomuscular atrophy, joint contracture (mainly in upper body), hyperhidrosis, short stature, low IQ, lymphadenopathy described, characteristic thin facial appearance, elongated clubbed fingers Constantly elevated ESR, CRP, chronic anemia, hypergammaglobulinemia, elevated IgG and IgE, positive ANA described Corticosteroids, kallikrein, dapsone Chronic and often lethal, most patients die of cardiac or respiratory failure Autoinflammatory syndrome
PAPA syndrome (pyogenic arthritis-pyoderma gangrenosum acne syndrome) [28, 39, 174,175,176,177] Only few patients from five families worldwide reported (34 until 2006), estimate < 1/1,000,000 Autosomal dominant, missense mutation in PSTPIP1/ CD2BP1, which causes hyperphosphorylation of PSTPIP1 protein and induction of inflammasome Clinical diagnosis with genetic confirmation Recurrent sterile arthritis, fever, pustulosis, abdominal pain, hidradenitis, acne, pyoderma gangrenosum, ulcerations Elevated ESR, CRP, IL-1β Corticosteroids, biologicals (IL-1 β) Chronic or remitting-relapsing Autoinflammatory syndrome
PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis; Marshall syndrome with periodic fever) [178,179,180,181,182] Unknown, incidence 2.3/10,000 in children up to 5 years (Norway), probably not so rare, estimate < 1/10,000 Unknown; many patients have heterozygous MEFV mutation, familial occurrence; polygenetic cause suspected; IL-1 and vitamin D may play a role in pathogenesis Diagnostic criteria by Marshall/Thomas; Cantarini et al. Disease onset usually in early infancy, slight male predominance, episodes last 5 days and recur every 28 days; prodromal: aphthous stomatitis, malaise, fatigue, irritability, headache; then sudden onset of high fever, pharyngitis, lymphadenopathy, chills, cough, headache, abdominal pain, nausea, diarrhea, rash; patients are remarkably healthy between episodes Leukocytosis and elevated ESR in episodes Corticosteroids, surgery (tonsillectomy), cimetidine, anakinra, colchicine Good prognosis, self-limited within 4–5 years, normal development Autoinflammatory syndrome
Schnitzler syndrome (chronic urticaria with gammopathy) [183,184,185,186] Unknown, ~ 250 reported patients, mainly from western Europe, estimate < 1/1,000,000 Unknown; involvement of IL-1β and IL-6 suspected Strasbourg diagnostic criteria Slight female predominance (1.6:1), disease onset in adulthood (mean age 51 years), recurrent urticarial rash (most constant symptom), fever, muscle/bone/joint pain, lymphadenopathy Monoclonal IgM (rarely IgG) gammopathy, elevated ESR, κ -light chain, leukocytosis Anakinra (IL-1) rapidly controls symptoms (diagnosis should be reconsidered if ineffective), canakinumab, colchicine, NSAIDs, pefloxacin, hydroxychloroquine Chronic, spontaneous remission and relapses common, complications include amyloidosis and overt lymphoproliferation Autoinflammatory syndrome
Macrophage activation syndrome [187,188,189,190,191,192] Seen in about 10% of patients with systemic onset JIA. Prevalence unknown, estimate < 1/1,000,000 Excessive Activation of T-lymphocytes and macrophages. Possible association with impaired NK cell cytotoxicity due to PRF1 mutation HLH-2004 diagnostic guidelines/2016 criteria for MAS complicating systemic JIA Fever, hepatosplenomegaly, cytopenias, coagulopathy, liver dysfunction, neurological symptoms, lymphadenopathy, skin rash, jaundice, edema cytopenia, elevated transaminases + ferritine, low NK cell activity, elevates sIL2-R Corticosteroids, Cyclosporine, Biologicals, IL-1 receptor blockade Mortality in one retrospective study 8% (higher mortality in adults) Autoinflammatory syndrome
Majeed syndrome (chronic recurrent multifocal osteomyelitis) [193,194,195] Unknown, only 4 families/14 patients with Middle Eastern origin reported, estimate < 1/1,000,000 Autosomal recessive, mutation in LPIN2, which plays a role in fat metabolism and, possibly, mitosis Clinical diagnosis, genetic testing Inflammation of bone and skin, resulting in growth disturbances and joint contractures; recurrent high fevers, severe pain; frequently associated with cutaneous inflammatory syndromes (e.g., psoriasis, Sweet syndrome) Dyserythropoietic anemia with microcytosis, elevated ESR Blood transfusions, NSAIDs, corticosteroids, biologicals (IL1 β) Chronic, osteomyelitis probably life-long, anemia is prominent in childhood Autoinflammatory syndrome
TRAPS (tumor necrosis factor receptor 1 associated periodic syndrome; familial Hibernian fever) [38, 39, 196,197,198] Unknown, incidence 1/1,785,714 for children < 16 (Germany); most patients are European Caucasian, estimate 1/1,000,000 Autosomal dominant with variable penetrance, mutations in TNFRSF1A, different hypotheses on pathophysiology, including intracellular trafficking, receptor shedding, or induction of apoptosis, leading to increase in cytokines; triggers include stress, menstrual cycle, fatigue, infections, exercise, vaccinations Eurofever clinical diagnostic/ classification criteria Disease onset usually in infancy or childhood, attacks last around 11 days, on average 70 symptomatic days a year with high fever, limb pain, abdominal pain, rash, cervical lymphadenopathy, periorbital edema Elevated ESR, CRP, leukocytosis, thrombocytosis, anemia, hypergammaglobulinemia; SAA levels correlate with disease activity NSAIDS, corticosteroids, biologicals (most promising is anti-IL-1) Often remitting-relapsing, but chronic course possible; complications include amyloidosis and MAS Autoinflammatory syndrome
Necrotizing autoimmune myopathy (anti-HMG-CoA myopathy) [199, 200] Unknown, estimate < 1/1,000,000 Unknown; immune-mediated muscle fiber necrosis without inflammation due to statin use, other drugs, malignancies, or connective tissue diseases Histopathological diagnosis Female predominance (73%), myalgia, dysphagia, weight loss, fatigue, ILD, arthralgia, Raynaud´s phenomenon Anti-SRP antibodies present in 16%, anti-HMGCR antibodies seem to be specific and present in ~ 60% of patients previously exposed to statins; CRP and CK elevated Statin withdrawal, corticosteroids, DMARDs Variable, good prognosis in case of treatable underlying cause, but chronic in most cases Myositis/myopathy
Antisynthetase syndrome [201,202,203,204] Unknown, 20–25% of patients diagnosed with PM/DM; prevalence of PM/DM approx. 15/100,000 → 3.4/100,000 Unknown; antibodies against anti-threonyl-tRNA-synthetase; relationship to exposure to airborne particles discussed Clinical diagnosis + antibody findings Females 2–3 times more often affected than males, at presentation often only RA-like arthritis, then inflammatory myopathy, interstitial lung disease, fever, Raynaud´s, Gottron´s papules, mechanic´s hands Anti-Jo-1, anti-Pl7/PL12, many other antibodies possibly positive Corticosteroids, immunosuppressants (rituximab), DMARDs Chronic, overall survival good but decreased in case of lung involvement Myositis/myopathy
Myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency [205, 206] Unknown, more than 300 published cases, one of the most common disorders of oxidative fatty acid metabolism, prevalence probably higher than suspected; estimate < 1/100,000 Autosomal recessive, mutation in CPTII; CPT is involved in the transportation of long chain fatty acids in mitochondria; impaired energy metabolism; frequent triggers are physical stress and exposure to cold Enzyme measurement, genetic testing Disease onset in adolescence or adulthood, males more commonly and more severely affected; myalgia, rhabdomyolysis, muscle weakness, pain, lipid accumulation in muscle Elevated CK, BUN, myoglobinuria, hepatic steatosis Avoidance of triggers (fasting, prolonged exercise), low fat and high carbohydrate diet, carnitine Chronic, but good prognosis; rhabdomyolysis can lead to renal failure Myositis/myopathy
Dermatomyositis/Polymyositis [207,208,209,210] 10–13/100,000 (Japan) 8.7/100,000 (Norway) 7–10/100,000 (Brazil) → 9.6/100,000 Unknown; humoral-mediated inflammation in DM, cell-mediated (CD8 + T-cells) in PM; often associated with other autoimmune diseases and malignancies Histopathological diagnosis Predominantly females, myalgia, arthritis, dyspnea, dysphagia, muscle weakness, rash (not in PM), myocarditis, Gottron´s papules Different myositis-specific autoantibodies can be found: anti-Jo-1, NXP2/MJ antibody, anti-155/140 antibodies, anti-MDA5, MI-2-antibodies Corticosteroids, immunosuppressants Variable, most patients improve over time with treatment, prognosis depends on associated diseases (malignancies) Myositis/myopathy
Inclusion body myositis [31, 211, 212] 33/1,000,000 (Norway) 10.7 – 71 /1,000,000 (USA) → 3.7/100,000 Hereditary autosomal recessive form with onset in young adults, mutations in GNE (very rare); sporadic form in elderly, associated with HLA-DR3 and MHC variants; genetic, environmental, aging, and immune-mediated factors probably related to pathogenesis Histopathological diagnosis Predominantly males (2:1) and elderly, slowly progressive muscle weakness (often beginning in wrists or quadriceps muscle), dysphagia CK may be elevated or normal Refractory to immune therapy, can be used tentatively in case of relation to other autoimmune diseases Chronic and slowly progressing, most patients wheelchair-reliant within 10 years Myositis/myopathy
Eosinophilia-myalgia syndrome [213] Unknown, 5000–10,000 people affected, predominantly females in the US (epidemic in 1989), estimate < 1/1,000,000 Unknown; consumption of manufactured L-tryptophan or 5-hydroxytryptophan associated with disease onset; increased TGF-β and IL-4 may be responsible for fibrosis Clinical diagnosis Rapid onset of severe myalgia, cough, fever, fatigue, joint pain, edema; long-term symptoms include eosinophilic fasciitis, alopecia, CNS involvement, myocarditis, arrhythmias, GI involvement Elevation of eosinophils, WBC Supportive treatment, corticosteroids in acute phase may be used tentatively Chronic course with systemic organ involvement not uncommon Myositis/ myopathy
Focal myositis [214, 215] Unknown, estimate < 1/1,000,000 Unknown; trigger factors poorly understood (e.g., physical trauma) Clinical, radiographic, and histopathological diagnosis Rapidly growing mass in a single muscle, most commonly in lower limbs, usually painless Usually no elevated acute phase reactants, CK may be elevated but usually normal No treatment, corticosteroids in case of inflammation or complications Usually self-limited within few weeks or months, relapses possible but uncommon Myositis/myopathy
McArdle’s disease (glycogenosis type 5) [216,217,218,219] Estimated 1:50,000 (US) – 1:140,000 (Spain) → 1.4/100,000 Autosomal recessive, mutations in PGYM, leading to glycogen phosphorylase deficiency Enzyme measurement, histopathology, genetic testing High clinical variability, rapid fatigue, myalgia and cramping with exercise and fast recovering with rest (“second-wind phenomenon”) Elevated baseline CK, myoglobinuria, rhabdomyolysis No treatment; moderately active lifestyle and ingestion of simple carbohydrates before exercise recommended Chronic, but variable in severity; complications include renal failure and cardiovascular diseases Myositis/myopathy
Tarui disease (GSD7) [220, 221] Unknown, more than 100 cases described, Common in Ashkenazi-Jews, estimate < 1/1,000,000 Autosomal recessive, mutations in PFKM, leading to muscle phosphofructokinase deficiency Histopathological diagnosis, genetic testing Exercise intolerance, myalgia, cramps, cardiomyopathy Myoglobinuria, hemolytic anemia, hyperuricemia, hyperCKemia, reticulocytosis No treatment; avoid extensive exercise Chronic, complications include renal and cardiac involvement Myositis/myopathy
Camurati-Engelmann disease (progressive diaphyseal dysplasia) [26, 222, 223] Unknown, estimate < 1/1,000,000 Autosomal dominant, mutations in TGFB1, resulting in increased growth factor signaling Genetic testing, clinical findings + radiographic images Hyperostosis of long bones and skull, severe limb pain, muscle atrophy, wide-based waddling gait, progressive joint contractures, hearing loss, absence of subcutaneous fat Increased levels of TGF-β1 Corticosteroids, NSAIDs, bisphosphonates, all with variable outcomes; experimental: anti-TGFβ (e.g., losartan) Chronic, patients may become wheelchair-reliant Bone disorder
Fibrodysplasia ossificans progressiva (Munchmeyer's disease) [224, 225] 0.36/1,000,000 (Spain) 1.36/1,000,000 (France) estimated worldwide prevalence (literature): 1/2,000,000 → 0.74/1,000,000 Autosomal dominant (most cases de novo), mutation in ACVR1, leading to enhanced BMP signaling with fibroproliferation, angiogenesis, enchondral ossification; risk seems to be increased with older age of mother and father, fathers often exposed to chemicals Clinical, radiographic, histopathological diagnosis Heterotopic ossification, tumor-like swellings and short, malformed great toes (early sign), cervical spine fusions, osteochondroma, hearing loss Usually normal, although ESR and AP may be elevated Short-term muscle relaxants, NSAIDs, Cox-2-inhibitors, corticosteroids, bisphosphonates; operations should be avoided (triggers new flare ups and bone growth) Chronic, progressive, and lethal within approximately 40 years, most patients wheelchair-reliant at the end of second decade of life Bone disorder
Osteomesopyknosis [226] Unknown, < 50 cases reported, predominantly from France, estimate < 1/1,000,000 Autosomal dominant, gene unknown Radiographic diagnosis Disease onset and diagnosis usually in adolescence, diffuse back pain Usually normal Symptomatic Benign and good prognosis, normal life expectancy Bone disorder
Fabry disease [227,228,229] Australia 0,85/100,000 alpha-galactosidase A deficiency due to mutation in GLA-gene on X-chromosome (X-linked disorder) Measurement of enzyme activity, genetic testing Neuropathic pain, hypohidrosis, gastrointestinal symptoms, kidney failure, cardiovascular disease renal function may be impaired Enzyme replacement therapy Chronic. Life expectancy increased with ERT, but limited by cardiovascular and renal function Bone disorder
Farber disease [230, 231] Unknown, estimate < 1/1,000,000 Autosomal-recessive, ASAH1-gene; acid ceramidase deficiency Measurement of enzyme activity; histopathology of granuloma; ceramide accumulation in granuloma Subcutaneous nodules, joint disease, hoarseness of voice, inflammatory granuloma   Enzyme replacement therapy in progress; Stem cell transplantation Chronic and progressive. Death due to respiratory insufficiency caused by pulmonary granulomas Bone disorder
Gaucher's disease (type 1 in 90% of cases) [232,233,234,235] Estimated 1–2/100,000 worldwide, 1/850 in Ashkenazi-Jews → 1.5/100,000 Autosomal recessive, mutations in GBA1; deficiency in lysosomal glucocerebrosidase leads to accumulation of glucocerebroside Measurement of enzyme activity, genetic testing Age of onset and disease course variable; fatigue, growth retardation, delayed puberty, bone pain, avascular necrosis of bone, gallstones, hepatosplenomegaly, Parkinson´s disease, malignancies (predominantly hematological) Thrombocytopenia, anemia, monoclonal gammopathy, vitamin D deficiency; biomarkers: chitotriosidase, CCL 18, glucosylsphingosine, ferritine Lifelong enzyme replacement or substrate reduction therapy Chronic, reduced life expectancy due to neurological involvement and malignancies Bone disorder
Hypophosphatasia (HP) [236,237,238] 1/300.000 for severe HP, 1/6370 for moderate HP Estimate 1/100,000 Autosomal-recessive or autosomal-dominant; mutations in TNSALP lead to accumulation of pyrophosphate, an inhibitor of mineralization Laboratory values + radiologic features, confirmed by genetic testing Age of onset and disease course very variable; perinatal death, bone deformities, stress fractures, loss of dentition, musculoskeletal pain and weakness low serum AP, hypercalcemia Enzyme replacement therapy for pediatric onset hypophosphatasia Chronic, mortality and morbidity varies with onset Bone disorder
Morquio disease (mucopolysaccharidosis type IVa) [239,240,241] 1/323,000 (Denmark) 1/599,000 (UK) 1/1,872,000 (Malaysia) 1/926,000 (Australia) → 1.6/1,000,000 Autosomal recessive, mutations in GALNS, resulting in N-acetylgalactosamine-6-sulfate sulfatase-deficiency Measurement of enzyme activity, genetic testing Disease onset in childhood; progressive skeletal dysplasia, short trunk dwarfism, spondyloepiphyseal dysplasia with ligamentous laxity, joint pain, preserved intelligence, odontoid hypoplasia pulmonary, cardiac, ophthalmologic, audiologic, dental, abdominal and neurologic involvement possible GAGs in urine Enzyme replacement therapy, pain management, supportive therapy, surgery Chronic, wheelchair-reliance beginning in adolescence, increased mortality due to cervical instability and pulmonary compromise Bone disorder
Melorheostosis (Leri´s disease) [105, 242,243,244]  ~ 400 cases reported, estimate 1/1,000,000 Usually sporadic; somatic LEMD3 mutations suspected as a possible cause; disturbance in bone formation and modeling; possible association with scleroderma and Buschke-Ollendorf syndrome Radiographic diagnostic criteria (Freyschmidt) Disease onset in childhood or adolescence; limb deformity, contractures, joint and bone pain, leg length discrepancy, stiffness, hyperostosis (usually long bones in lower extremity) usually in one limb, but may be bilateral, soft tissue involvement (hypertrichosis, fibrosis, erythema) above affected bone Markers of bone metabolism usually normal (calcium, AP, etc.) Pain management, bisphosphonates, surgery (relapses common) Chronic and progressive, morbidity mostly due to pain, stiffness, and reduced range of motion Bone disorder
Pachydermoperiostosis (primary hypertrophic osteoarthropathy; Touraine-Solente-Golé syndrome) [23, 24, 245,246,247] Unknown, estimate < 1/1,000,000 Autosomal dominant with incomplete penetrance proven, autosomal recessive and X-linked inheritance also suggested, mutations in SLCOA21, HPGD, possibly also related to HLA-B12 or BMP pathway; involvement of testosterone promoting proliferation suspected Clinical diagnosis Occurs predominantly in males (7:1), disease onset often in puberty, progression for 5–20 years; pachydermia, digital clubbing, periostosis, cranioosteoarthropathy, congenital heart diseases (especially patent ductus arteriosus), hyperhidrosis, rash, myelofibrosis, gastrointestinal involvement Unspecific NSAIDs, corticosteroids, colchicine, bisphosphonates, retinoids, plastic surgery Chronic, progressive for 5–20 years Bone disorder
Mucopolysaccharidosis type 2 (Hunter syndrome) [248,249,250] 0.65/1,000,000 (Sweden) 0.44/1,000,000 (Norway) 0.91/1,000,000 (Denmark) → 0.67/1,000,000 X-linked recessive, mutation in IDS; lysosomal storage disorder: iduronate-2-sulfatase enzyme deficiency Measurement of enzyme activity, genetic testing Disease onset in childhood; peau d´orange, cognitive impairment, joint stiffness, contractures, cardiac and respiratory involvement, short stature, carpal tunnel syndrome, hepatosplenomegaly, glaucoma GAGs in urine Enzyme replacement therapy, supportive treatment, pain management Chronic, often lethal within 20—30 years (cardiovascular involvement limiting), patients with attenuated form may have normal life expectancy Bone disorder
Caffey disease (infantile cortical hyperostosis, Caffey-Silverman syndrome, Smyth syndrome) [251,252,253] Unknown, estimate < 1/1,000,000 Autosomal dominant, heterozygous mutation in COL1A1 with incomplete penetrance Clinical and radiographic diagnosis with genetic confirmation Fever, swelling of soft tissues, hyperostosis of outer cortical surface in first 5 months of life, unusual irritability Elevated ESR, AP, thrombocytosis, anemia, increased immunoglobulin Symptomatic: NSAIDs Good, usually self-limiting in early childhood, chronic or remitting-relapsing course possible Connective tissue disease
Ehlers-Danlos syndrome [254,255,256] 1/10,000 – 1/25,000 = 7/100,000 Autosomal dominant or autosomal recessive, mutations in COL5A1/COL5A2/COL5A3/COL3A1 and other, depending on subtype Villefranche classification Depending on subtype: joint hyperlaxity and luxation, easy bruising, arthralgia, vascular aneurysm, muscle hypotonia Normal coagulation status despite easy bruising Only symptomatic and supportive treatment Chronic, worst prognosis in vascular subtype, obstetrical complications common Connective tissue disease
Fibrosing mediastinitis [257,258,259] Unknown, estimate < 1/1,000,000 Most cases idiopathic, or due to infections (histoplasma, aspergillus) or sarcoidosis; proliferation of fibrous tissue, possibly IgG4-related Radiographic diagnosis Often younger people affected; cough, hemoptysis, dyspnea, other symptoms depend on grade of obstruction of surrounding structures Usually normal Corticosteroids, local therapies, surgery Variable, often chronic and progressive, potentially lethal because of invading/ displacing growth Connective tissue disease
IgG4-related Disease [260,261,262,263] 6/100.000 (Japan) Immune mediated, multiple possible risk factors ACR/EULAR Classification Criteria Elderly men primarily affected; any organ involvement possible, most often gastrointestinal organs or salivary glands, leading to fibrosis and subsequent organ dysfunction Serum IgG4 may be elevated Corticosteroids Chronic, remitting-relapsing. Usually mild symptoms, only slowly progressing Connective tissue disease
Marfan syndrome [264,265,266] 6.5/100,000 (genetically proven patients in Denmark) Autosomal dominant, mutation in FBN1, resulting in disturbed fibrillin 1 function and altered TGF β regulation, large phenotypic variability Revised Ghent criteria Tall stature, joint hypermobility, arachnodactyly, aortic aneurysm, mitral valve prolapse, ectopia lentis, scoliosis, dural ectasia Usually normal β–blockers, cardiac and/or orthopedic surgery Chronic, mortality depends on cardiovascular involvement, life expectancy normal with regular follow-up and treatment Connective tissue disease
Shulman disease (eosinophilic fasciitis) [267, 268] Unknown, estimate < 1/1,000,000 Association with HLA-A2 described, many different theories on pathogenesis and possible triggers (e.g., physical exercise) exist Proposed diagnostic criteria by Pinal-Fernandez et al. Disease onset at any age (mean 4th-5th decade); abrupt onset of painful swelling and thickening of skin and other soft tissues, joint contractures, most often extremities symmetrical involved Blood eosinophilia, hypergammaglobulinemia, elevated ESR, TIMP-1 possibly marker for disease activity Corticosteroids, MTX; not all patients require treatment Variable, remission usually occurs spontaneously or with therapy Connective tissue disease
Sharp syndrome (mixed connective tissue disease) [269,270,271] 3.8/100,000 Unknown, B cells may play a role in pathogenesis Different diagnostic criteria exist (Sharp´s, Alarcón-Segovia and Villareal, Kasukawa) Female predominance (3.3:1), Raynaud´s phenomenon, puffy hands, arthritis, pleuritis, pericarditis, myositis, interstitial lung disease, PAH, esophageal dysmotility, dyspnea, cardiovascular involvement Anti-ribonucleoprotein antibodies (anti-U1RNP) NSAIDs, corticosteroids, immunosuppressants Chronic and progressive, may evolve into other connective tissue disease, mortality increased with cardiovascular involvement Connective tissue disease
Systemic sclerosis [30, 44, 45, 272,273,274,275] More common in Europe than Asia, less common in northern countries, highest ever reported prevalence in population of Choctaw Indians in Oklahoma (469/100,000), worldwide → 15–30/100,000 (= 22.5) Unknown, HLA-association suspected, different pathophysiological factors suspected (vasculopathy, autoantibodies, fibroblast dysfunction, immune system alteration, silica dust, toxins, infections) ACR criteria Female predominance (3:1), peak incidence at age 45 – 64 years; skin thickening, Raynaud´s phenomenon, pulmonary fibrosis, PAH, digital ulcers, esophageal hypomobility, arthralgia, myalgia, variable organ involvement Anti-centromere-AB, anti-topoisomerase-I-AB (Scl70), anti-RNA-polymerase III Symptomatic and supportive treatment of Raynaud´s phenomenon, digital ulcer, skin, lung, and GI disease Chronic and progressive, worst prognosis among all connective tissue diseases, mean survival 11–12 years after diagnosis Connective tissue disease
CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi syndrome) [276,277,278,279] Unknown, only a few cases reported, estimate < 1/1,000,000 Mosaic activating, postzygotic mutation in PIK3CA, causing tissue overgrowth Clinical diagnostic criteria for PIK3CA-related overgrowth spectrum (Keppler-Noreuil et al.), genetic testing Vascular malformations, thoracic lipomatous hyperplasia, asymmetric growth, visceral and neurological disorders, linear epidermal nevus, gigantism of hand and feet, macrodactyly, sandal gap toe, renal anomalies Normal Clinical trials with mTOR kinase-inhibitors and selective PIK3CA-inhibitors; laser, sclerosing, or surgical treatment Chronic, severity depends on somatic mosaic, frequent recurrence of lipomatous masses, increased risk of tumors (e.g., Wilms tumor) Overgrowth syndrome
Klippel-Trénaunay-Weber syndrome complex (angio-osteohypertrophic syndrome = Klippel-Trenaunay, special form with AV fistulas = Parkes-Weber syndrome) [280,281,282,283] Unknown, ~ 1000 reported cases in literature, estimated incidence 1/100,000
estimate < 1/1,000,000
Unknown, multiple different inheritance modes suspected; current candidate genes: VG5Q, PIK3CA, AGGF1, ING5, HDAC9; congenital defects in spinal cord, vessels, and mesodermal tissues suspected Clinical and radiographic diagnosis Cutaneous capillary malformations (portwine stain), varicous veins, hypertrophy of bone and soft tissue (often resulting in different limb lengths), usually isolated to one extremity (most commonly leg), pain, edema, pruritus; in Parkes-Weber syndrome: + AV fistulas Normal Symptomatic: compression stockings, laser surgery, treatment of infections, thromboembolic events Chronic, but rarely cause of death, higher mortality in Parkes-Weber syndrome because of AV fistulas, complications include coagulopathy and thromboembolic events Overgrowth syndrome
Proteus syndrome [284,285,286] Unknown, possibly over-/misdiagnosed because of similarities to other overgrowth spectrum disorders, incidence estimated 1/1,000,000 estimate < 1/1,000,000 Somatic mosaic activating AKT1 mutation, increased growth in affected cells Revised diagnostic criteria (Turner et al., Cohen), genetic testing of affected tissue Males more commonly affected than females (2:1); overgrowth of different tissues: cerebriform connective tissue nevus, vascular malformations, deep vein thromboses, dysregulated adipose tissue (lipomas), pulmonary abnormalities, asymmetric and disproportionate overgrowth, tumors, facial phenotype, intellectual impairment, seizures Coagulopathy and DVT possible Supportive: antithrombotic prophylaxis, orthopedic surgeries, psychological support Chronic, premature death in 20% due to respiratory or neurological involvement Overgrowth syndrome
Erdheim-Chester disease [287,288,289,290] Unknown, ~ 600 reported cases, estimate < 1/1,000,000 In more than 50% BRAF-mutations, non-Langerhans cell-histiocytosis with hyperactivation of cytokines Radiographic and histopathological diagnosis, genetic testing Predominantly males in 5th-7th decade of life; bone involvement nearly always present, CNS involvement (diabetes insipidus, visual disturbances, pyramidal/extra-pyramidal syndromes), other organ involvement possible (cardiac/lung/retroperitoneal/cutaneous, etc.) Elevated ESR, AP, or CRP, signs of pituitary insufficiency Interferon, corticosteroids, immunosuppressants, biologicals (TNFi, IL-1i), BRAF-inhibitors Chronic and often lethal, 5-year survival < 70% Other
Hyaline fibromatous syndrome (infantile systemic hyalinosis/juvenile hyaline fibromatosis) [291,292,293,294] Unknown, ~ 150 cases reported (predominantly from Middle East), estimate < 1/1,000,000 Autosomal recessive, mutations in CMG2/ANTXR2-gene, CMG2 is a transmembrane protein that plays a role in capillary morphogenesis (also binds anthrax toxins); higher carrier frequency in Middle Eastern populations suspected Demonstration of hyaline deposition in dermis, genetic testing Subcutaneous skin nodules, gingival hypertrophy, joint contractures, hyaline deposition, osteopenia. infections, protein-losing enteropathy; cognitive development normal No specific findings depending on complications (e.g., diarrhea) Symptomatic: surgery, D-penicillamine, physiotherapy, NSAIDs, nutritional therapy Chronic, variable course, but often lethal within first 2 years of life (infantile form), oldest known patient is 58 years old Other
Sweet syndrome (SS, acute febrile neutrophilic dermatosis) [295,296,297,298,299,300] Unknown, estimate < 1/1,000,000 Unknown; classic SS (idiopathic), malignancy-associated, and drug-induced histiocytoid SS; commonly related to inflammatory bowel diseases (especially females with Crohn´s disease) Classic SS: diagnostic criteria by Su and Liu (modified by van den Driesch); drug-induced SS: diagnostic criteria by Walker and Cohen Slight female predominance, abrupt onset of fever, peripheral neutrophilia, tender erythematous skin lesions, diffuse neutrophilic dermal infiltrate, arthralgia, malaise, headaches, myalgia Leukocytosis, elevated ESR, CRP Corticosteroids, potassium iodide, colchicine, immunosuppressants in relapsing cases, treatment of underlying cause if found Spontaneous or therapy-induced remission, relapses more common in malignancy-associated SS Other
Relapsing polychondritis [301,302,303,304,305,306] 2/100,000 (Hungary) estimated prevalence in literature: 4.5/1,000,000 → 1.2/100,000 Association with HLA-DR4, 30% of all patients have associated autoimmune or hematological disease (MDS); vasculitis of all sized vessels occurs Michet´s criteria, McAdams´ criteria, Damiani and Levine criteria Typically onset in middle-aged adults; recurrent inflammation of cartilage, especially ears, nose, respiratory tract; vasculitis of all sized vessels, aortic or mitral valve disease, joints, eyes and skin possible Elevated CRP, ANCA may be positive NSAIDs, corticosteroids, dapsone, colchicine, immunosuppressants, biologicals Chronic, survival rate variable, but recent studies report good survival rates Other
Cogan syndrome [307,308,309] Unknown, over 250 cases reported, estimate < 1/1,000,000 Unknown, autoimmune process suggested (additional autoimmune disease diagnosed in ~ 10% of patients), association with cigarette smoking suspected Clinical diagnostic criteria for typical and atypical Cogan syndrome Non-syphilitic interstitial keratitis (or other ocular symptoms, then called atypical Cogan), vestibulo-auditory symptoms, fever, weight loss, arthromyalgia, headache Anemia, leukocytosis, thrombocytosis, elevated ESR or CRP possible Corticosteroids, DMARDs, immunosuppressants, biologicals; vestibulo-auditory symptoms often unresponsive to treatment Chronic or remitting-relapsing, complications include persistent hearing loss and cardiovascular involvement with increased mortality Other
Weber-Christian panniculitis (relapsing febrile nodular nonsuppurative panniculitis; idiopathic lobular panniculitis) [310,311,312,313] Unknown, only a few cases reported, estimate < 1/1,000,000 Unknown, inflammation and necrosis of subcutaneous adipose tissue, mechanism unclear, probably autoimmune Histopathological diagnosis Predominantly middle-aged females affected, recurrent subcutaneous inflammatory painful nodules, fever, malaise, arthralgia, hepatosplenomegaly, anorexia, weight loss, ocular inflammation, lung nodules, systemic organ involvement possible Elevated ESR, anemia, leukocytosis or leucopenia, hypocomplementemia Corticosteroids, immunosuppressants, biologicals Chronic, prognosis variable, poor in case of systemic organ involvement Other
Systemic mastocytosis (mast cell disease) [314,315,316,317,318] 9.59/100,000 (Denmark, including all systemic subtypes) Somatic gain of function mutation in KIT, KIT is a tyrosine kinase receptor essential for correct mast cell development and function WHO diagnostic criteria Abnormal proliferation and accumulation of mast cells cause urticaria pigmentosa, flushing, urticaria, GI symptoms, musculoskeletal pain, headaches, anaphylaxis, weight loss, osteoporosis Anemia, thrombocytopenia, leukocytosis, eosinophilia, elevated tryptase, uric acid, LDH, bilirubin, ferritin, hypoalbuminemia Imatinib, symptomatic treatment, interferon-α, corticosteroids, 2-chlorodeoxyadenosine Chronic, variable progression, may evolve into leukemia Other
Sarcoidosis (Boeck’s sarcoid) [319,320,321] 11.16/100,000 (Northern Ireland) 28.13/100,000 (Ireland) → 19.6/100,000 Associated with different HLA subtypes and BTNL-2, inhaled antigens are considered a possible trigger Clinical and histopathological diagnosis Females more often and more severely affected, peak onset in second decade, many patients are asymptomatic or have unspecific symptoms, such as fever, fatigue, weight loss; most commonly affected organ: lung Elevated acute phase reactants, ACE, s-IL2R Corticosteroids, immunosuppressants, biologicals Variable, often self-limiting within 24 months, increased mortality with systemic organ involvement Other